Mutagenic Potential of Nitroguanidine in the Drosophila melanogaster Sex-Linked Recessive Lethal Test

DTIC Science & Technology

1988-07-01

Security Classification) Mtutagenic potential of nitroguan idine in the Drosophila melano- gaster sex-linked recessive lethal test 12. PERSONAL AUTHOR(S...Frederick, MD 21701-5012 Commander Commandant US Army Environmental Hygine Academy of Health Sciences. US Army Agency ATTN: AHS-CDM ATTN: Librarian, HSDH

[Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options].

PubMed

Martos-Moreno, Gabriel A; Calzada, Joan; Couce, María L; Argente, Jesús

2018-06-01

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin.

PubMed

Pincus, Seth H; Bhaskaran, Manoj; Brey, Robert N; Didier, Peter J; Doyle-Meyers, Lara A; Roy, Chad J

2015-06-09

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome.

The effect of lonidamine (LND) on radiation and thermal responses of human and rodent cell lines

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

Raaphorst, G.P.; Feeley, M.M.; Danjoux, C.E.

1991-03-01

Rodent and human cells were tested for response to Lonidamine (LND) (1-(2,4 dichlorobenzyl) 1-indazol-3-carboxylic acid) combined with radiation or hyperthermia. Lonidamine exposure before, during, and after irradiation caused varying degrees of inhibition of potentially lethal damage (PLD) repair which was cell line dependent. In human glioma, melanoma, squamous cell carcinoma, and fibroblasts, LND exposure did not inhibit or only partially inhibited repair of potentially lethal damage. LND up to 100 micrograms/ml produced only a low level of toxicity in these cells and only slightly inhibited glucose consumption at the maximum concentration. In human glioma cells, LND treatment alone did notmore » inhibit PLD repair, but when combined with hyperthermia treatment at moderate levels easily achievable in the clinic, there was complete inhibition of potentially lethal damage repair. These data suggest that LND effectiveness is cell type dependent. Combinations of LND, hyperthermia, and radiation may be effective in cancer therapy especially in tumors such as glioma in which repair of potentially lethal damage may be extensive.« less

Issues surrounding lethal injection as a means of capital punishment.

PubMed

Romanelli, Frank; Whisman, Tyler; Fink, Joseph L

2008-12-01

Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

In vitro study of the photodynamic antimicrobial therapy (PACT) against promastigotes form of the leishmania (viannia) braziliensis: in vitro study

NASA Astrophysics Data System (ADS)

Barbosa, Artur F. S.; Sangiorgi, Bruno B.; Galdino, Suely L.; Pitta, Ivan R.; Barral-Netto, Manoel; Pinheiro, Antônio L. B.

2013-03-01

Leishmaniasis, a protozoan parasitic disease that remains a major worldwide health problem with high endemicity in developing countries. Treatment of cutaneous Leishmaniasis (CL) should be decided by the clinical lesions, etiological species and its potential to develop into mucosal Leishmaniasis. High cost, systemic toxicity, and diminished efficacy due to development of parasite resistance are the serious drawbacks of current treatment options. Thus, identifying new, effective, and safer anti-leishmanial drug(s) is of paramount importance. The aim of this study was to verify the effectiveness of PACT in vitro, as a new technique for the treatment of Leishmaniasis. For this, semiconductor laser (λ = 660nm, 40mW, 8.4J/cm2, CW) associated to phenothiazine's derivatives (5 and 10 μg/ml, TBO, Methylene Blue or Phenothiazine) on the promastigotes form of Leishmania braziliensis in a single session was used. Viability of the parasites was assessed in quadruplicates of each group. The samples were removed and analyzed in a hemocytometer 72h after PACT. We found an important decrease in the number of viable parasites on all treated groups in comparison to their controls. The results of present study showed significant percentage of lethality (above 92%) of the protocol. The 98.33% of lethality was achieved with 10 μg/ml of FTZ. No lethality was seen on groups treated neither with laser nor with each compounds separately. The results are promising and indicative that the use of PACT may be a powerful treatment of Leishmaniasis when compared to already available ones.

Sequence editing by Apolipoprotein B RNA-editing catalytic component-B and epidemiological surveillance of transmitted HIV-1 drug resistance

PubMed Central

Gifford, Robert J.; Rhee, Soo-Yon; Eriksson, Nicolas; Liu, Tommy F.; Kiuchi, Mark; Das, Amar K.; Shafer, Robert W.

2008-01-01

Design Promiscuous guanine (G) to adenine (A) substitutions catalysed by apolipoprotein B RNA-editing catalytic component (APOBEC) enzymes are observed in a proportion of HIV-1 sequences in vivo and can introduce artifacts into some genetic analyses. The potential impact of undetected lethal editing on genotypic estimation of transmitted drug resistance was assessed. Methods Classifiers of lethal, APOBEC-mediated editing were developed by analysis of lentiviral pol gene sequence variation and evaluated using control sets of HIV-1 sequences. The potential impact of sequence editing on genotypic estimation of drug resistance was assessed in sets of sequences obtained from 77 studies of 25 or more therapy-naive individuals, using mixture modelling approaches to determine the maximum likelihood classification of sequences as lethally edited as opposed to viable. Results Analysis of 6437 protease and reverse transcriptase sequences from therapy-naive individuals using a novel classifier of lethal, APOBEC3G-mediated sequence editing, the polypeptide-like 3G (APOBEC3G)-mediated defectives (A3GD) index’, detected lethal editing in association with spurious ‘transmitted drug resistance’ in nearly 3% of proviral sequences obtained from whole blood and 0.2% of samples obtained from plasma. Conclusion Screening for lethally edited sequences in datasets containing a proportion of proviral DNA, such as those likely to be obtained for epidemiological surveillance of transmitted drug resistance in the developing world, can eliminate rare but potentially significant errors in genotypic estimation of transmitted drug resistance. PMID:18356601

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

PubMed

Downer, Mary K; Allard, Christopher B; Preston, Mark A; Gaziano, J Michael; Stampfer, Meir J; Mucci, Lorelei A; Batista, Julie L

2017-11-01

Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Action of caffeine on x-irradiated HeLa cells. V. Identity of the sector of cells that expresses potentially lethal damage in G/sub 1/ and G/sub 2/

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

Beetham, K.L.; Tolmach, L.J.

1982-07-01

When HeLa S3 cells are irradiated in early G/sub 1/ with 4 Gy of 220-kV x rays and are then incubated in growth medium containing up to 5 mM caffeine, survival is reduced (as reported previously), reaching a concentration-dependent plateau. Cell killing presumably occurs as a result of the fixation of a portion of the potentially lethal damage the cells contain. These cells respond to continued treatment with caffeine at concentrations greater than 2 mM during S, but less so than during G/sub 1/. When they reach G/sub 2/ arrest, however, extensive cell killing again occurs (reported previously), presumably alsomore » the result of potentially lethal damage fixation. G/sub 1/-irradiated cultures that are treated with caffeine either continuously at a concentration in the range 1 to 5 mM, or at 10 mM for 8 hr and subsequently with the low concentration, achieve the same survival level in G/sub 2/, provided that the potentially lethal damage is not repaired during G/sub 1/ and S. Repair seems to be completely inhibited in the presence of 3 to 4 mM caffeine. The results indicate that fixation of potentially lethal damage occurs in the same sector of cells in G/sub 1/ and G/sub 2/, suggesting that the same cellular lesion gives rise to cell killing in the two phases.« less

Breakdown of the balanced lethals in Rhoeo: the structure of the Alethal Renner complex of the homozygotic stock of Rhoeo.

PubMed

Golczyk, H

2011-01-01

Fluorescence in situ hybridization, base-specific fluorescence, C-banding and silver-staining were performed to reveal the cyto-molecular constitution of the karyotype in the bivalent-forming Rhoeo spathacea concolor. It was shown that the genome of this form is almost identical to the β-complex of the ring-forming rhoeos. In spite of some modifications in the arrangement of a few distal rDNA sites and in the amount of pericentromeric AT-rich heterochromatin, the alethal genome of the bivalent-forming Rhoeo seems segmentally unaltered. Thus, the breakdown of balanced lethals in Rhoeo is most likely uncoupled from creating new chromosome arm combinations. Copyright © 2011 S. Karger AG, Basel.

Risk-taking behaviors and subgrouping of suicide in Iran: A latent class analysis of national registries data.

PubMed

Hajebi, Ahmad; Abbasi-Ghahramanloo, Abbas; Hashemian, Seyed Sepehr; Khatibi, Seyed Reza; Ghasemzade, Masomeh; Khodadost, Mahmoud

2017-09-01

Suicide is one the most important public health problem which is rapidly growing concerns. The aim of this study was to subgroup suicide using LCA method. This cross-sectional study was conducted in Iran based on 66990 records registered in Ministry of Health in 2014. A case report questionnaire in the form of software was used for case registries. Latent class analysis was used to achieve the research objectives. Four latent classes were identified; (a) Non-lethal attempters without a history of psychiatric disorders, (b) Non-lethal attempters with a history of psychiatric disorders, (c) Lethal attempters without a history of psychiatric disorders, (d) Lethal attempters with a history of psychiatric disorders. The probability of completed/an achieved suicide is high in lethal attempter classes. Being male increases the risk of inclusion in lethal attempters' classes (OR = 4.93). Also, being single (OR = 1.16), having an age lower than 25 years (OR = 1.14) and being a rural citizen (OR = 2.36) associate with lethal attempters classes. The males tend to use more violent methods and have more completed suicide. Majority of the individuals are non-lethal attempters who need to be addressed by implementing preventive interventions and mental support provision. Copyright © 2017. Published by Elsevier B.V.

Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques.

PubMed

Warren, Travis K; Whitehouse, Chris A; Wells, Jay; Welch, Lisa; Charleston, Jay S; Heald, Alison; Nichols, Donald K; Mattix, Marc E; Palacios, Gustavo; Kugleman, Jeffrey R; Iversen, Patrick L; Bavari, Sina

2016-02-01

Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

Photo-activated disinfection based on indocyanine green against cell viability and biofilm formation of Porphyromonas gingivalis.

PubMed

Pourhajibagher, Maryam; Chiniforush, Nasim; Ghorbanzadeh, Roghayeh; Bahador, Abbas

2017-03-01

Photo-activated disinfection (PAD) is a novel treatment approach, in which bacteria in the root canal system may be exposed to sub-lethal doses of PAD. Such exposure can affect bacterial survival and virulence features, such as biofilm formation ability. The aim of this study was to evaluate the effects of sub-lethal doses of PAD (sPAD) using indocyanine green (ICG) on load and biofilm formation ability of Porphyromonas gingivalis as an anaerobic bacterium associated with endodontic infection. The anti-bacterial and anti-biofilm potential of sPAD against P. gingivalis at sub-lethal doses of ICG as a photosensitizer and using 810nm wavelength of diode laser light via colony forming unit and crystal violet assays, respectively, was determined. High concentrations of ICG and light irradiation time significantly reduced bacteria. High doses of sPAD markedly reduced the number of bacteria and the formation of biofilm, up to 30.4% and 25.1%, respectively. High doses of sPAD affected cell viability and the biofilm formation ability of P. gingivalis; lower doses did not. Thus, selection of appropriate PAD dosage should be considered for the successful treatment of endodontic in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin

PubMed Central

Pincus, Seth H.; Bhaskaran, Manoj; Brey, Robert N.; Didier, Peter J.; Doyle-Meyers, Lara A.; Roy, Chad J.

2015-01-01

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome. PMID:26067369

Attacks on German public figures, 1968-2004: warning behaviors, potentially lethal and non-lethal acts, psychiatric status, and motivations.

PubMed

Hoffmann, Jens; Meloy, J Reid; Guldimann, Angela; Ermer, Anneliese

2011-01-01

Fourteen non-terrorist attackers of public figures in Germany between 1968 and 2004 were intensively studied, with a particular focus on warning behaviors, attack behaviors, and the relationship between psychiatric diagnosis, symptoms, and motivations for the assault. A large proportion of the attackers were severely mentally ill, and most likely to be in the potentially lethal rather than the non-lethal group. A new typology of seven warning behaviors was applied to the data, and all were present, most frequently fixation and pathway warning behavior, and least frequently a direct threat. Psychiatric diagnosis could be closely linked to motivation when analyzed at the level of symptom and content of thought, often delusional. Most of the attacks were directed at political figures, and the majority occurred after 1995. Copyright © 2011 John Wiley & Sons, Ltd.

Temperature responses of some North Atlantic Cladophora species (Chlorophyceae) in relation to their geographic distribution

NASA Astrophysics Data System (ADS)

Cambridge, M.; Breeman, A. M.; van Oosterwijk, R.; van den Hoek, C.

1984-09-01

The temperature responses for growth and survival have been experimentally tested for 6 species of the green algal genus Cladophora (Chlorophyceae; Cladophorales) (all isolated from Roscoff, Brittany, France, one also from Connecticut, USA), selected from 4 distribution groups, in order to determine which phase in the annual temperature regime might prevent the spread of a species beyond its present latitudinal range on the N. Atlantic coasts. For five species geographic limits could be specifically defined as due to a growth limit in the growing season or to a lethal limit in the adverse season. These species were: (1) C. coelothrix (Amphiatlantic tropical to warm temperate), with a northern boundary on the European coasts formed by a summer growth limit near the 12°C August isotherm. On the American coasts sea temperatures should allow its occurrence further north. (2) C. vagabunda (Amphiatlantic tropical to temperate), with a northern boundary formed by a summer growth limit near the 15°C August isotherm on both sides of the Atlantic. (3) C. dalmatica, as for C. vagabunda. (4) C. hutchinsiae (Mediterranean-Atlantic warm temperate), with a northern boundary formed by a summer growth limit near the 12°C August isotherm, and possibly also a winter lethal limit near the 6°C February isotherm; and a southern boundary formed by a southern lethal limit near the 26°C August isotherm. It is absent from the warm temperate American coast because its lethal limits, 5° and 30°C, are regularly reached there. (5) Preliminary data for C. rupestris (Amphiatlantic temperate), suggest the southeastern boundary on the African coast to be a summer lethal limit near the 26°C August isotherm; the southwestern boundary on the American coast lies on the 20°C August isotherm. For one species, C. albida, the experimental growth and survival range was wider than expected from its geographic distribution, and reasons to account for this are suggested.

Rancher-reported efficacy of lethal and non-lethal livestock predation mitigation strategies for a suite of carnivores.

PubMed

Scasta, J D; Stam, B; Windh, J L

2017-10-26

Pastoralists have dealt with livestock losses from predators for millennia, yet effective mitigation strategies that balance wildlife conservation and sustainable agriculture are still needed today. In Wyoming, USA, 274 ranchers responded to a retrospective survey, and rated the efficacy of predation mitigation strategies for foxes, dogs, coyotes, wolves, bobcats, mountain lions, bears, and birds (buzzards, eagles, hawks, ravens). Rancher reported efficacy of mitigation varied by predator species, mitigation strategy, and lethality of strategies, but not livestock type. Ranchers perceive they were most effective at mitigating predation by foxes and coyotes, moderately effective at mitigating large carnivores, and the least effective at mitigating birds. Ranchers also reported that avian predators seem to be the most challenging predator type. The general perception was lethal mitigation strategies were more effective than non-lethal strategies, with guard animals showing the most potential among the non-lethal options. In general, ranchers did not perceive non-lethal strategies as a proxy for lethal strategies. However, a few ranchers reported being successful with non-lethal options such as herding, fencing, and stalling at night but more details about such successful applications are needed. Innovation in current or novel non-lethal mitigation strategies, and examples of efficacy, are needed to justify producer adoption.

Risks of non-lethal weapon use: case studies of three French victims of stinger grenades.

PubMed

Scolan, V; Herry, C; Carreta, M; Stahl, C; Barret, L; Romanet, J P; Paysant, F

2012-11-30

The development of non-lethal weapons started in the 1960s. In France, they have been used by the police for about 10 years. We relate the cases of three French women, victims of stinger grenades, non-lethal weapons recently adopted by the French law enforcement to distract and disperse crowds. The three victims presented serious injuries requiring emergency surgical care. One lost her eye. Based on these cases, we discuss the lethal character of these weapons and propose measures to be taken to prevent their dramatic consequences. Although the danger is obviously less than for firearms, stinger grenades are nonetheless potentially lethal and cause serious physical injuries. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Smyd1 Facilitates Heart Development by Antagonizing Oxidative and ER Stress Responses

PubMed Central

Park, Chong Yon; Harriss, June; Pierce, Stephanie A.; Dekker, Joseph D.; Valenzuela, Nicolas; Srivastava, Deepak; Schwartz, Robert J.; Stewart, M. David; Tucker, Haley O.

2015-01-01

Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense—a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality. PMID:25803368

[Screening of full human anthrax lethal factor neutralizing antibody in transgenic mice].

PubMed

Wang, Xiaolin; Chi, Xiangyang; Liu, Ju; Liu, Weicen; Liu, Shuling; Qiu, Shunfang; Wen, Zhonghua; Fan, Pengfei; Liu, Kun; Song, Xiaohong; Fu, Ling; Zhang, Jun; Yu, Changming

2016-11-25

Anthrax is a highly lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis. The major virulence factor of B. anthracis consists of protective antigen (PA), lethal factor (LF) and edema factor (EF). PA binds with LF to form lethal toxin (LT), and PA binds with EF to form edema toxin (ET). Antibiotics is hard to work in advanced anthrax infections, because injuries and deaths of the infected are mainly caused by lethal toxin (LT). Thus, the therapeutic neutralizing antibody is the most effective treatment of anthrax. Currently most of the anthrax toxin antibodies are monoclonal antibodies (MAbs) for PA and US FDA has approved ABTHRAX humanized PA monoclonal antibody for the treatment of inhalational anthrax. Once B. anthracis was artificially reconstructed or PA had mutations within recognized neutralization epitopes, anti-PA MAbs would no longer be effective. Therefore, anti-LF MAbs is an important supplement for anthrax treatment. Most of the anti-LF antibodies are murine or chimeric antibodies. By contrast, fully human MAbs can avoid the high immunogenicity of murine antibodies. First, we used LF to immunize the transgenic mice and used fluorescent cell sorting to get antigen-specific memory B cells from transgenic mice spleen lymphocytes. By single cell PCR method, we quickly found two strains of anti-LF MAbs with binding activity, 1D7 and 2B9. Transiently transfected Expi 293F cells to obtain MAbs protein after purification. Both 1D7 and 2B9 efficiently neutralized LT in vitro, and had good synergistic effect when mixed with anti-PA MAbs. In summary, combining the advantages of transgenic mice, fluorescent cell sorting and single-cell PCR methods, this study shows new ideas and methods for the rapid screening of fully human monoclonal antibodies.

Interaction of metronidazole with resistant and susceptible Bacteroides fragilis.

PubMed Central

McLafferty, M A; Koch, R L; Goldman, P

1982-01-01

The kinetics of the lethal action of metronidazole and the formation of acetamide have been studied in a strain of Bacteroides fragilis which is relatively resistant to metronidazole. As with a susceptible strain of B. fragilis, the data are consistent with a model in which a labile intermediate in metronidazole metabolism interacts either with water to form acetamide or with a bacterium to cause its death. Although the relatively resistant strain grows more slowly than the susceptible one and is killed less rapidly by metronidazole, the resistant strain displays the same relationship between the lethal action of metronidazole and metronidazole metabolism to acetamide. The relatively resistant strain, like the susceptible one, has an enhanced lethal response to metronidazole in the presence of a strain of Escherichia coli. The results suggest that the proposed labile reactive intermediate of metronidazole forms more slowly in the resistant strains. PMID:7081970

Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.

PubMed

Speir, Mary; Lawlor, Kate E; Glaser, Stefan P; Abraham, Gilu; Chow, Seong; Vogrin, Adam; Schulze, Keith E; Schuelein, Ralf; O'Reilly, Lorraine A; Mason, Kylie; Hartland, Elizabeth L; Lithgow, Trevor; Strasser, Andreas; Lessene, Guillaume; Huang, David C S; Vince, James E; Naderer, Thomas

2016-02-24

Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue.

PubMed

Strobl, Frederic; Ross, J Alexander; Stelzer, Ernst H K

2017-01-01

The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.

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

Greenberg, C.R.; Taylor, C.D.; Haworth, J.C.

The authors have discovered a single homoallelic nucleotide substitution as the putative cause of the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites. Previous linkage and haplotype analysis in this population suggested that a single mutational event was responsible for this autosomal recessive form of hypophosphatasia. The mutation is a guanosine-to-adenosine substitution at nucleotide position 1177 in exon 10 of the tissue nonspecific (liver/bone/kidney) alkaline phosphatase gene. This Gly[sup 317] [yields] Asp mutation segregates exclusively with the heterozygote phenotype previously assigned by biochemical testing (maximum combined lod score of 18.24 at [theta] = 0.00). This putative disease-causing mutation has notmore » been described in controls nor in other non-Mennonite probands with both lethal and nonlethal forms of hypophosphatasia studied to date. This Gly[sup 317] [yields] Asp mutation changes a polar glycine to an acidic aspartate at amino acid position 317 within the highly conserved active site region of the 507-amino-acid polypeptide. Carrier screening for this lethal mutation in a high-risk population is now feasible. 15 refs., 2 figs.« less

Possible role of gamma ray bursts on life extinction in the universe.

PubMed

Piran, Tsvi; Jimenez, Raul

2014-12-05

As a copious source of gamma rays, a nearby galactic gamma ray burst (GRB) can be a threat to life. Using recent determinations of the rate of GRBs, their luminosity function, and properties of their host galaxies, we estimate the probability that a life-threatening (lethal) GRB would take place. Amongst the different kinds of GRBs, long ones are most dangerous. There is a very good chance (but no certainty) that at least one lethal GRB took place during the past 5 gigayears close enough to Earth as to significantly damage life. There is a 50% chance that such a lethal GRB took place during the last 500×10^{6}  years, causing one of the major mass extinction events. Assuming that a similar level of radiation would be lethal to life on other exoplanets hosting life, we explore the potential effects of GRBs to life elsewhere in the Galaxy and the Universe. We find that the probability of a lethal GRB is much larger in the inner Milky Way (95% within a radius of 4 kpc from the galactic center), making it inhospitable to life. Only at the outskirts of the Milky Way, at more than 10 kpc from the galactic center, does this probability drop below 50%. When considering the Universe as a whole, the safest environments for life (similar to the one on Earth) are the lowest density regions in the outskirts of large galaxies, and life can exist in only ≈10% of galaxies. Remarkably, a cosmological constant is essential for such systems to exist. Furthermore, because of both the higher GRB rate and galaxies being smaller, life as it exists on Earth could not take place at z>0.5. Early life forms must have been much more resilient to radiation.

Caffeine-enhanced survival of radiation-sensitive, repair-deficient Chinese hamster cells

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

Utsumi, H.; Elkind, M.M.

1983-11-01

A clone of V79 Chinese hamster cells (V79-AL162/S-10) with unique properties has been isolated after a challenge of parental cells (V79-AL162) with 1 mM ouabain. Compared with parental cells, or with other clones isolated after the ouabain challenge, these cells form smaller colonies, are more sensitive to both x rays and fission-spectrum neutrons, and respond atypically to a postirradiation treatment with caffeine. Their enhanced response to x rays results mainly from a large reduction in the shoulder of their survival curve, probably because in late S phase, the most resistant phase in the cell cycle, the survival curve of thesemore » cells has a reduced shoulder width. Caffeine, and to a lesser extent theophylline, added to the colony-forming medium immediately after exposure appreciably increases the width of the shoulder of these sensitive cells, whereas caffeine has the opposite effect on the response of normal V79 cells. Thus the unique response of the V79-AL162/S-10 cells to a radiation posttreatment with caffeine (increased survival) results from a net increase in their ability to repair damage that is otherwise lethal; caffeine treatment ordinarly prevents normal V79 cells from repairing damage that is only potentially lethal.« less

Antimicrobial photodynamic therapy for inactivation of biofilms formed by oral key pathogens

PubMed Central

Cieplik, Fabian; Tabenski, Laura; Buchalla, Wolfgang; Maisch, Tim

2014-01-01

With increasing numbers of antibiotic-resistant pathogens all over the world there is a pressing need for strategies that are capable of inactivating biofilm-state pathogens with less potential of developing resistances in pathogens. Antimicrobial strategies of that kind are especially needed in dentistry in order to avoid the usage of antibiotics for treatment of periodontal, endodontic or mucosal topical infections caused by bacterial or yeast biofilms. One possible option could be the antimicrobial photodynamic therapy (aPDT), whereby the lethal effect of aPDT is based on the principle that visible light activates a photosensitizer (PS), leading to the formation of reactive oxygen species, e.g., singlet oxygen, which induce phototoxicity immediately during illumination. Many compounds have been described as potential PS for aPDT against bacterial and yeast biofilms so far, but conflicting results have been reported. Therefore, the aim of the present review is to outline the actual state of the art regarding the potential of aPDT for inactivation of biofilms formed in vitro with a main focus on those formed by oral key pathogens and structured regarding the distinct types of PS. PMID:25161649

Non-Lethal Weapons: Setting Our Phasers on Stun? Potential Stratetgic Blessings and Curses of Non-Lethal Weapons on the Battlefield

DTIC Science & Technology

2003-08-01

improve our ability to verify compliance with the treaty’s global ban on biological weapons and would put national security and confidential business ...he was Assistant Professor of Aeronautics at the U.S. Air Force Academy, Colorado, where he was also instructor pilot in the T - 41 flight-screening...fielded on a greater scale are explored. The ability of non-lethal weapons to positively influence the global war on terrorism is also assessed. It

Anthrax biosensor, protective antigen ion channel asymmetric blockade.

PubMed

Halverson, Kelly M; Panchal, Rekha G; Nguyen, Tam L; Gussio, Rick; Little, Stephen F; Misakian, Martin; Bavari, Sina; Kasianowicz, John J

2005-10-07

The significant threat posed by biological agents (e.g. anthrax, tetanus, botulinum, and diphtheria toxins) (Inglesby, T. V., O'Toole, T., Henderson, D. A., Bartlett, J. G., Ascher, M. S., Eitzen, E., Friedlander, A. M., Gerberding, J., Hauer, J., Hughes, J., McDade, J., Osterholm, M. T., Parker, G., Perl, T. M., Russell, P. K., and Tonat, K. (2002) J. Am. Med. Assoc. 287, 2236-2252) requires innovative technologies and approaches to understand the mechanisms of toxin action and to develop better therapies. Anthrax toxins are formed from three proteins secreted by fully virulent Bacillus anthracis, protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). Here we present electrophysiological measurements demonstrating that full-length LF and EF convert the current-voltage relationship of the heptameric PA63 ion channel from slightly nonlinear to highly rectifying and diode-like at pH 6.6. This effect provides a novel method for characterizing functional toxin interactions. The method confirms that a previously well characterized PA63 monoclonal antibody, which neutralizes anthrax lethal toxin in animals in vivo and in vitro, prevents the binding of LF to the PA63 pore. The technique can also detect the presence of anthrax lethal toxin complex from plasma of infected animals. The latter two results suggest the potential application of PA63 nanopore-based biosensors in anthrax therapeutics and diagnostics.

BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose.

PubMed

Lucantoni, Federico; Düssmann, Heiko; Llorente-Folch, Irene; Prehn, Jochen H M

2018-05-25

Cancer cells display differences regarding their engagement of glycolytic vs. mitochondrial oxidative phosphorylation (OXPHOS) pathway. Triple negative breast cancer, an aggressive form of breast cancer, is characterized by elevated glycolysis, while estrogen receptor positive breast cancer cells rely predominantly on OXPHOS. BCL2 proteins control the process of mitochondrial outer membrane permeabilization during apoptosis, but also regulate cellular bioenergetics. Because BCL2 proteins are overexpressed in breast cancer and targetable by selective antagonists, we here analysed the effect of BCL2 and BCL(X)L selective inhibitors, Venetoclax and WEHI-539, on mitochondrial bioenergetics and cell death. Employing single cell imaging using a FRET-based mitochondrial ATP sensor, we found that MCF7 breast cancer cells supplied with mitochondrial substrates reduced their mitochondrial ATP production when treated with Venetoclax or WEHI-539 at concentrations that per se did not induce cell death. Treatments with lower concentrations of both inhibitors also reduced the length of the mitochondrial network and the dynamics, as evaluated by quantitative confocal microscopy. We next tested the hypothesis that mitochondrial ATP production inhibition with BCL2 or BCL(X)L antagonists was synthetically lethal when combined with glycolysis inhibition. Treatment with 2-deoxy-D-glucose in combination with Venetoclax or WEHI-539 synergistically reduced the cellular bioenergetics of ER+ and TNBC breast cancer cells and abolished their clonogenic potential. Synthetic lethality was also observed when cultures were grown in 3D spheres. Our findings demonstrate that BCL2 antagonists exert potent effects on cancer metabolism independent of cell death-inducing effects, and demonstrate a synthetic lethality when these are applied in combination with glycolysis inhibitors.

BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose

PubMed Central

Lucantoni, Federico; Düssmann, Heiko; Llorente-Folch, Irene; Prehn, Jochen H.M.

2018-01-01

Cancer cells display differences regarding their engagement of glycolytic vs. mitochondrial oxidative phosphorylation (OXPHOS) pathway. Triple negative breast cancer, an aggressive form of breast cancer, is characterized by elevated glycolysis, while estrogen receptor positive breast cancer cells rely predominantly on OXPHOS. BCL2 proteins control the process of mitochondrial outer membrane permeabilization during apoptosis, but also regulate cellular bioenergetics. Because BCL2 proteins are overexpressed in breast cancer and targetable by selective antagonists, we here analysed the effect of BCL2 and BCL(X)L selective inhibitors, Venetoclax and WEHI-539, on mitochondrial bioenergetics and cell death. Employing single cell imaging using a FRET-based mitochondrial ATP sensor, we found that MCF7 breast cancer cells supplied with mitochondrial substrates reduced their mitochondrial ATP production when treated with Venetoclax or WEHI-539 at concentrations that per se did not induce cell death. Treatments with lower concentrations of both inhibitors also reduced the length of the mitochondrial network and the dynamics, as evaluated by quantitative confocal microscopy. We next tested the hypothesis that mitochondrial ATP production inhibition with BCL2 or BCL(X)L antagonists was synthetically lethal when combined with glycolysis inhibition. Treatment with 2-deoxy-D-glucose in combination with Venetoclax or WEHI-539 synergistically reduced the cellular bioenergetics of ER+ and TNBC breast cancer cells and abolished their clonogenic potential. Synthetic lethality was also observed when cultures were grown in 3D spheres. Our findings demonstrate that BCL2 antagonists exert potent effects on cancer metabolism independent of cell death-inducing effects, and demonstrate a synthetic lethality when these are applied in combination with glycolysis inhibitors. PMID:29899841

Oxidative stress induces senescence in human mesenchymal stem cells

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

Brandl, Anita; Meyer, Matthias; Bechmann, Volker

Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated {beta}-galactosidase positivity. Prolongedmore » low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in aging cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells.« less

Inhalation toxicology. XII., Comparison of toxicity rankings of six polymers by lethality and by incapacitation in rats.

DOT National Transportation Integrated Search

1991-12-01

Polymeric aircraft cabin materials have the potential to produce toxic gases in fires. Lethality (LC50) in animal models is a standard index to rank polymers on the basis of their combustion product toxicity. However, the use of times-toincapacitatio...

A Content Analysis of News Reports of Averted School Rampages

ERIC Educational Resources Information Center

Daniels, Jeffrey A.; Buck, Ilene; Croxall, Susan; Gruber, Julia; Kime, Peter; Govert, Heidi

2007-01-01

Although the majority of research into school violence have focused attention on lethal or injury-producing incidents, this focus provides only partial information about school violence prevention. Moore, Petrie, Braga, and McLaughlin (2003) suggested that researchers turn their attention to those incidents in which a potentially lethal situation…

Bigeye Bomb: Unresolved Development Issues

DTIC Science & Technology

1989-08-11

the lethal agent formed inside the Bigeye bomb) at the purity or equivalent- biotoxicity level required by the Test and Eval- uation Master Plan (TEMP...during the 5 through 30-second period after mixing starts, with- out specifying either wheit the required purity or equivalent biotoxicity level should...revision of the purity or equivalent biotoxicity requirement. However, we believe that a bomb that produces lethal agent at the required purity level for 1

Galantamine is a Novel Post-Exposure Therapeutic Against Lethal VX Challenge

DTIC Science & Technology

2009-01-01

administered as a post- exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality...The standard U.S. military therapy for intoxication by anticholinesterase agents consists of administering ATR to antagonize excessive muscarinic...2003). A ball-and-stick repre- sentation of GAL is shown in Fig. 1 docking to the active site of two different acetylcholinesterase forms. GAL

Crystallographic studies of the Anthrax lethal toxin. Annual report

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

Frederick, C.A.

1996-07-01

The lethal form of Anthrax results from the inhalation of anthrax spores. Death is primarily due to the effects of the lethal toxin (Protective Antigen (PA) + Lethal Factor) from the causative agent, Bacillus anthracis. All the Anthrax vaccines currently in use or under development contain or produce PA, the major antigenic component of anthrax toxin, and there is a clear need for an improved vaccine for human use. In the previous report we described the first atomic resolution structure of PA, revealing that the molecule is composed largely of beta-sheets organized into four domains. This information can be usedmore » in the design. of recombinant PA vaccines. In this report we describe additional features of the full-length PA molecule derived from further crystallographic refinement and careful examination of the structure. We compare two crystal forms of PA grown at different pH values and discuss the functional implications. A complete definition of the function of each domain must await the crystal structure of the PA63 heptamer. We have grown crystals of the heptamer under both detergent and detergent-free conditions, and made substantial progress towards the crystal structure. The mechanism of anthrax intoxication in the light of our results is reviewed.« less

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.

Biomineralization of copper: Solutions for waste remediation and biomining

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

Ashby, C.R.; Thompson, S.A.; Crusberg, T.C.

1997-12-31

The fungus Penicillium ochro-chloron is able to extract copper from aqueous solutions and form insoluble copper precipitates within the matrix of fungal mycelia. The formation of these complexes is probably a detoxification mechanism used by the organism to deal with the potentially lethal concentrations of heavy metals. Metal immobilization occurs external to the cells but within the mycelia when the solubility products of copper phosphate and copper oxalate are exceeded. This process may be exploited in biomining to remove and recover copper and perhaps other heavy metals that have become solubilized in pit mine lakes.

Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers

PubMed Central

Feld, Geoffrey K.; Thoren, Katie L.; Kintzer, Alexander F.; Sterling, Harry J.; Tang, Iok I.; Greenberg, Shoshana G.; Williams, Evan R.; Krantz, Bryan A.

2011-01-01

The protein transporter, anthrax lethal toxin, is comprised of protective antigen (PA), a transmembrane translocase, and lethal factor (LF), a cytotoxic enzyme. Following assembly into holotoxin complexes, PA forms an oligomeric channel that unfolds LF and translocates it into the host cell. We report the crystal structure of the core of a lethal toxin complex to 3.1-Å resolution; the structure contains a PA octamer bound to four LF PA-binding domains (LFN). The first α helix and β strand of each LFN unfold and dock into a deep amphipathic cleft on the surface of the PA octamer, which we call the α clamp. The α clamp possesses nonspecific polypeptide binding activity and is functionally relevant to efficient holotoxin assembly, PA octamer formation, and LF unfolding and translocation. This structure provides insight on the mechanism of translocation-coupled protein unfolding. PMID:21037566

Significance of Rib Fractures Potentially Caused by Blunt Impact Non Lethal Weapons

DTIC Science & Technology

2017-03-01

Center Drive Alexandria, Virginia 22311-1882 I N S T I T U T E F O R D E F E N S E A N A L Y S E S Significance of Rib Fractures Potentially...F E N S E A N A L Y S E S IDA Document D-8277 Significance of Rib Fractures Potentially Caused by Blunt-Impact Non-Lethal Weapons Shelley M. Cazares...deterrent by inducing pain or muscle spasm at the site of impact of the affected individual. These weapons may induce rib fractures —the focus of this

Interleukin-10 protects neonatal mice from lethal group B streptococcal infection.

PubMed Central

Cusumano, V; Genovese, F; Mancuso, G; Carbone, M; Fera, M T; Teti, G

1996-01-01

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis. PMID:8698523

Lethal coalitionary aggression and long-term alliance formation among Yanomamö men.

PubMed

Macfarlan, Shane J; Walker, Robert S; Flinn, Mark V; Chagnon, Napoleon A

2014-11-25

Some cross-cultural evidence suggests lethal coalitionary aggression in humans is the product of residence and descent rules that promote fraternal interest groups, i.e., power groups of coresident males bonded by kinship. As such, human lethal coalitions are hypothesized to be homologous to chimpanzee (Pan troglodytes) border patrols. However, humans demonstrate a unique metagroup social structure in which strategic alliances allow individuals to form coalitions transcending local community boundaries. We test predictions derived from the fraternal interest group and strategic alliance models using lethal coalition data from a lowland South American population, the Yanomamö. Yanomamö men who kill an enemy acquire a special status, termed unokai. We examine the social characteristics of co-unokais or men who jointly kill others. Analyses indicate co-unokais generally are (i) from the same population but from different villages and patrilines, (ii) close age mates, and (iii) maternal half-first cousins. Furthermore, the incident rate for co-unokai killings increases if men are similar in age, from the same population, and from different natal communities. Co-unokais who have killed more times in the past and who are more genetically related to each other have a higher probability of coresidence in adulthood. Last, a relationship exists between lethal coalition formation and marriage exchange. In this population, internal warfare unites multiple communities, and co-unokais strategically form new residential groups and marriage alliances. These results support the strategic alliance model of coalitionary aggression, demonstrate the complexities of human alliance formation, and illuminate key differences in social structure distinguishing humans from other primates.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013)

PubMed Central

Brahim, Lucia Regina; Valete-Rosalino, Cláudia Maria; Antônio, Liliane de Fátima; Pimentel, Maria Inês Fernandes; Lyra, Marcelo Rosandiski; Paes, Luiz Eduardo de Carvalho; da Costa, Ananda Dutra; Vieira, Iracema Forni; Dias, Cristina Maria Giordano; Duque, Maria Cristina de Oliveira; Marzochi, Mauro Celio de Almeida; Schubach, Armando de Oliveira

2017-01-01

BACKGROUND American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence. PMID:29211245

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

PubMed

Brahim, Lucia Regina; Valete-Rosalino, Cláudia Maria; Antônio, Liliane de Fátima; Pimentel, Maria Inês Fernandes; Lyra, Marcelo Rosandiski; Paes, Luiz Eduardo de Carvalho; Costa, Ananda Dutra da; Vieira, Iracema Forni; Dias, Cristina Maria Giordano; Duque, Maria Cristina de Oliveira; Marzochi, Mauro Celio de Almeida; Schubach, Armando de Oliveira

2017-12-01

American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. Data were recovered from records of all ATL patients diagnosed during that period. Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Lethal coalitionary aggression and long-term alliance formation among Yanomamö men

PubMed Central

Macfarlan, Shane J.; Walker, Robert S.; Flinn, Mark V.; Chagnon, Napoleon A.

2014-01-01

Some cross-cultural evidence suggests lethal coalitionary aggression in humans is the product of residence and descent rules that promote fraternal interest groups, i.e., power groups of coresident males bonded by kinship. As such, human lethal coalitions are hypothesized to be homologous to chimpanzee (Pan troglodytes) border patrols. However, humans demonstrate a unique metagroup social structure in which strategic alliances allow individuals to form coalitions transcending local community boundaries. We test predictions derived from the fraternal interest group and strategic alliance models using lethal coalition data from a lowland South American population, the Yanomamö. Yanomamö men who kill an enemy acquire a special status, termed unokai. We examine the social characteristics of co-unokais or men who jointly kill others. Analyses indicate co-unokais generally are (i) from the same population but from different villages and patrilines, (ii) close age mates, and (iii) maternal half-first cousins. Furthermore, the incident rate for co-unokai killings increases if men are similar in age, from the same population, and from different natal communities. Co-unokais who have killed more times in the past and who are more genetically related to each other have a higher probability of coresidence in adulthood. Last, a relationship exists between lethal coalition formation and marriage exchange. In this population, internal warfare unites multiple communities, and co-unokais strategically form new residential groups and marriage alliances. These results support the strategic alliance model of coalitionary aggression, demonstrate the complexities of human alliance formation, and illuminate key differences in social structure distinguishing humans from other primates. PMID:25349394

Pathophysiology of hypophosphatasia and the potential role of asfotase alfa.

PubMed

Orimo, Hideo

2016-01-01

Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP.

Enhanced malignant transformation is accompanied by increased survival recovery after ionizing radiation in Chinese hamster embryo fibroblasts

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

Boothman, D.A.

Transformed Chinese hamster embryo fibroblasts (CHEF), which gradually increase in tumor-forming ability in nude mice, were isolated from normal diploid CHEF/18 cells. Transformed CHEF cells (i.e., T30-4 > 21-2M3 > 21-2 > normal CHEF/18) showed gradual increases in potentially lethal damage (PLD) survival recovery. {beta}-Lapachone and camptothecin, modulators of topoisomerase I (Topo I) activity, not only prevented survival recovery in normal as well as in tumor cells, but enhanced unscheduled DNA synthesis. These seemingly conflicting results are due to the fact that Topo I activity can be modulated by inhibitors to convert single-stranded DNA lesions into double-stranded breaks. Increases inmore » unscheduled DNA synthesis may result from a continual supply of free ends, on which DNA repair processes may act. Altering Topo I activity with modulators appears to increase X-ray lethality via a DNA lesion modification suicide pathway. Cells down-regulate Topo I immediately after ionizing radiation to prevent Topo I-mediated lesion modification and to enhance survival recovery. 16 refs., 3 figs., 1 tab.« less

Forensic Features of Clothing-Related Deaths: Historical and Cultural Aspects.

PubMed

Byard, Roger W

2017-12-01

Clothing may both cause death and contribute to ongoing lethal mechanisms by a variety of quite disparate mechanisms. The manner of death may be accidental, suicidal, or homicidal. Accidental deaths include burning from clothing catching on fire, strangulation from clothing tangling in vehicle wheels or exposed machinery, and drowning. Entanglement of clothing in machinery may also result in significant injuries, which are not uncommon in farming communities. Excessive clothing, or its absence, may significantly alter body temperature, and hanging from clothing is a feature in the young or in mentally or physically handicapped adults, or in adults who are intoxicated with alcohol or drugs. In previous years, potentially lethal amounts of arsenic were present in clothing and accessories from dyes. Clothing may also be used to form nooses or to pad ropes in suicides and may be used in cases of strangulation, suffocation, or choking in homicides. The contribution of clothing to mortality has changed over the years with changes in fashions and in manufacturing techniques. Geographical differences in clothing-related deaths persist because of variable social and cultural practices and legislative frameworks.

Leaf gas exchange performance and the lethal water potential of five European species during drought.

PubMed

Li, Shan; Feifel, Marion; Karimi, Zohreh; Schuldt, Bernhard; Choat, Brendan; Jansen, Steven

2016-02-01

Establishing physiological thresholds to drought-induced mortality in a range of plant species is crucial in understanding how plants respond to severe drought. Here, five common European tree species were selected (Acer campestre L., Acer pseudoplatanus L., Carpinus betulus L., Corylus avellana L. and Fraxinus excelsior L.) to study their hydraulic thresholds to mortality. Photosynthetic parameters during desiccation and the recovery of leaf gas exchange after rewatering were measured. Stem vulnerability curves and leaf pressure-volume curves were investigated to understand the hydraulic coordination of stem and leaf tissue traits. Stem and root samples from well-watered and severely drought-stressed plants of two species were observed using transmission electron microscopy to visualize mortality of cambial cells. The lethal water potential (ψlethal) correlated with stem P99 (i.e., the xylem water potential at 99% loss of hydraulic conductivity, PLC). However, several plants that were stressed beyond the water potential at 100% PLC showed complete recovery during the next spring, which suggests that the ψlethal values were underestimated. Moreover, we observed a 1 : 1 relationship between the xylem water potential at the onset of embolism and stomatal closure, confirming hydraulic coordination between leaf and stem tissues. Finally, ultrastructural changes in the cytoplasm of cambium tissue and mortality of cambial cells are proposed to provide an alternative approach to investigate the point of no return associated with plant death. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ethylhexylglycerin Impairs Membrane Integrity and Enhances the Lethal Effect of Phenoxyethanol

PubMed Central

Langsrud, Solveig; Steinhauer, Katrin; Lüthje, Sonja; Weber, Klaus; Goroncy-Bermes, Peter; Holck, Askild L.

2016-01-01

Preservatives are added to cosmetics to protect the consumers from infections and prevent product spoilage. The concentration of preservatives should be kept as low as possible and this can be achieved by adding potentiating agents. The aim of the study was to investigate the mechanisms behind potentiation of the bactericidal effect of a commonly used preservative, 2-phenoxyethanol (PE), by the potentiating agent ethylhexylglycerin (EHG). Sub-lethal concentrations of EHG (0.075%) and PE (0.675%) in combination led to rapid killing of E. coli (> 5 log reduction of cfu after 30 min), leakage of cellular constituents, disruption of the energy metabolism, morphological deformities of cells and condensation of DNA. Used alone, EHG disrupted the membrane integrity even at low concentrations. In conclusion, sub-lethal concentrations of EHG potentiate the effect of PE through damage of the cell membrane integrity. Thus, adding EHG to PE in a 1:9 ratio has a similar effect on membrane damage and bacterial viability as doubling the concentration of PE. This study provides insight about the mechanism of action of a strong potentiating agent, EHG, which is commonly used in cosmetics together with PE. PMID:27783695

Ganoderma lucidum (Reishi) inhibits cancer cell growth and expression of key molecules in inflammatory breast cancer.

PubMed

Martínez-Montemayor, Michelle M; Acevedo, Raysa Rosario; Otero-Franqui, Elisa; Cubano, Luis A; Dharmawardhane, Suranganie F

2011-01-01

Inflammatory breast cancer (IBC) is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the lymphatic system and absence of a palpable tumor mass. Different from other metastatic breast cancer cells, IBC cells invade by forming tumor spheroids that retain E-cadherin-based cell-cell adhesions. Herein we describe the potential of the medicinal mushroom Ganoderma lucidum (Reishi) as an attractive candidate for anti-IBC therapy. Reishi contains biological compounds that are cytotoxic against cancer cells. We report the effects of Reishi on viability, apoptosis, invasion, and its mechanism of action in IBC cells (SUM-149). Results show that Reishi selectively inhibits cancer cell viability although it does not affect the viability of noncancerous mammary epithelial cells. Apoptosis induction is consistent with decreased cell viability. Reishi inhibits cell invasion and disrupts the cell spheroids that are characteristic of the IBC invasive pathology. Reishi decreases the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB), and invasion and metastasis (MMP-9), whereas it increases the expression of IL8. Reishi reduces BCL-2, BCL-XL, E-cadherin, eIF4G, p120-catenin, and c-Myc protein expression and gelatinase activity. These findings suggest that Reishi is an effective anti-IBC therapeutic.

Ganoderma lucidum (Reishi) Inhibits Cancer Cell Growth and Expression of Key Molecules in Inflammatory Breast Cancer

PubMed Central

Martínez-Montemayor, Michelle M.; Acevedo, Raysa Rosario; Otero-Franqui, Elisa; Cubano, Luis. A.; Dharmawardhane, Suranganie F.

2011-01-01

Inflammatory breast cancer (IBC) is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the lymphatic system and absence of a palpable tumor mass. Different from other metastatic breast cancer cells, IBC cells invade by forming tumor spheroids that retain E-cadherin-based cell–cell adhesions. Herein we describe the potential of the medicinal mushroom Ganoderma lucidum (Reishi) as an attractive candidate for anti-IBC therapy. Reishi contains biological compounds that are cytotoxic against cancer cells. We report the effects of Reishi on viability, apoptosis, invasion, and its mechanism of action in IBC cells (SUM-149). Results show that Reishi selectively inhibits cancer cell viability although it does not affect the viability of noncancerous mammary epithelial cells. Apoptosis induction is consistent with decreased cell viability. Reishi inhibits cell invasion and disrupts the cell spheroids that are characteristic of the IBC invasive pathology. Reishi decreases the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB), and invasion and metastasis (MMP-9), whereas it increases the expression of IL8. Reishi reduces BCL-2, BCL-XL, E-cadherin, eIF4G, p120-catenin, and c-Myc protein expression and gelatinase activity. These findings suggest that Reishi is an effective anti-IBC therapeutic. PMID:21888505

Neoplastic cell transformation by high-LET radiation - Molecular mechanisms

NASA Technical Reports Server (NTRS)

Yang, Tracy Chui-Hsu; Craise, Laurie M.; Tobias, Cornelius A.; Mei, Man-Tong

1989-01-01

Quantitative data were collected on dose-response curves of cultured mouse-embryo cells (C3H10T1/2) irradiated with heavy ions of various charges and energies. Results suggests that two breaks formed on DNA within 80 A may cause cell transformation and that two DNA breaks formed within 20 A may be lethal. From results of experiments with restriction enzymes which produce DNA damages at specific sites, it was found that DNA double strand breaks are important primary lesions for radiogenic cell transformation and that blunt-ended double-strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship for high-LET radiation is similar to that for HGPRT locus mutation, chromosomal deletion, and cell transformation, indicating that common lesions may be involved in these radiation effects.

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress*

PubMed Central

Kemp, Michael G.; Sancar, Aziz

2016-01-01

ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected non-replicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens. PMID:26940878

Wolf management in the 21st century: From public input to sterilization

USGS Publications Warehouse

Mech, L.D.; Fritts, S.H.; Nelson, M.E.

1996-01-01

Human-population increase and land development portend increasing conflict with large predators. Concurrently, changes and diversification of human attitudes are bringing increased disagreement about wildlife management. Animal-rights advocacy resulting from urbanization of human populations conflicts with traditional wildlife management. These forces focus more on wolves than on other wildlife because of strong public and media interest in wolves. Thus wolf management in the future will come under even greater public scrutiny, involve more public input, and may have greater restrictions imposed on it. This will lead to increased complexity in wolf management including more zoning, more experimentation with lethal and non-lethal capture techniques and alternate methods of alleviating damage to pets, livestock, and large ungulate herds, and greater public and private subsidy of wolf damage. One form of non-lethal control of wolf populations that may hold some promise is direct sterilization of males to reduce the biotic potential of the wolf population. Experimental vasectomy of five wild male wolves from four packs in Minnesota indicates that sterile males will continue to hold mates and territories, which would be necessary if sterilization is to be a viable technique for assisting with population control. If sterile males held territories but failed to produce pups, such territories might contain only about a third the number of wolves as fertile pack territories. Because wolves are long-lived in unexploited populations and their territories are large, direct sterilization of relatively few animals each year might significantly reduce populations.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

PubMed

Albright, Frederick S; Stephenson, Robert A; Agarwal, Neeraj; Cannon-Albright, Lisa A

2017-01-01

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila.

PubMed

Alves, Ema; Henriques, Bárbara J; Rodrigues, João V; Prudêncio, Pedro; Rocha, Hugo; Vilarinho, Laura; Martinho, Rui G; Gomes, Cláudio M

2012-08-01

Following a screening on EMS-induced Drosophila mutants defective for formation and morphogenesis of epithelial cells, we have identified three lethal mutants defective for the production of embryonic cuticle. The mutants are allelic to the CG12140 gene, the fly homologue of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). In humans, inherited defects in this inner membrane protein account for multiple acyl-CoA dehydrogenase deficiency (MADD), a metabolic disease of β-oxidation, with a broad range of clinical phenotypes, varying from embryonic lethal to mild forms. The three mutant alleles carried distinct missense mutations in ETF:QO (G65E, A68V and S104F) and maternal mutant embryos for ETF:QO showed lethal morphogenetic defects and a significant induction of apoptosis following germ-band elongation. This phenotype is accompanied by an embryonic accumulation of short- and medium-chain acylcarnitines (C4, C8 and C12) as well as long-chain acylcarnitines (C14 and C16:1), whose elevation is also found in severe MADD forms in humans under intense metabolic decompensation. In agreement the ETF:QO activity in the mutant embryos is markedly decreased in relation to wild type activity. Amino acid sequence analysis and structural mapping into a molecular model of ETF:QO show that all mutations map at FAD interacting residues, two of which at the nucleotide-binding Rossmann fold. This structural domain is composed by a β-strand connected by a short loop to an α-helix, and its perturbation results in impaired cofactor association via structural destabilisation and consequently enzymatic inactivation. This work thus pinpoints the molecular origins of a severe MADD-like phenotype in the fruit fly and establishes the proof of concept concerning the suitability of this organism as a potential model organism for MADD. © 2012 Elsevier B.V. All rights reserved.

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations

NASA Astrophysics Data System (ADS)

Sardanyés, Josep; Simó, Carles; Martínez, Regina; Solé, Ricard V.; Elena, Santiago F.

2014-04-01

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Defects in cholesterol synthesis genes in mouse and in humans: lessons for drug development and safer treatments.

PubMed

Horvat, Simon; McWhir, Jim; Rozman, Damjana

2011-02-01

This review describes the mouse knockout models of cholesterol synthesis, together with human malformations and drugs that target cholesterogenic enzymes. Generally, the sooner a gene acts in cholesterol synthesis, the earlier the phenotype occurs. Humans with loss of function of early cholesterogenic enzymes have not yet been described, and in the mouse, loss of Hmgcr is preimplantation lethal. Together, these results indicate that the widely prescribed cholesterol-lowering statins are potentially teratogenic. The Mvk knockout is early embryonic lethal in the mouse, the absence of Fdft1 is lethal at E9.5-12.5 dpc, while the Cyp51 knockouts die at 15.0 dpc. Fungal CYP51 inhibitor azoles are teratogenic in humans, potentially leading to symptoms of Antley-Bixler syndrome. The X-linked mutations in Nsdhl and Ebp are embryonic lethal in male mice, while heterozygous females are also affected. Consequently, the anticancer drugs, tamoxifen and toremifene, inhibiting human EBP, may be harmful in early pregnancy. The Dhcr7 and Dhcr24 knockout mice die shortly after birth, while humans survive with Smith-Lemli-Opitz syndrome or desmosterolosis. Since cholesterol is essential for hedgehog signaling, disturbance of this pathway by antipsychotics and -depressants explains some drug side effects. In conclusion, defects in cholesterol synthesis are generally lethal in mice, while humans with impaired later steps of the pathway can survive with severe malformations. Evidence shows that drugs targeting or, by coincidence, inhibiting human cholesterol synthesis are better avoided in early pregnancy. Since some drugs with teratogenic potential still stay on the market, this should be avoided in new cholesterol-related drug development.

De Novo Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells Formed against Antituberculosis Drugs In Vitro

PubMed Central

Sebastian, Jees; Swaminath, Sharmada; Nair, Rashmi Ravindran; Jakkala, Kishor; Pradhan, Atul

2016-01-01

ABSTRACT Bacterial persisters are a subpopulation of cells that can tolerate lethal concentrations of antibiotics. However, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell populations, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. In the present study, we found that Mycobacterium tuberculosis cells exposed continuously to lethal concentrations of rifampin (RIF) or moxifloxacin (MXF) for prolonged durations showed killing, RIF/MXF persistence, and regrowth phases. RIF-resistant or MXF-resistant mutants carrying clinically relevant mutations in the rpoB or gyrA gene, respectively, were found to emerge at high frequency from the RIF persistence phase population. A Luria-Delbruck fluctuation experiment using RIF-exposed M. tuberculosis cells showed that the rpoB mutants were not preexistent in the population but were formed de novo from the RIF persistence phase population. The RIF persistence phase M. tuberculosis cells carried elevated levels of hydroxyl radical that inflicted extensive genome-wide mutations, generating RIF-resistant mutants. Consistent with the elevated levels of hydroxyl radical-mediated genome-wide random mutagenesis, MXF-resistant M. tuberculosis gyrA de novo mutants could be selected from the RIF persistence phase cells. Thus, unlike previous studies, which showed emergence of genetically resistant mutants upon exposure of bacteria for short durations to sublethal concentrations of antibiotics, our study demonstrates that continuous prolonged exposure of M. tuberculosis cells to lethal concentrations of an antibiotic generates antibiotic persistence phase cells that form a reservoir for the generation of genetically resistant mutants to the same antibiotic or another antibiotic. These findings may have clinical significance in the emergence of drug-resistant tubercle bacilli. PMID:27895008

Lethality of firearms relative to other suicide methods: a population based study.

PubMed

Shenassa, E D; Catlin, S N; Buka, S L

2003-02-01

(1) To quantify lethality of firearms relative to other suicide methods, (2) to quantify the extent to which suicide mortality may be reduced by limiting access to firearms. Data on suicides and hospitalised para-suicides that occurred in the state of Illinois from 1990 to 1997 were combined. Total number of episodes for each suicide method was estimated as the sum of the number of suicides and the number of para-suicides for that method. Gender and suicide method were used as proxies for intention to die, and estimated lethality of suicide methods within method-gender groups (for example, male firearm users). Logistic regression was used to quantify the lethality of firearms relative to other suicide methods. Excess mortality associated with the use of firearms was estimated by conservatively assuming that in the absence of firearms the next most lethal suicide method would be used. From January 1990 to December 1997, among individuals 10 years or older in the state of Illinois, there were 37,352 hospital admissions for para-suicide and 10,287 completed suicides. Firearms are the most lethal suicide method. Episodes involving firearms are 2.6 times (95% CI 2.1 to 3.1) more lethal than those involving suffocation-the second most lethal suicide method. Preventing access to firearms can reduce the proportion of fatal firearms related suicides by 32% among minors, and 6.5% among adults. Limiting access to firearms is a potentially effective means of reducing suicide mortality.

Non-lethal sampling of walleye for stable isotope analysis: a comparison of three tissues

USGS Publications Warehouse

Chipps, Steven R.; VanDeHey, J.A.; Fincel, M.J.

2012-01-01

Stable isotope analysis of fishes is often performed using muscle or organ tissues that require sacrificing animals. Non-lethal sampling provides an alternative for evaluating isotopic composition for species of concern or individuals of exceptional value. Stable isotope values of white muscle (lethal) were compared with those from fins and scales (non-lethal) in walleye, Sander vitreus (Mitchill), from multiple systems, size classes and across a range of isotopic values. Isotopic variability was also compared among populations to determine the potential of non-lethal tissues for diet-variability analyses. Muscle-derived isotope values were enriched compared with fins and depleted relative to scales. A split-sample validation technique and linear regression found that isotopic composition of walleye fins and scales was significantly related to that in muscle tissue for both δ13C and δ15N (r2 = 0.79–0.93). However, isotopic variability was significantly different between tissue types in two of six populations for δ15N and three of six populations for δ13C. Although species and population specific, these findings indicate that isotopic measures obtained from non-lethal tissues are indicative of those obtained from muscle.

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined "Complementary Lethality".

PubMed

Rytelewski, Mateusz; Ferguson, Peter J; Maleki Vareki, Saman; Figueredo, Rene; Vincent, Mark; Koropatnick, James

2013-03-12

A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergistically potentiated drugs with mechanisms of action related to BRCA2 function (cisplatin, melphalan), a phenomenon we named "complementary lethality." TS knockdown induced complementary lethality to TS-targeting drugs (5-FUdR and pemetrexed) but not DNA cross-linking agents. Combined targeting of BRCA2 and TS induced complementary lethality to both DNA-damaging and TS-targeting agents, thus creating multidrug sensitive tumors. In addition, we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population. In this study, we propose and define the concept of "complementary lethality" and show that actively targeting BRCA2 and TS is of potential therapeutic benefit in multidrug treatment of human tumors. This work has contributed to the development of a BRCA2-targeting antisense oligdeoxynucleotide (ASO) "BR-1" which we will test in vivo in combination with our TS-targeting ASO "SARI 83" and attempt early clinical trials in the future.Molecular Therapy - Nucleic Acids (2013) 2, e78; doi:10.1038/mtna.2013.7 published online 12 March 2013.

Research supporting potential modification of the NASA specification for dry heat microbial reduction of spacecraft hardware

NASA Astrophysics Data System (ADS)

Spry, James A.; Beaudet, Robert; Schubert, Wayne

Dry heat microbial reduction (DHMR) is the primary method currently used to reduce the microbial load of spacecraft and component parts to comply with planetary protection re-quirements. However, manufacturing processes often involve heating flight hardware to high temperatures for purposes other than planetary protection DHMR. At present, the specifica-tion in NASA document NPR8020.12, describing the process lethality on B. atrophaeus (ATCC 9372) bacterial spores, does not allow for additional planetary protection bioburden reduction credit for processing outside a narrow temperature, time and humidity window. Our results from a comprehensive multi-year laboratory research effort have generated en-hanced data sets on four aspects of the current specification: time and temperature effects in combination, the effect that humidity has on spore lethality, and the lethality for spores with exceptionally high thermal resistance (so called "hardies"). This paper describes potential modifications to the specification, based on the data set gener-ated in the referenced studies. The proposed modifications are intended to broaden the scope of the current specification while still maintaining confidence in a conservative interpretation of the lethality of the DHMR process on microorganisms.

Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

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

McDonough, J.H.; Shih, T.M.

1995-12-31

A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonizedmore » NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.« less

New Lethal Skeletal Dysplasia with Dandy-Walker Malformation, Congenital Heart Defects, Abnormal Thumbs, Hypoplastic Genitalia, and Distinctive Facies

PubMed Central

Stevens, Cathy A.; Lachman, Ralph S.

2011-01-01

We report on two sibs with a lethal form of bone dysplasia with distinctive skeletal findings including rhizomelic and mesomelic limb shortening, hooked clavicles, dumbbell femurs, and absence of talus and calcaneus ossification. Other clinical features include Dandy-Walker malformation, congenital heart defects, joint contractures, genital hypoplasia, and distinctive facial features. These sibs appear to have a previously undescribed skeletal dysplasia, which is most likely inherited in an autosomal recessive fashion. PMID:20602491

African Security Challenges: Now and Over the Horizon Improving African Security Through the Use of Non/Less-Than -Lethal Force: Challenges , Issues and Approaches

DTIC Science & Technology

2010-05-01

donor funding is no longer available. For instance, Brazil and Colombia were unable to sustain their CP programs when funding from donors to establish...forces. Other more advanced forms of non/less-than-lethal weapons which are common in the West, such as Tasers , are far less common on the continent...31 As part of this discussion, several experts discussed Tasers , in particular, though one expert also mentioned

Prevalence of a potentially lethal parasite of wading birds in natural and agricultural wetlands in south Louisiana

USGS Publications Warehouse

Luent, Margaret C.; Collins, Melissa; Jeske, Clinton; Leberg, Paul

2012-01-01

Gambusia affinis (Western Mosquitofish) were sampled from 18 sites representing marsh, forested wetlands, and agricultural wetlands in south Louisiana to determine distribution and infection parameters of Eustrongylides ignotus, a potentially lethal nematode parasite of wading birds, (n = 400 per site). Overall, prevalence of infection was 0.3%, with significantly higher prevalence in agricultural wetlands than in marshes or swamps. Our findings are similar to work in Florida suggesting parasite prevalence is higher in disturbed wetlands, and suggest that birds foraging in crayfish ponds and rice fields may be at increased risk of exposure.

Canatoxin, a toxic protein from jack beans (Canavalia ensiformis), is a variant form of urease (EC 3.5.1.5): biological effects of urease independent of its ureolytic activity.

PubMed Central

Follmer, C; Barcellos, G B; Zingali, R B; Machado, O L; Alves, E W; Barja-Fidalgo, C; Guimarães, J A; Carlini, C R

2001-01-01

Canatoxin is a toxic protein from Canavalia ensiformis seeds, lethal to mice (LD(50)=2 mg/kg) and insects. Further characterization of canatoxin showed that its main native form (184 kDa) is a non-covalently linked dimer of a 95 kDa polypeptide containing zinc and nickel. Partial sequencing of internal peptides indicated homology with urease (EC 3.5.1.5) from the same seed. Canatoxin has approx. 30% of urease's activity for urea, and K(m) of 2-7 mM. The proteins differ in their affinities for metal ions and were separated by affinity chromatography on a Zn(2+) matrix. Similar to canatoxin, urease activates blood platelets and interacts with glycoconjugates. In contrast with canatoxin, no lethality was seen in mice injected with urease (10 mg/kg). Pretreatment with p-hydroxymercuribenzoate irreversibly abolished the ureolytic activity of both proteins. On the other hand, p-hydroxymercuribenzoate-treated canatoxin was still lethal to mice, and both treated proteins were fully active in promoting platelet aggregation and binding to glycoconjugates. Taken together, our data indicate that canatoxin is a variant form of urease. Moreover, we show for the first time that these proteins display several biological effects that are unrelated to their enzymic activity for urea. PMID:11696010

'Refeeding syndrome' in a Kuwaiti child: clinical diagnosis and management.

PubMed

Al Sharkawy, Ibrahim; Ramadan, Dina; El-Tantawy, Amira

2010-01-01

To report a case of refeeding syndrome in a Kuwaiti child, its clinical presentation and management. A 13-month-old Kuwaiti boy presented with acute severe malnutrition in the form of marasmic kwashiorkor. On admission, blood sugar and serum electrolytes were normal but on the 3rd day he developed typical biochemical features of refeeding syndrome in the form of hyperglycemia, severe hypophosphatemia, hypokalemia, hypocalcemia and hypomagnesemia. The child then received treatment appropriate for refeeding syndrome in the form of lower calorie intake with gradual increase, as well as supplementation of electrolytes, thiamine and vitamins and he eventually made a safe recovery. This case showed that during rehabilitation of a malnourished child, a severe potentially lethal electrolyte disturbance (refeeding syndrome) can occur. Careful monitoring of electrolytes before and during the refeeding phase was needed and helped to detect this syndrome early. We suggest that slow and gradual calorie increase in the 'at-risk' patient can help prevent its occurrence. Copyright (c) 2010 S. Karger AG, Basel.

[Phthiriasis, the mysterious lousy disease of antiquity. Fact or fiction?].

PubMed

Bahmer, F A; Eckert, A

2015-02-01

The lousy disease (phthiriasis) and its potentially deadly consequences is well attested from antiquity until the 19th century. Intensely itching, vesicular or tumorous skin lesions defile the body and release swarms of insects spontaneously or after incision. Several well-known persons from antiquity and the early modern period are supposed to have died of the lousy disease. Both classicists and physicians have questioned the credibility of said accounts. By means of our interdisciplinary approach based on an analysis of different descriptions of the lousy disease from antiquity to the 19th century, this paper will present strong arguments for the existence of a potentially lethal form of phthiriasis. In contrast to its name, the lousy disease was most likely caused by a species of mites, similar to the one causing cystic subepidermal tumors in birds.

Laboratory Diagnostics of Botulism

PubMed Central

Lindström, Miia; Korkeala, Hannu

2006-01-01

Botulism is a potentially lethal paralytic disease caused by botulinum neurotoxin. Human pathogenic neurotoxins of types A, B, E, and F are produced by a diverse group of anaerobic spore-forming bacteria, including Clostridium botulinum groups I and II, Clostridium butyricum, and Clostridium baratii. The routine laboratory diagnostics of botulism is based on the detection of botulinum neurotoxin in the patient. Detection of toxin-producing clostridia in the patient and/or the vehicle confirms the diagnosis. The neurotoxin detection is based on the mouse lethality assay. Sensitive and rapid in vitro assays have been developed, but they have not yet been appropriately validated on clinical and food matrices. Culture methods for C. botulinum are poorly developed, and efficient isolation and identification tools are lacking. Molecular techniques targeted to the neurotoxin genes are ideal for the detection and identification of C. botulinum, but they do not detect biologically active neurotoxin and should not be used alone. Apart from rapid diagnosis, the laboratory diagnostics of botulism should aim at increasing our understanding of the epidemiology and prevention of the disease. Therefore, the toxin-producing organisms should be routinely isolated from the patient and the vehicle. The physiological group and genetic traits of the isolates should be determined. PMID:16614251

Effect on the growth and development and induction of abnormalities by a glyphosate commercial formulation and its active ingredient during two developmental stages of the South-American Creole frog, Leptodactylus latrans.

PubMed

Bach, Nadia Carla; Natale, Guillermo Sebastián; Somoza, Gustavo Manuel; Ronco, Alicia Estela

2016-12-01

We evaluated the acute lethal and sublethal effects of technical-grade glyphosate (GLY) and the GLY-based commercial formulation Roundup ULTRA MAX® (RU) on two Gosner stages (Gss) 25 and 36 of the South-American Creole frog, Leptodactylus latrans. Bioassays were performed following standardized methods within a wide range of concentrations (0.0007-9.62 mg of acid equivalents per liter-a.e./L-of RU and 3-300 mg/L of GLY). The endpoints evaluated were mortality, swimming activity, growth, development, and the presence of morphologic abnormalities, especially in the mouthparts. No lethal effects were observed on larvae exposed to GLY during either Gs-25 or Gs-36. The concentrations inducing 50 % lethality in RU-exposed larvae at different exposure times and Gss ranged from 3.26 to 9.61 mg a.e./L. Swimming activity was affected by only RU. Effects on growth and development and the induction of morphologic abnormalities-like oral abnormalities and edema-were observed after exposure to either GLY or RU. Gs-25 was the most sensitive stage to both forms of the herbicide. The commercial formulation was much more toxic than the active ingredient on all the endpoints assessed. Effects on growth, development, and the induction of morphologic abnormalities observed in the range of environmental concentrations reported for agroecosystems of Argentina constitute an alert to the potential detrimental effects of the herbicide that could be affecting the fitness and survival of anurans in agroecosystems.

Levofloxacin Cures Experimental Pneumonic Plague in African Green Monkeys

PubMed Central

McDonald, Jacob D.; Brasel, Trevor L.; Barr, Edward B.; Gigliotti, Andrew P.; Koster, Frederick

2011-01-01

Background Yersinia pestis, the agent of plague, is considered a potential bioweapon due to rapid lethality when delivered as an aerosol. Levofloxacin was tested for primary pneumonic plague treatment in a nonhuman primate model mimicking human disease. Methods and Results Twenty-four African Green monkeys (AGMs, Chlorocebus aethiops) were challenged via head-only aerosol inhalation with 3–145 (mean = 65) 50% lethal (LD50) doses of Y. pestis strain CO92. Telemetered body temperature >39°C initiated intravenous infusions to seven 5% dextrose controls or 17 levofloxacin treated animals. Levofloxacin was administered as a “humanized” dose regimen of alternating 8 mg/kg and 2 mg/kg 30-min infusions every 24-h, continuing until animal death or 20 total infusions, followed by 14 days of observation. Fever appeared at 53–165 h and radiographs found multilobar pneumonia in all exposed animals. All control animals died of severe pneumonic plague within five days of aerosol exposure. All 16 animals infused with levofloxacin for 10 days survived. Levofloxacin treatment abolished bacteremia within 24 h in animals with confirmed pre-infusion bacteremia, and reduced tachypnea and leukocytosis but not fever during the first 2 days of infusions. Conclusion Levofloxacin cures established pneumonic plague when treatment is initiated after the onset of fever in the lethal aerosol-challenged AGM nonhuman primate model, and can be considered for treatment of other forms of plague. Levofloxacin may also be considered for primary presumptive-use, multi-agent antibiotic in bioterrorism events prior to identification of the pathogen. PMID:21347450

Psychosocial influences on prisoner suicide: a case-control study of near-lethal self-harm in women prisoners.

PubMed

Marzano, Lisa; Hawton, Keith; Rivlin, Adrienne; Fazel, Seena

2011-03-01

We examined the psychosocial influences on female prisoner suicide by carrying out a study of near-lethal self-harm. We interviewed 60 women prisoners who had recently engaged in near-lethal self-harm (cases) and 60 others who had never carried out near-lethal acts in prison (controls) from all closed female prison establishments in England and Wales, using mixed quantitative and qualitative methods. We gathered information on socio-demographic and criminological variables, life events and childhood trauma, exposure to suicidal behaviour, contributory and precipitating factors for near-lethal self-harm, social support and psychological characteristics. While socio-demographic factors were only modestly associated with near-lethal self-harm, being on remand, in single cell accommodation, and reporting negative experiences of imprisonment were strong correlates. Recent life events and past trauma, including different forms of childhood abuse, were also significantly associated with near-lethal self-harm, as were a family history of suicide and high scores on measures of depression, aggression, impulsivity and hostility, and low levels of self-esteem and social support. Our findings underline the importance of both individual and prison-related factors for suicide in custody, and hence the need for a comprehensive approach to suicide prevention in women's prisons. Given the multiple needs of female prisoners at-risk of self-harm and suicide, complex psychosocial interventions are likely to be required, including interventions for abused and bereaved women, and initiatives to improve staff-prisoner relationships and reduce bullying. The findings of this research may provide insights into factors leading to suicidal behaviour in other forensic and institutional settings, such as detention centres and psychiatric hospitals, and may assist in developing suicide prevention policies for prisoners and other at-risk populations. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comparison of injuries due to lethal weapons during and after civil strife in Sri Lanka: A medico-legal study.

PubMed

Vidanapathirana, Muditha; Ruwanpura, Rohan P; Amararatne, Sriyantha Rrg; Ratnaweera, Ajith Rhi

2016-01-01

"Injuries due to lethal weapons" has emerged as a subject of public discussion in Sri Lanka. This study was conducted to describe the nature and characteristics of injuries due to lethal weapons during civil strife and to compare those with injuries after civil strife. A cross-sectional study was conducted on patients reported with injuries caused by lethal weapons from 2004 to 2014. Periods before and after May 19, 2009 were considered as during and after civil strife periods, respectively. A total of 21,210 medico-legal examination forms were studied. There were 358 (1.7%) injuries caused by lethal weapons. Of them, 41% (n = 148) were during and 59% (n = 210) were after the civil strife. During civil strife, 63% occurred during daytime (P < 0.05). Types of lethal weapons that caused injuries were sharp weapons (n = 282), explosives (n = 49), and firearms (n = 27). Of them, 32% of during and 01% of after civil strife were explosive injuries (P < 0.01). Regarding severity, 73% of during and 57% of after civil strife injuries were severe (P < 0.05). During civil strife, 34% injuries were in lower limbs (P < 0.01) and after civil strife, 37% were in upper limbs (P < 0.05). The presence of many similarities indicated that both groups learnt their basis in a society that breeds violence. During civil strife, more injuries occurred during daytime, to lower limbs by explosive weapons and after the civil strife during nighttime, to upper limbs by nonexplosive weapons. Nonexplosive lethal weapon use after civil strife needs further investigation to develop evidence-based interventions.

Comparison of injuries due to lethal weapons during and after civil strife in Sri Lanka: A medico-legal study

PubMed Central

Vidanapathirana, Muditha; Ruwanpura, Rohan P; Amararatne, Sriyantha RRG; Ratnaweera, Ajith RHI

2016-01-01

Background and Aims: “Injuries due to lethal weapons” has emerged as a subject of public discussion in Sri Lanka. This study was conducted to describe the nature and characteristics of injuries due to lethal weapons during civil strife and to compare those with injuries after civil strife. Methods: A cross-sectional study was conducted on patients reported with injuries caused by lethal weapons from 2004 to 2014. Periods before and after May 19, 2009 were considered as during and after civil strife periods, respectively. A total of 21,210 medico-legal examination forms were studied. Results: There were 358 (1.7%) injuries caused by lethal weapons. Of them, 41% (n = 148) were during and 59% (n = 210) were after the civil strife. During civil strife, 63% occurred during daytime (P < 0.05). Types of lethal weapons that caused injuries were sharp weapons (n = 282), explosives (n = 49), and firearms (n = 27). Of them, 32% of during and 01% of after civil strife were explosive injuries (P < 0.01). Regarding severity, 73% of during and 57% of after civil strife injuries were severe (P < 0.05). During civil strife, 34% injuries were in lower limbs (P < 0.01) and after civil strife, 37% were in upper limbs (P < 0.05). Conclusions: The presence of many similarities indicated that both groups learnt their basis in a society that breeds violence. During civil strife, more injuries occurred during daytime, to lower limbs by explosive weapons and after the civil strife during nighttime, to upper limbs by nonexplosive weapons. Nonexplosive lethal weapon use after civil strife needs further investigation to develop evidence-based interventions. PMID:27127743

Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

PubMed

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

2010-07-01

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

Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium☆

PubMed Central

Bromage, Daniel I.; Davidson, Sean M.; Yellon, Derek M.

2014-01-01

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting. PMID:24704323

Further heterogeneity within lethal neonatal short-limbed dwarfism: the platyspondylic types.

PubMed

Horton, W A; Rimoin, D L; Hollister, D W; Lachman, R S

1979-05-01

Twelve infants, initially considered to have thanatophoric dysplasia, were studied by a combined radiographic-histochemical-biochemical approach. Three distinct forms of platyspondylic lethal neonatal short-limbed dwarfism could be distinguished: (1) Thanatophoric type, (2) Torrance type, and (3) San Diego type. The latter two disorders had similar radiographic abnormalities that were clearly different from those of typical thanatophoric dysplasia. All three disorders had clearly different condroosseous histopathologic abnormalities. Preliminary biochemical studies have revealed different electrophorectic abnormalities in solubilized type II collagen chains of cartilage in each of these three disorders.

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

PubMed Central

2014-01-01

Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp.

PubMed

Londo, Jason Paul; McKinney, John; Schwartz, Matthew; Bollman, Mike; Sagers, Cynthia; Watrud, Lidia

2014-03-21

Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate.

[The results of delivering surgical care to the wounded and sick in military medical establishments and impending tasks].

PubMed

Briusov, P G; Efimenko, N A

1997-07-01

In article results of activity of the military surgeons on rendering of the surgical care to wounded and sick in 1996 are analyzed. During combat actions in Chechnya despite of severe forms of wounds and significant increase of combined battle traumas lethality among heavy wounded was reduced in 2 times. At common lethality rate in 1.3%, in hospitals from wounds 1.5% of wounded died, from traumas--0.7%, burns--2.9%, frostbitten--0.5%. As to peace time surgery, the analysis of main parameters of surgical work in military medical establishments, structure of diseases of servicemen, surgical activity, average terms of treatment, lethality after operations, defects in rendering of the surgical care is given. In conclusions the authors say about problems, that the military surgeons have today.

A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells

PubMed Central

Guarnerio, Jlenia; Riccardi, Luisa; Taulli, Riccardo; Maeda, Takahiro; Wang, Guocan; Hobbs, Robin M.; Song, Min Sup; Sportoletti, Paolo; Bernardi, Rosa; Bronson, Roderick T.; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Lunardi, Andrea; Pandolfi, Pier Paolo

2015-01-01

The regulatory factors governing adult mesenchymal stem cells (MSCs) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal form of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSCs transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma with important therapeutic implications. PMID:25614485

Inhibition of Clostridium perfringens epsilon toxin by β-cyclodextrin derivatives.

PubMed

Robinson, Tanisha M; Jicsinszky, Laszlo; Karginov, Andrei V; Karginov, Vladimir A

2017-10-15

Clostridium perfringens epsilon toxin (ETX) is considered as one of the most dangerous potential biological weapons. The goal of this work was to identify inhibitors of ETX using a novel approach for the inactivation of pore-forming toxins. The approach is based on the blocking of the target pore with molecules having the same symmetry as the pore itself. About 200 various β-cyclodextrin derivatives were screened for inhibitors of ETX activity using a colorimetric cell viability assay. Several compounds with dose-dependent activities at low micromolar concentrations have been identified. The same compounds were also able to inhibit lethal toxin of Bacillus anthracis. Copyright © 2017 Elsevier B.V. All rights reserved.

Epithelial plasticity in prostate cancer: principles and clinical perspectives.

PubMed

Das, Rajdeep; Gregory, Philip A; Hollier, Brett G; Tilley, Wayne D; Selth, Luke A

2014-11-01

Over the past decade, the capacity of cancer cells to oscillate between epithelial and mesenchymal phenotypes, termed epithelial plasticity (EP), has been demonstrated to play a critical role in metastasis. This phenomenon may be particularly important for prostate cancer (PC) progression, since recent studies have revealed interplay between EP and signaling by the androgen receptor (AR) oncoprotein. Moreover, EP appears to play a role in dictating the response to therapies for metastatic PC. This review will evaluate preclinical and clinical evidence for the relevance of EP in PC progression and consider the potential of targeting and measuring EP as a means to treat and manage lethal forms of the disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

Non-lethal effects of an invasive species in the marine environment: the importance of early life-history stages.

PubMed

Rius, Marc; Turon, Xavier; Marshall, Dustin J

2009-04-01

Studies examining the effects of invasive species have focussed traditionally on the direct/lethal effects of the invasive on the native community but there is a growing recognition that invasive species may also have non-lethal effects. In terrestrial systems, non-lethal effects of invasive species can disrupt early life-history phases (such as fertilisation, dispersal and subsequent establishment) of native species, but in the marine environment most studies focus on adult rather than early life-history stages. Here, we examine the potential for an introduced sessile marine invertebrate (Styela plicata) to exert both lethal and non-lethal effects on a native species (Microcosmus squamiger) across multiple early life-history stages. We determined whether sperm from the invasive species interfered with the fertilisation of eggs from the native species and found no effect. However, we did find strong effects of the invasive species on the post-fertilisation performance of the native species. The invasive species inhibited the settlement of native larvae and, in the field, the presence of the invasive species was associated with a ten-fold increase in the post-settlement mortality of the native species, as well as an initial reduction of growth in the native. Our results suggest that larvae of the native species avoid settling near the invasive species due to reduced post-settlement survival in its presence. Overall, we found that invasive species can have complex and pervasive effects (both lethal and non-lethal) across the early life-history stages of the native species, which are likely to result in its displacement and to facilitate further invasion.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

PubMed Central

Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

2012-01-01

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

Lethal and sub-lethal effects of spinosad on bumble bees (Bombus impatiens Cresson).

PubMed

Morandin, Lora A; Winston, Mark L; Franklin, Michelle T; Abbott, Virginia A

2005-07-01

Recent developments of new families of pesticides and growing awareness of the importance of wild pollinators for crop pollination have stimulated interest in potential effects of novel pesticides on wild bees. Yet pesticide toxicity studies on wild bees remain rare, and few studies have included long-term monitoring of bumble bee colonies or testing of foraging ability after pesticide exposure. Larval bees feeding on exogenous pollen and exposed to pesticides during development may result in lethal or sub-lethal effects during the adult stage. We tested the effects of a naturally derived biopesticide, spinosad, on bumble bee (Bombus impatiens Cresson) colony health, including adult mortality, brood development, weights of emerging bees and foraging efficiency of adults that underwent larval development during exposure to spinosad. We monitored colonies from an early stage, over a 10-week period, and fed spinosad to colonies in pollen at four levels: control, 0.2, 0.8 and 8.0 mg kg(-1), during weeks 2 through 5 of the experiment. At concentrations that bees would likely encounter in pollen in the wild (0.2-0.8 mg kg(-1)) we detected minimal negative effects to bumble bee colonies. Brood and adult mortality was high at 8.0 mg kg(-1) spinosad, about twice the level that bees would be exposed to in a 'worst case' field scenario, resulting in colony death two to four weeks after initial pesticide exposure. At more realistic concentrations there were potentially important sub-lethal effects. Adult worker bees exposed to spinosad during larval development at 0.8 mg kg(-1) were slower foragers on artificial complex flower arrays than bees from low or no spinosad treated colonies. Inclusion of similar sub-lethal assays to detect effects of pesticides on pollinators would aid in development of environmentally responsible pest management strategies. Copyright 2005 Society of Chemical Industry

Public acceptance of management methods under different human-wildlife conflict scenarios.

PubMed

Liordos, Vasilios; Kontsiotis, Vasileios J; Georgari, Marina; Baltzi, Kerasia; Baltzi, Ioanna

2017-02-01

Wildlife management seeks to minimise public controversy for successful application of wildlife control methods. Human dimensions research in wildlife seeks a better understanding of public preferences for effective human-wildlife conflict resolution. In face to face interviews, 630 adults in Greece were asked to rate on a 5-point Likert-like scale their acceptance of 3 management methods, i.e., do nothing, non-lethal control, and lethal control, in the context of 5 human-wildlife conflict scenarios: 1) corvids damage crops; 2) starlings damage crops; 3) starlings foul urban structures; 4) coypus damage crops; and 5) coypus transfer disease. Univariate GLMs determined occupation, hunting membership and their interaction as the stronger predictors of public acceptance, generating 4 stakeholder groups: the general public, farmers, hunters, and farmers-hunters. Differences in acceptance and consensus among stakeholder groups were assessed using the Potential for Conflict Index 2 (PCI 2 ). All 4 stakeholder groups agreed that doing nothing was unacceptable and non-lethal control acceptable in all 5 scenarios, with generally high consensus within and between groups. The lethal control method was more controversial and became increasingly more acceptable as the severity of scenarios was increased and between non-native and native species. Lethal control was unacceptable for the general public in all scenarios. Farmers accepted lethal methods in the corvids and starlings scenarios, were neutral in the coypus damage crops scenario, whereas they accepted lethal control when coypus transfer disease. Hunters' opinion was neutral in the corvids, starlings and coypus damage crops and starlings foul urban structures scenarios, but they accepted lethal methods in the coypus transfer disease scenario. Farmers-hunters considered lethal control acceptable in all 5 scenarios. Implications from this study could be used for designing a socio-ecological approach which incorporates wildlife management with public interests. The studied species have a wide distribution, therefore present findings might also prove useful elsewhere. Copyright © 2016 Elsevier B.V. All rights reserved.

Toxicologic study of carboxyatractyloside (active principle in cocklebur--Xanthium strumarium) in rats treated with enzyme inducers and inhibitors and glutathione precursor and depletor.

PubMed

Hatch, R C; Jain, A V; Weiss, R; Clark, J D

1982-01-01

Male rats (10 rats/group) were treated with phenobarbital (PB), phenylbutazone (PBZ), stanozolol (3 inducers of cytochrome P450-dependent enzymes), piperonyl butoxide (PBO; a P450 inhibitor), cobaltous chloride (CoCl2; an inhibitor of hemoprotein synthesis), 5,6-benzoflavone (BNF; an inducer of cytochrome P448 dependent enzymes), cysteine [CYS; a glutathione (GSH) precursor], or ethyl maleate (EM; a GSH depletor). The rats were then given a calculated LD50 dosage (13.5 mg/kg of body weight) of carboxyatractyloside (CAT) intraperitoneally. Clinical signs of toxicosis, duration of illness, lethality, gross lesions, and hepatic and renal histopathologic lesions were recorded. Seemingly, (i) CAT toxicosis has independent lethal and cytotoxic components (PBZ decreased lethality and cytotoxicity; CoCl2 decreased cytotoxicity but not lethality; BNF decreased duration of illness, and perhaps lethality, but not cytotoxicity); (ii) CAT cytotoxicity could be partly due to an active metabolite formed by de novo-synthesized, P450-/P448-independent hemoprotein (PBZ and CoCl2 had anticytotoxic effects, but PB, stanozolol, PBO, and BNF did not); (iii) CAT detoxification may occur partly through a hemoprotein-independent, PBZ-inducible enzyme, and partly through a P448-dependent (BNF-inducible) enzyme; and (iv) CAT detoxification apparently is not P450 or GSH-dependent because PB, stanozolol, and CYS had no beneficial effects, and PBO, CoCl2, and EM did not enhance toxicosis. Metabolism of CAT may have a role in its cytotoxic and lethal effects.

Stage-dependent teratogenic and lethal effects exerted by ultraviolet B radiation on Rhinella (Bufo) arenarum embryos.

PubMed

Castañaga, Luis A; Asorey, Cynthia M; Sandoval, María T; Pérez-Coll, Cristina S; Argibay, Teresa I; Herkovits, Jorge

2009-02-01

The adverse effects of ultraviolet B radiation from 547.2 to 30,096 J/m2 on morphogenesis, cell differentiation, and lethality of amphibian embryos at six developmental stages were evaluated from 24 up to 168 h postexposure. The ultraviolet B radiation lethal dose 10, 50, and 90 values were obtained for all developmental stages evaluated. The lethal dose 50 values, considered as the dose causing lethality in the 50% of the organisms exposed, in J/m2 at 168 h postexposure, ranged from 2,307 to 18,930; gill circulation and blastula were the most susceptible and resistant stages, respectively. Ultraviolet B radiation caused malformations in all developmental stages but was significantly more teratogenic at the gill circulation and complete operculum stages. Moreover, at the gill circulation stage, even the lowest dose (547.2 J/m2) resulted in malformations to 100% of embryos. The most common malformations were persistent yolk plug, bifid spine, reduced body size, delayed development, asymmetry, microcephaly and anencephaly, tail and body flexures toward the irradiated side, agenesia or partial gill development, abnormal pigment distribution, and hypermotility. The stage-dependent susceptibility to ultraviolet B radiation during amphibian embryogenesis could be explained in the framework of evoecotoxicology, considering ontogenic features as biomarkers of environmental signatures of living forms ancestors during the evolutionary process. The stage-dependent susceptibility to ultraviolet B radiation on Rhinella (Bufo) arenarum embryos for both lethal and teratogenic effects could contribute to a better understanding of the role of the increased ultraviolet B radiation on worldwide amphibian populations decline.

Characterization of conditionally expressed mutants affecting age-specific survival in inbred lines of Drosophila melanogaster: lethal conditions and temperature-sensitive periods.

PubMed Central

Vermeulen, C J; Bijlsma, R

2004-01-01

The specific genetic basis of inbreeding depression is poorly understood. To address this question, two conditionally expressed lethal effects that were found to cause line-specific life span reductions in two separate inbred lines of Drosophila melanogaster were characterized phenotypically and genetically in terms of whether the accelerated mortality effects are dominant or recessive. The mortality effect in one line (I4) is potentially a temperature-sensitive semilethal that expresses in adult males only and is partially dominant. The other line (I10) responds as one would expect for a recessive lethal. It requires a cold shock for expression and is cold sensitive. Flies exhibiting this lethal condition responded as pupae and freshly eclosed imagoes. The effect is recessive in both males and females. The expression of the lethal effects in both lines is highly dependent upon environmental conditions. These results will serve as a basis for more detailed and mechanistic genetic research on inbreeding depression and are relevant to sex- and environment-specific effects on life span observed in quantitative trait loci studies using inbred lines. PMID:15280238

Chronic Exposure of Corals to Fine Sediments: Lethal and Sub-Lethal Impacts

PubMed Central

Flores, Florita; Hoogenboom, Mia O.; Smith, Luke D.; Cooper, Timothy F.; Abrego, David; Negri, Andrew P.

2012-01-01

Understanding the sedimentation and turbidity thresholds for corals is critical in assessing the potential impacts of dredging projects in tropical marine systems. In this study, we exposed two species of coral sampled from offshore locations to six levels of total suspended solids (TSS) for 16 weeks in the laboratory, including a 4 week recovery period. Dose-response relationships were developed to quantify the lethal and sub-lethal thresholds of sedimentation and turbidity for the corals. The sediment treatments affected the horizontal foliaceous species (Montipora aequituberculata) more than the upright branching species (Acropora millepora). The lowest sediment treatments that caused full colony mortality were 30 mg l−1 TSS (25 mg cm−2 day−1) for M. aequituberculata and 100 mg l−1 TSS (83 mg cm−2 day−1) for A. millepora after 12 weeks. Coral mortality generally took longer than 4 weeks and was closely related to sediment accumulation on the surface of the corals. While measurements of damage to photosystem II in the symbionts and reductions in lipid content and growth indicated sub-lethal responses in surviving corals, the most reliable predictor of coral mortality in this experiment was long-term sediment accumulation on coral tissue. PMID:22662225

[Secondary metabolites, lethality and antimicrobial activity of extracts from three corals and three marine mollusks from Sucre, Venezuela].

PubMed

Ordaz, Gabriel; D'Armas, Haydelba; Yáñez, Dayanis; Hernández, Juan; Camacho, Angel

2010-06-01

The study of biochemical activity of extracts obtained from marine organisms is gaining interest as some have proved to have efficient health or industrial applications. To evaluate lethality and antimicrobial activities, some chemical tests were performed on crude extracts of the octocorals Eunicea sp., Muricea sp. and Pseudopterogorgia acerosa and the mollusks Pteria colymbus, Phyllonotus pomum and Chicoreus brevifrons, collected in Venezuelan waters. The presence of secondary metabolites like alkaloids, unsaturated sterols and pentacyclic triterpenes in all invertebrates, was evidenced. Additionally, sesquiterpenlactones, saponins, tannins, cyanogenic and cardiotonic glycosides were also detected in some octocoral extracts, suggesting that biosynthesis of these metabolites is typical in this group. From the lethality bioassays, all extracts resulted lethal to Artemia salina (LC50<1000 microg/ml) with an increased of lethal activity with exposition time. P. pomum extract showed the highest lethality rate (LC50=46.8 microg/ml). Compared to the octocorals, mollusks extracts displayed more activity and a greater action spectrum against different bacterial strains, whereas octocorals also inhibited some fungi strains growth. Staphylococcus aureus was the most susceptible to the antimicrobial power of the extracts (66.7%), whereas Pseudomonas aeruginosa, Candida albicans and Aspergillus niger were not affected. The antibiosis shown by marine organisms extracts indicates that some of their biosynthesized metabolites are physiologically active, and may have possible cytotoxic potential or as a source of antibiotic components.

Metastatic potential of tumor-initiating cells in solid tumors.

PubMed

Adhikari, Amit S; Agarwal, Neeraj; Iwakuma, Tomoo

2011-01-01

The lethality of cancer is mainly caused by its properties of metastasis, drug resistance, and subsequent recurrence. Understanding the mechanisms governing these properties and developing novel strategies to overcome them will greatly improve the survival of cancer patients. Recent findings suggest that tumors are comprised of heterogeneous cell populations, and only a small fraction of these are tumorigenic with the ability to self-renew and produce phenotypically diverse tumor cell populations. Cells in this fraction are called tumor-initiating cells (TICs) or cancer stem cells (CSCs). TICs have been identified from many types of cancer. They share several similarities with normal adult stem cells including sphere-forming ability, self-renewability, and expression of stem cell surface markers and transcription factors. TICs have also been proposed to be responsible for cancer metastasis, however, scarce evidence for their metastatic potential has been provided. In this review article, we have attempted to summarize the studies which have examined the metastatic potential of TICs in solid tumors.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

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

Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu; Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854; Velíšková, Jana, E-mail: jana_veliskova@nymc.edu

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the numbermore » of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death. ► Ketamine and MK-801 display biphasic actions on TMDT seizures. ► Diazepam stops convulsions, but ictal EEG events persist to cause lethality hrs later. ► Diazepam repeat dose or paired with ketamine/MK-801 may more effectively block TMDT.« less

Correlation between In Vitro Cytotoxicity and In Vivo Lethal Activity in Mice of Epsilon Toxin Mutants from Clostridium perfringens

PubMed Central

Dorca-Arévalo, Jonatan; Pauillac, Serge; Díaz-Hidalgo, Laura; Martín-Satué, Mireia; Popoff, Michel R.; Blasi, Juan

2014-01-01

Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB. PMID:25013927

Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens.

PubMed

Dorca-Arévalo, Jonatan; Pauillac, Serge; Díaz-Hidalgo, Laura; Martín-Satué, Mireia; Popoff, Michel R; Blasi, Juan

2014-01-01

Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB.

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

Kumar, Gyanendra; Swaminathan, Subramanyam

Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are also potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, andmore » these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.« less

Ceramide induced mitophagy and tumor suppression

PubMed Central

Dany, Mohammed; Ogretmen, Besim

2015-01-01

Sphingolipids are bioactive lipid effectors, which are involved in the regulation of various cellular signaling pathways. Sphingolipids play essential roles in controlling cell inflammation, proliferation, death, migration, senescence, metastasis and autophagy. Alterations in sphingolipid metabolism has been also implicated in many human cancers. Macroautophagy (referred to here as autophagy) is a form of nonselective sequestering of cytosolic materials by double membrane structures, autophagosomes, which can be either protective or lethal for cells. Ceramide, a central molecule of sphingolipid metabolism is involved in the regulation of autophagy at various levels, including the induction of lethal mitophagy, a selective autophagy process to target and eliminate damaged mitochondria. In this review, we focused on recent studies with regard to the regulation of autophagy, in particular lethal mitophagy, by ceramide, and aimed at providing discussion points for various context-dependent roles and mechanisms of action of ceramide in controlling mitophagy. PMID:25634657

Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals

PubMed Central

Bellinger, Andrew M.; Jafari, Mousa; Grant, Tyler M.; Zhang, Shiyi; Slater, Hannah C.; Wenger, Edward A.; Mo, Stacy; Lee, Young-Ah Lucy; Mazdiyasni, Hormoz; Kogan, Lawrence; Barman, Ross; Cleveland, Cody; Booth, Lucas; Bensel, Taylor; Minahan, Daniel; Hurowitz, Haley M.; Tai, Tammy; Daily, Johanna; Nikolic, Boris; Wood, Lowell; Eckhoff, Philip A.; Langer, Robert; Traverso, Giovanni

2017-01-01

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra–long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra–long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy. PMID:27856796

[High anion gap metabolic acidosis (pyroglutamic acidosis) induced by chronic acetaminophen use].

PubMed

Tchougang Nono, J; Mistretta, V; Noirot, I; Canivet, J L; Damas, P

2018-01-01

Acetaminophen is the most consumable analgesic in the world in the form of medical prescription or self-medication. It is one of the active ingredients most often involved in voluntary poisoning. Lethal dose of acetaminophen classically induces acute hepatic failure on hepatic necrosis. Chronic intake of sub-lethal doses (i.e. near recommended therapeutic doses) of acetaminophen in the presence of certain risk factors may be responsible for another much less recognized pathological manifestation: severe metabolic acidosis with an increased anion gap due to the accumulation of 5-oxoproline or pyroglutamic acid.

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

PubMed Central

Wynn, James Lawrence; Wilson, Chris S.; Hawiger, Jacek; Scumpia, Philip O.; Marshall, Andrew F.; Liu, Jin-Hua; Zharkikh, Irina; Wong, Hector R.; Lahni, Patrick; Benjamin, John T.; Plosa, Erin J.; Weitkamp, Jörn-Hendrik; Sherwood, Edward R.; Moldawer, Lyle L.; Ungaro, Ricardo; Baker, Henry V.; Lopez, M. Cecilia; McElroy, Steven J.; Colliou, Natacha; Mohamadzadeh, Mansour; Moore, Daniel Jensen

2016-01-01

Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18–null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G+ myeloid cells, and blocking IL-17A reduced IL-18–potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18–mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis. PMID:27114524

Manhattan transfer: lethal radiation, bone marrow transplantation, and the birth of stem cell biology, ca. 1942-1961.

PubMed

Kraft, Alison

2009-01-01

This study investigates how, in the late 1940s and 1950s, fears of nuclear accidents and nuclear warfare shaped postwar radiobiology. The new and intense forms of radiation generated by nuclear reactor technology, and which would be released in the event of a nuclear war, created concerns about a public-health hazard unprecedented in form and scale. Fears of inadvertent exposure to acute and potentially lethal radiation launched a search for anti-radiation therapies, out of which emerged the new technique of bone marrow transplantation (BMT). This study analyzes the use of BMT first as a research tool to explore the biological effects of ionizing radiation, and then as an adjunct to radiotherapy for the treatment of cancer. In highlighting how BMT became the province of different research and clinical constituencies, this study develops an understanding of the forces and contingencies that shaped its development. Exploring the emergence of BMT and the uses to which it was put, it reveals that BMT remained a technique in the making -- unstable and far from standardized, even as it became both a widely used research tool and rapidly made its way into the clinic. More broadly, it casts new light on one route through which the Manhattan Project influenced postwar radiobiology; it also affords new insights into one means by which radiobiology came to serve the interests of the Cold War state. In its focus on BMT this paper provides a new perspective on the evolving relationship between radiobiology and biomedicine in the postwar period.

Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells.

PubMed

Shikata, Yuki; Kiga, Masaki; Futamura, Yushi; Aono, Harumi; Inoue, Hiroyuki; Kawada, Manabu; Osada, Hiroyuki; Imoto, Masaya

2017-04-01

The wingless/int-1 (Wnt) signal transduction pathway plays a central role in cell proliferation, survival, differentiation and apoptosis. When β-catenin: a component of the Wnt pathway, is mutated into an active form, cell growth signaling is hyperactive and drives oncogenesis. As β-catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions. Therefore, we screened an in-house natural product library for compounds that exhibited synthetic lethality towards β-catenin mutations and isolated nonactin, an antibiotic mitochondrial uncoupler, as a hit compound. Nonactin, as well as other mitochondrial uncouplers, induced apoptosis selectively in β-catenin mutated tumor cells. Significant tumor regression was observed in the β-catenin mutant HCT 116 xenograft model, but not in the β-catenin wild type A375 xenograft model, in response to daily administration of nonactin in vivo. Furthermore, we found that expression of an active mutant form of β-catenin induced a decrease in the glycolysis rate. Taken together, our results demonstrate that tumor cells with mutated β-catenin depend on mitochondrial oxidative phosphorylation for survival. Therefore, they undergo apoptosis in response to mitochondrial dysfunction following the addition of mitochondrial uncouplers, such as nonactin. These results suggest that targeting mitochondria is a potential chemotherapeutic strategy for tumor cells that harbor β-catenin mutations. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

PubMed

Ebot, Ericka M; Gerke, Travis; Labbé, David P; Sinnott, Jennifer A; Zadra, Giorgia; Rider, Jennifer R; Tyekucheva, Svitlana; Wilson, Kathryn M; Kelly, Rachel S; Shui, Irene M; Loda, Massimo; Kantoff, Philip W; Finn, Stephen; Vander Heiden, Matthew G; Brown, Myles; Giovannucci, Edward L; Mucci, Lorelei A

2017-11-01

Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10 -4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. © 2017 American Cancer Society.

Acute Effect of Pore-Forming Clostridium perfringens ε-Toxin on Compound Action Potentials of Optic Nerve of Mouse.

PubMed

Cases, Mercè; Llobet, Artur; Terni, Beatrice; Gómez de Aranda, Inmaculada; Blanch, Marta; Doohan, Briain; Revill, Alexander; Brown, Angus M; Blasi, Juan; Solsona, Carles

2017-01-01

ε-Toxin is a pore forming toxin produced by Clostridium perfringens types B and D. It is synthesized as a less active prototoxin form that becomes fully active upon proteolytic activation. The toxin produces highly lethal enterotoxaemia in ruminants, has the ability to cross the blood-brain barrier (BBB) and specifically binds to myelinated fibers. We discovered that the toxin induced a release of ATP from isolated mice optic nerves, which are composed of myelinated fibers that are extended from the central nervous system. We also investigated the effect of the toxin on compound action potentials (CAPs) in isolated mice optic nerves. When nerves were stimulated at 100 Hz during 200 ms, the decrease of the amplitude and the area of the CAPs was attenuated in the presence of ε-toxin. The computational modelling of myelinated fibers of mouse optic nerve revealed that the experimental results can be mimicked by an increase of the conductance of myelin and agrees with the pore forming activity of the toxin which binds to myelin and could drill it by making pores. The intimate ultrastructure of myelin was not modified during the periods of time investigated. In summary, the acute action of the toxin produces a subtle functional impact on the propagation of the nerve action potential in myelinated fibers of the central nervous system with an eventual desynchronization of the information. These results may agree with the hypothesis that the toxin could be an environmental trigger of multiple sclerosis (MS).

Acute Effect of Pore-Forming Clostridium perfringens ε-Toxin on Compound Action Potentials of Optic Nerve of Mouse

PubMed Central

Terni, Beatrice; Gómez de Aranda, Inmaculada; Blanch, Marta; Brown, Angus M.

2017-01-01

ε-Toxin is a pore forming toxin produced by Clostridium perfringens types B and D. It is synthesized as a less active prototoxin form that becomes fully active upon proteolytic activation. The toxin produces highly lethal enterotoxaemia in ruminants, has the ability to cross the blood–brain barrier (BBB) and specifically binds to myelinated fibers. We discovered that the toxin induced a release of ATP from isolated mice optic nerves, which are composed of myelinated fibers that are extended from the central nervous system. We also investigated the effect of the toxin on compound action potentials (CAPs) in isolated mice optic nerves. When nerves were stimulated at 100 Hz during 200 ms, the decrease of the amplitude and the area of the CAPs was attenuated in the presence of ε-toxin. The computational modelling of myelinated fibers of mouse optic nerve revealed that the experimental results can be mimicked by an increase of the conductance of myelin and agrees with the pore forming activity of the toxin which binds to myelin and could drill it by making pores. The intimate ultrastructure of myelin was not modified during the periods of time investigated. In summary, the acute action of the toxin produces a subtle functional impact on the propagation of the nerve action potential in myelinated fibers of the central nervous system with an eventual desynchronization of the information. These results may agree with the hypothesis that the toxin could be an environmental trigger of multiple sclerosis (MS). PMID:28798954

Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity

PubMed Central

Satyamitra, Merriline; Kumar, Vidya P.; Biswas, Shukla; Cary, Lynnette; Dickson, Leonora; Venkataraman, Srinivasan; Ghosh, Sanchita P.

2017-01-01

Filgrastim (Neupogen®, granulocyte-colony stimulating factor) is among the few countermeasures recommended for management of patients in the event of lethal total-body irradiation. Despite the plethora of studies using filgrastim as a radiation countermeasure, relatively little is known about the optimal dose schedule of filgrastim to mitigate radiation lethality. We evaluated the efficacy of filgrastim in improving 30-day survival of CD2F1 mice irradiated with a lethal dose (LD70/30) in the AFRRI cobalt-60 facility. We tested different schedules of 1, 3, 5,10 or 16 once-daily injections of filgrastim initiated one day after irradiation. Time optimization studies with filgrastim treatment were also performed, beginning 6–48 h postirradiation. Maximum survival was observed with 3 daily doses of 0.17 mg/kg filgrastim. Survival efficacy of the 3-day treatment was compared against the conventional 16-day filgrastim treatment after irradiation in four mouse strains with varying radiation sensitivities: C3H/HeN, C57BL/6, B6C3F1 and CD2F1. Blood indices, bone marrow histopathology and colony forming unit assays were also evaluated. Filgrastim significantly increased 30-day survival (P < 0.001) with a 3-day treatment compared to 16-day treatment. Filgrastim did not prevent cytopenia nadirs, but facilitated faster recovery of white blood cells, neutrophils, red blood cells, platelets, lymphocytes and hematocrits in all four strains. Accelerated hematopoietic recovery was also reflected in faster bone marrow reconstitution and significant increase in hematopoietic progenitors (P < 0.001) in all four mouse strains. These data indicate that prompt and abbreviated filgrastim treatment has potential benefit for triage in the event of a radiological incident for treating acute hematopoietic syndrome. PMID:28362168

Intracellular ice and cell survival in cryo-exposed embryonic axes of recalcitrant seeds of Acer saccharinum: an ultrastructural study of factors affecting cell and ice structures

PubMed Central

Wesley-Smith, James; Berjak, Patricia; Pammenter, N. W.; Walters, Christina

2014-01-01

Background and Aims Cryopreservation is the only long-term conservation strategy available for germplasm of recalcitrant-seeded species. Efforts to cryopreserve this form of germplasm are hampered by potentially lethal intracellular freezing events; thus, it is important to understand the relationships among cryo-exposure techniques, water content, structure and survival. Methods Undried embryonic axes of Acer saccharinum and those rapidly dried to two different water contents were cooled at three rates and re-warmed at two rates. Ultrastructural observations were carried out on radicle and shoot tips prepared by freeze-fracture and freeze-substitution to assess immediate (i.e. pre-thaw) responses to cooling treatments. Survival of axes was assessed in vitro. Key Results Intracellular ice formation was not necessarily lethal. Embryo cells survived when crystal diameter was between 0·2 and 0·4 µm and fewer than 20 crystals were distributed per μm2 in the cytoplasm. Ice was not uniformly distributed within the cells. In fully hydrated axes cooled at an intermediate rate, the interiors of many organelles were apparently ice-free; this may have prevented the disruption of vital intracellular machinery. Intracytoplasmic ice formation did not apparently impact the integrity of the plasmalemma. The maximum number of ice crystals was far greater in shoot apices, which were more sensitive than radicles to cryo-exposure. Conclusions The findings challenge the accepted paradigm that intracellular ice formation is always lethal, as the results show that cells can survive intracellular ice if crystals are small and localized in the cytoplasm. Further understanding of the interactions among water content, cooling rate, cell structure and ice structure is required to optimize cryopreservation treatments without undue reliance on empirical approaches. PMID:24368198

The Hmr and Lhr Hybrid Incompatibility Genes Suppress a Broad Range of Heterochromatic Repeats

PubMed Central

Satyaki, P. R. V.; Cuykendall, Tawny N.; Wei, Kevin H-C.; Brideau, Nicholas J.; Kwak, Hojoong; Aruna, S.; Ferree, Patrick M.; Ji, Shuqing; Barbash, Daniel A.

2014-01-01

Hybrid incompatibilities (HIs) cause reproductive isolation between species and thus contribute to speciation. Several HI genes encode adaptively evolving proteins that localize to or interact with heterochromatin, suggesting that HIs may result from co-evolution with rapidly evolving heterochromatic DNA. Little is known, however, about the intraspecific function of these HI genes, the specific sequences they interact with, or the evolutionary forces that drive their divergence. The genes Hmr and Lhr genetically interact to cause hybrid lethality between Drosophila melanogaster and D. simulans, yet mutations in both genes are viable. Here, we report that Hmr and Lhr encode proteins that form a heterochromatic complex with Heterochromatin Protein 1 (HP1a). Using RNA-Seq analyses we discovered that Hmr and Lhr are required to repress transcripts from satellite DNAs and many families of transposable elements (TEs). By comparing Hmr and Lhr function between D. melanogaster and D. simulans we identify several satellite DNAs and TEs that are differentially regulated between the species. Hmr and Lhr mutations also cause massive overexpression of telomeric TEs and significant telomere lengthening. Hmr and Lhr therefore regulate three types of heterochromatic sequences that are responsible for the significant differences in genome size and structure between D. melanogaster and D. simulans and have high potential to cause genetic conflicts with host fitness. We further find that many TEs are overexpressed in hybrids but that those specifically mis-expressed in lethal hybrids do not closely correlate with Hmr function. Our results therefore argue that adaptive divergence of heterochromatin proteins in response to repetitive DNAs is an important underlying force driving the evolution of hybrid incompatibility genes, but that hybrid lethality likely results from novel epistatic genetic interactions that are distinct to the hybrid background. PMID:24651406

Intracellular ice and cell survival in cryo-exposed embryonic axes of recalcitrant seeds of Acer saccharinum: an ultrastructural study of factors affecting cell and ice structures.

PubMed

Wesley-Smith, James; Berjak, Patricia; Pammenter, N W; Walters, Christina

2014-03-01

Cryopreservation is the only long-term conservation strategy available for germplasm of recalcitrant-seeded species. Efforts to cryopreserve this form of germplasm are hampered by potentially lethal intracellular freezing events; thus, it is important to understand the relationships among cryo-exposure techniques, water content, structure and survival. Undried embryonic axes of Acer saccharinum and those rapidly dried to two different water contents were cooled at three rates and re-warmed at two rates. Ultrastructural observations were carried out on radicle and shoot tips prepared by freeze-fracture and freeze-substitution to assess immediate (i.e. pre-thaw) responses to cooling treatments. Survival of axes was assessed in vitro. Intracellular ice formation was not necessarily lethal. Embryo cells survived when crystal diameter was between 0·2 and 0·4 µm and fewer than 20 crystals were distributed per μm(2) in the cytoplasm. Ice was not uniformly distributed within the cells. In fully hydrated axes cooled at an intermediate rate, the interiors of many organelles were apparently ice-free; this may have prevented the disruption of vital intracellular machinery. Intracytoplasmic ice formation did not apparently impact the integrity of the plasmalemma. The maximum number of ice crystals was far greater in shoot apices, which were more sensitive than radicles to cryo-exposure. The findings challenge the accepted paradigm that intracellular ice formation is always lethal, as the results show that cells can survive intracellular ice if crystals are small and localized in the cytoplasm. Further understanding of the interactions among water content, cooling rate, cell structure and ice structure is required to optimize cryopreservation treatments without undue reliance on empirical approaches.

Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.

PubMed

Zhang, Donghui; Li, Yifei; Heims-Waldron, Danielle; Bezzerides, Vassilios; Guatimosim, Silvia; Guo, Yuxuan; Gu, Fei; Zhou, Pingzhu; Lin, Zhiqiang; Ma, Qing; Liu, Jianming; Wang, Da-Zhi; Pu, William T

2018-01-05

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction. © 2017 American Heart Association, Inc.

Activation analyses of authenticated hairs of Napoleon Bonaparte confirm arsenic poisoning.

PubMed

Weider, B; Fournier, J H

1999-12-01

In 1960, activation analyses at the Harwell Nuclear Research Laboratory of the University of Glascow, London of authenticated hairs of Napoleon Bonaparte taken immediately after his death confirmed Napoleon's chronic arsenic poisoning on the island of St. Helena. Timeline correlation of his clinical symptomatology of the preceding 4 months, as reported in the written diaries of his exiled companions, further supports the effect of fluctuating, elevated toxic levels of arsenic on his health. Independent analyses of authenticated hairs of Napoleon by the Toxicology Crime Laboratory of the United States Federal Bureau of Investigation in 1995 reveals toxic levels of arsenic. The successful assassination of Napoleon included both a cosmetic and lethal phase. The cosmetic phase consisted of arsenic poisoning over time to weaken Napoleon, making the associated debility appear to be a natural illness and thus allay any suspicions prior to instituting the lethal phase. On May 3, 1821, at 5:30 P.M., the lethal phase was carried out. Napoleon was given Calomel (HgCl), a cathartic, and a popular orange-flavored drink called orgeat, which was flavored with the oil of bitter almonds. Together they formed mercury cyanide, which is lethal. Napoleon lost consciousness and died two days later.

A Single Dose of Modified Vaccinia Ankara expressing Ebola Virus Like Particles Protects Nonhuman Primates from Lethal Ebola Virus Challenge.

PubMed

Domi, Arban; Feldmann, Friederike; Basu, Rahul; McCurley, Nathanael; Shifflett, Kyle; Emanuel, Jackson; Hellerstein, Michael S; Guirakhoo, Farshad; Orlandi, Chiara; Flinko, Robin; Lewis, George K; Hanley, Patrick W; Feldmann, Heinz; Robinson, Harriet L; Marzi, Andrea

2018-01-16

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013-2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.

Radiosensitizing effects of neem (Azadirachta indica) oil.

PubMed

Kumar, Ashok; Rao, A R; Kimura, H

2002-02-01

Radiosensitization by neem oil was studied using Balbc/3T3 cells and SCID cells. Neem oil enhanced the radiosensitivity of the cells when applied both during and after x-irradiation under aerobic conditions. Neem oil completely inhibited the repair of sublethal damage and potentially lethal damage repair in Balbc/3T3 cells. The cytofluorimeter data show that neem oil treatment before and after x-irradiation reduced the G(2) + M phase, thus inhibiting the expression of the radiation induced arrest of cells in the G(2) phase of the cell cycle. However, SCIK cells (derived from the SCID mouse), deficient in DSB repair, treated with neem oil did not show any enhancement in the radiosensitivity. There was no effect of neem oil on SLD repair or its inhibition in SCIK cells. These results suggest that neem oil enhanced the radiosensitivity of cells by interacting with residual damage after x-irradiation, thereby converting the sublethal damage or potentially lethal damage into lethal damage, inhibiting the double-strand break repair or reducing the G(2) phase of the cell cycle. Copyright 2002 John Wiley & Sons, Ltd.

Body burdens of heavy metals in Lake Michigan wetland turtles.

PubMed

Smith, Dayna L; Cooper, Matthew J; Kosiara, Jessica M; Lamberti, Gary A

2016-02-01

Tissue heavy metal concentrations in painted (Chrysemys picta) and snapping (Chelydra serpentina) turtles from Lake Michigan coastal wetlands were analyzed to determine (1) whether turtles accumulated heavy metals, (2) if tissue metal concentrations were related to environmental metal concentrations, and (3) the potential for non-lethal sampling techniques to be used for monitoring heavy metal body burdens in freshwater turtles. Muscle, liver, shell, and claw samples were collected from painted and snapping turtles and analyzed for cadmium, chromium, copper, iron, lead, magnesium, manganese, and zinc. Turtle tissues had measurable quantities of all eight metals analyzed. Statistically significant correlations between tissue metal concentrations and sediment metal concentrations were found for a subset of metals. Metals were generally found in higher concentrations in the larger snapping turtles than in painted turtles. In addition, non-lethal samples of shell and claw were found to be possible alternatives to lethal liver and muscle samples for some metals. Human consumption of snapping turtles presents potential health risks if turtles are harvested from contaminated areas. Overall, our results suggest that turtles could be a valuable component of contaminant monitoring programs for wetland ecosystems.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom.

PubMed

Soni, Pranay; Bodakhe, Surendra H

2014-05-01

To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents.

Species Origin of Genomic Factors in Nicotiana nudicaulis Watson Controlling Hybrid Lethality in Interspecific Hybrids between N. nudicaulis Watson and N. tabacum L

PubMed Central

Liu, Hongshuo; Marubashi, Wataru

2014-01-01

Hybrid lethality is expressed at 28°C in the cross Nicotiana nudicaulis×N. tabacum. The S subgenome of N. tabacum has been identified as controlling this hybrid lethality. To clarify the responsible genomic factor(s) of N. nudicaulis, we crossed N. trigonophylla (paternal progenitor of N. nudicaulis) with N. tabacum, because hybrids between N. sylvestris (maternal progenitor of N. nudicaulis) and N. tabacum are viable when grown in a greenhouse. In the cross N. trigonophylla×N. tabacum, approximately 50% of hybrids were vitrified, 20% were viable, and 20% were nonviable at 28°C. To reveal which subgenome of N. tabacum was responsible for these phenotypes, we crossed N. trigonophylla with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT). In the cross N. sylvestris×N. trigonophylla, we confirmed that over half of hybrids of N. sylvestris×N. trigonophylla were vitrified, and none of the hybrids of N. trigonophylla×N. tomentosiformis were. The results imply that the S subgenome, encoding a gene or genes inducing hybrid lethality in the cross between N. nudicaulis and N. tabacum, has one or more genomic factors that induce vitrification. Furthermore, in vitrified hybrids of N. trigonophylla×N. tabacum and N. sylvestris×N. trigonophylla, we found that nuclear fragmentation, which progresses during expression of hybrid lethality, was accompanied by vitrification. This observation suggests that vitrification has a relationship to hybrid lethality. Based on these results, we speculate that when N. nudicaulis was formed approximately 5 million years ago, several causative genomic factors determining phenotypes of hybrid seedlings were inherited from N. trigonophylla. Subsequently, genome downsizing and various recombination-based processes took place. Some of the causative genomic factors were lost and some became genomic factor(s) controlling hybrid lethality in extant N. nudicaulis. PMID:24806486

Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer.

PubMed

Zhao, Na; Cao, Jin; Xu, Longyong; Tang, Qianzi; Dobrolecki, Lacey E; Lv, Xiangdong; Talukdar, Manisha; Lu, Yang; Wang, Xiaoran; Hu, Dorothy Z; Shi, Qing; Xiang, Yu; Wang, Yunfei; Liu, Xia; Bu, Wen; Jiang, Yi; Li, Mingzhou; Gong, Yingyun; Sun, Zheng; Ying, Haoqiang; Yuan, Bo; Lin, Xia; Feng, Xin-Hua; Hartig, Sean M; Li, Feng; Shen, Haifa; Chen, Yiwen; Han, Leng; Zeng, Qingping; Patterson, John B; Kaipparettu, Benny Abraham; Putluri, Nagireddy; Sicheri, Frank; Rosen, Jeffrey M; Lewis, Michael T; Chen, Xi

2018-04-02

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Baicalin Inhibits the Lethality of Ricin in Mice by Inducing Protein Oligomerization*

PubMed Central

Dong, Jing; Zhang, Yong; Chen, Yutao; Niu, Xiaodi; Zhang, Yu; Li, Rui; Yang, Cheng; Wang, Quan; Li, Xuemei; Deng, Xuming

2015-01-01

Toxic ribosome-inactivating proteins abolish cell viability by inhibiting protein synthesis. Ricin, a member of these lethal proteins, is a potential bioterrorism agent. Despite the grave challenge posed by these toxins to public health, post-exposure treatment for intoxication caused by these agents currently is unavailable. In this study, we report the identification of baicalin extracted from Chinese herbal medicine as a compound capable of inhibiting the activity of ricin. More importantly, post-exposure treatment with baicalin significantly increased the survival of mice poisoned by ricin. We determined the mechanism of action of baicalin by solving the crystal structure of its complex with the A chain of ricin (RTA) at 2.2 Å resolution, which revealed that baicalin interacts with two RTA molecules at a novel binding site by hydrogen bond networks and electrostatic force interactions, suggesting its role as molecular glue of the RTA. Further biochemical and biophysical analyses validated the amino acids directly involved in binding the inhibitor, which is consistent with the hypothesis that baicalin exerts its inhibitory effects by inducing RTA to form oligomers in solution, a mechanism that is distinctly different from previously reported inhibitors. This work offers promising leads for the development of therapeutics against ricin and probably other ribosome-inactivating proteins. PMID:25847243

Effects of particle size and coating on nanoscale Ag and TiO₂ exposure in zebrafish (Danio rerio) embryos.

PubMed

Osborne, Olivia J; Johnston, Blair D; Moger, Julian; Balousha, Mohammed; Lead, Jamie R; Kudoh, Tetsuhiro; Tyler, Charles R

2013-12-01

Manufactured metal (oxide) nanoparticles are entering the aquatic environment with little understanding on their potential health impacts for exposed organisms. Adopting an integrative approach, we investigated effects of particle size and coating on biological responses for two of the most commonly used metal (oxide) nanoscale particles, silver (Ag) and titanium dioxide (TiO₂) in zebrafish embryos. Titanium dioxide nanoparticles (nominally, 4 nm, 10 nm, 30 nm and 134 nm) had little or no toxicity on the endpoints measured. Ag both in nano form (10 nm and 35 nm) and its larger counterpart (600-1600 nm) induced dose-dependent lethality and morphological defects, occurring predominantly during gastrula stage. Of the silver material tested 10 nm nanoparticles appeared to be the most toxic. Coating Ag nanoparticles with citrate or fulvic acid decreased toxicity significantly. In situ hybridisation analysis identified the yolk syncytial layer (YSL) as a target tissue for Ag-nano toxicity where there was a significant induction of the heavy metal stress response gene, metallothionein 2 (Mt2) at sub-lethal exposures. Coherent Anti-stroke Raman Scattering (CARS) microscopy provided no evidence for silver particles crossing the chorionic membrane in exposed embryos. Collectively, our data suggest that silver ions play a major role in the toxicity of Ag nanoparticles.

Characterization of potential driver mutations involved in human breast cancer by computational approaches

PubMed Central

Rajendran, Barani Kumar; Deng, Chu-Xia

2017-01-01

Breast cancer is the second most frequently occurring form of cancer and is also the second most lethal cancer in women worldwide. A genetic mutation is one of the key factors that alter multiple cellular regulatory pathways and drive breast cancer initiation and progression yet nature of these cancer drivers remains elusive. In this article, we have reviewed various computational perspectives and algorithms for exploring breast cancer driver mutation genes. Using both frequency based and mutational exclusivity based approaches, we identified 195 driver genes and shortlisted 63 of them as candidate drivers for breast cancer using various computational approaches. Finally, we conducted network and pathway analysis to explore their functions in breast tumorigenesis including tumor initiation, progression, and metastasis. PMID:28477017

Anthrax Pathogenesis.

PubMed

Moayeri, Mahtab; Leppla, Stephen H; Vrentas, Catherine; Pomerantsev, Andrei P; Liu, Shihui

2015-01-01

Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

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

PubMed

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

2009-01-01

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

50th Annual Fuze Conference Session 5

DTIC Science & Technology

2006-05-11

level •Underwater Shock NDIA Fuze Conf 2006 5 Warhead Lethality MOFN has two potential warheads EX 183 HE-MOFN •MK 64 PROJECTILE BODY • PBXN - 106 ...EXPLOSIVE FILL EX 184 HE-MOFN •HIFRAG PROJECTILE BODY • PBXN - 106 EXPLOSIVE FILL Warhead lethality effect is fragmentation NDIA Fuze Conf 2006 6 Warhead...NDIA Fuze Conf 2006 19 Min Engagement Hazard • Worst Case Operational Configuration: – Projectile = EX 184 HE-MOFN • MK 64 Projectile w PBXN - 106 fill

'Munchausen syndrome by proxy' presenting as battered child syndrome: a report of two cases.

PubMed

Sugandhan, Selvendran; Gupta, Somesh; Khandpur, Sujay; Khanna, Neena; Mehta, Manju; Inna, Prashanth

2010-06-01

Child abuse is a major public health crisis and is on the rise. Dermatologists are frequently involved in its evaluation in differentiating abusive injuries from accidental injuries and in excluding pathological conditions that may mimic abuse. Battered child syndrome or physical abuse is not only a common form of child abuse but can also result from a rarer form of child abuse known as Munchausen syndrome by proxy. In this form of abuse, mother, who is the usual perpetrator, induces an illness or abuses the child for her own self-serving psychological needs. We report two cases of battered child syndrome. In both the cases, Psychiatric evaluation was performed on both parents. Observation through one-way mirror was done with the mother and the child alone. Routine hematological and biochemical investigations were done. Diagnosis of Munchausen syndrome by proxy was firmly established in one case and was considered as a possibility in the other. A multidisciplinary team effort is essential in evaluating such cases, and dermatologists should be aware and be well informed about this condition that can be potentially lethal but easily overlooked.

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.

Toxicity of sediments from a mangrove forest patch in an urban area in Pernambuco (Brazil).

PubMed

Oliveira, D D; Souza-Santos, L P; Silva, H K P; Macedo, S J

2014-06-01

Industrial and urban residues are discharged every day to the rivers and may arrive at the mangrove forest and prejudice the quality of the environment and the organisms present there. The mangrove forest patch studied is encircled by an urban area of the city of Recife (Brazil) that has approximate 1.5 million inhabitants and is one of the most industrialized centers in Northeast Brazil. The aim of this study was to assess the quality of the sediments of this mangrove patch in terms of metal contamination and ecotoxicology. Samples of surface sediment were collected in six stations for toxicological tests and trace metal determination (Cr, Zn, Mn, Fe, Cu, Pb, Co and Ni), in July and August, 2006 (rainy season); and in January and February 2007 (dry season). Toxicity tests with solid-phase sediments were carried out with the copepod Tisbe biminiensis in order to observe lethal and sub-lethal endpoints and correlate them with chemical data. In June, there were no observed lethal effect, but two stations presented sub-lethal effects. In January, lethal effect occurred in three stations and sub-lethal in one station. The levels for Zn and Cr were at higher levels than international proposed guidelines (NOAA). There was a negative significant correlation between the copepods׳ fecundity, and Zn and Cr concentrations. Therefore, the studied sediments can be considered to have potential toxic to benthos due to the high content of Zn and Cr. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats

PubMed Central

Collins, Gregory T.; Zaks, Matthew E.; Cunningham, Alyssa R.; St. Clair, Carley; Nichols, Joseph; Narasimhan, Diwahar; Ko, Mei-Chuan; Sunahara, Roger K.; Woods, James H.

2011-01-01

Background A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine’s cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine’s cardiovascular, convulsant, and lethal effects in male and female rats. Methods Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. Results Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4 hrs, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. Conclusions Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity. PMID:21481548

Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells

PubMed Central

Molenaar, Jan J.; Ebus, Marli E.; Geerts, Dirk; Koster, Jan; Lamers, Fieke; Valentijn, Linda J.; Westerhout, Ellen M.; Versteeg, Rogier; Caron, Huib N.

2009-01-01

Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN amplification and over-expression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification, and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by 3 RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53, and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetically lethal relationship between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. PMID:19525400

Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study.

PubMed

Platz, Elizabeth A; Drake, Charles G; Wilson, Kathryn M; Sutcliffe, Siobhan; Kenfield, Stacey A; Mucci, Lorelei A; Stampfer, Meir J; Willett, Walter C; Camargo, Carlos A; Giovannucci, Edward

2015-08-15

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-up Study. We included 47,880 men aged 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51-1.00) and fatal (RR = 0.64, 95% CI = 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92-1.33) and fatal (RR = 1.12, 95% CI = 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer. © 2015 UICC.

Altered cytoskeletal organization characterized lethal but not surviving Brtl+/− mice: insight on phenotypic variability in osteogenesis imperfecta

PubMed Central

Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella

2015-01-01

Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579

Lethal Injection for Execution: Chemical Asphyxiation?

PubMed Central

Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

2007-01-01

Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

[Gunshot wounds caused by non-lethal ammunition on the porcine model post-mortem].

PubMed

Jabrocký, Peter; Pivko, Juraj; Vondráková, Mária; Tažký, Boris

2013-10-01

In this article we focus on the effects of so called non-lethal ammunition. We studied possible mechanism of firearm injury formation as a consequence of using firearm on the body, to present a more comprehensive material in wound ballistics. We pointed out possible actions of a projectile causes on human, respectively other animal organisms, as well as to a manner in which an injury is caused by rifles or shotguns using non-lethal ammunition with rubber projectiles. In the experiment, we have focused on macroscopic analysis of the tissue penetrated by a rubber projectile fired from a long firearm and pump-action shotgun while focusing on the anatomical-morphological analysis of entry wounds to determine the effectiveness respectively, the wounding potential of the projectile. The results of the experiment based on the macroscopic analysis of entry wounds, cavities and exit wounds, show that when a rubber projectile penetrates the body it causes loss of the tissue (i.e. the minus effect) and mechanical disruption of the tissue similar to lethal projectile. Based on the measures and ballistic computations we concluded that in specific cases, like for example in a close range hit, a penetration of vital organs can cause serious or even lethal injuries.

Sublethal Effects of Insecticide Exposure on Megacopta cribraria (Fabricius) Nymphs: Key Biological Traits and Acetylcholinesterase Activity.

PubMed

Miao, Jin; Reisig, Dominic D; Li, Guoping; Wu, Yuqing

2016-01-01

Megacopta cribraria F. (Hemiptera: Plataspidae), the kudzu bug, is an invasive insect pest of U.S. soybean. At present, insecticide application is the primary and most effective control option for M. cribraria In this study, the potential effects of sublethal and low-lethal concentrations (LC10 and LC40) of three common insecticides on key biological traits and acetylcholinesterase (AChE) activity of the treated nymphal stage of insect were assessed. The results show that the sublethal concentration of imidacloprid significantly reduced adult emergence rate of M. cribraria A low-lethal concentration of imidacloprid significantly increased nymphal development time, but significantly decreased adult emergence rate and adult longevity. Both sublethal and low-lethal concentrations of acephate caused an increase in nymphal development time and a reduction in adult emergence rate and adult longevity. Fecundity of females was significantly reduced only by exposure to low-lethal concentrations of acephate. Sublethal and low-lethal concentrations of bifenthrin increased nymphal development time, but significantly decreased adult emergence rate. In addition, we found that the AChE activity of M. cribraria was significantly increased only by LC40 imidacloprid, but strongly inhibited by acephate. © The Author 2016. Published by Oxford University Press on behalf of the Entomological Society of America.

An Ethical Governor for Constraining Lethal Action in an Autonomous System

DTIC Science & Technology

2009-01-01

property is prohibited from being attacked, including buildings dedicated to religion, art , science … Activity Active Logical Form TargetDiscriminated...attacked, including buildings dedicated to religion, art , science , charitable purposes, and historic monuments. Prohibition LOW Civilian

Weapons used in serious violence against a parent: retrospective comparative register study.

PubMed

Liettu, Anu; Säävälä, Hannu; Hakko, Helinä; Joukamaa, Matti; Räsänen, Pirkko

2012-08-01

Our aim was to compare the weapons used in lethal or potentially lethal violence against parents according to the age (adolescent vs. adult) of the offender and victim (mother vs. father) of the offence. All forensic psychiatric examination statements of male offenders who had offended violently against one of their parents during 1973-2004 in Finland (n=192) were reviewed retrospectively. Data on the weapons used by adolescent and adult offenders in relation to the sex of the victim, mental disorder, criminal responsibility and intelligence were gathered. In the whole sample, sharp-edged weapons were the most commonly used weapons. Firearms were more commonly used in offences against fathers (i.e. patricidal offences) than against mothers (i.e. matricidal offences). Adolescent offenders were more likely to use firearms than adult offenders in violent acts against a parent. Among personality-disordered subjects, patricidal offenders used firearms more commonly than did matricidal offenders. Homicidal matricidal offenders had higher full-scale and verbal IQ scores as compared to homicidal patricidal offenders. The matricidal offenders using firearms were shown to be more intelligent as measured by full-scale and verbal scale IQs than the patricidal offenders using firearms. Consistent with the physical strength hypothesis, firearms are used more often in lethal or potentially lethal violence against parents by adolescents than by adults in Finland. As firearms legislation in Finland is currently under reform the study findings suggest that restriction of gun availability may have an influence on intrafamilial homicides, particularly those committed by adolescents.

Point of no return: experimental determination of the lethal hydraulic threshold during drought for loblolly pine (Pinus taeda)

NASA Astrophysics Data System (ADS)

Hammond, W.; Yu, K.; Wilson, L. A.; Will, R.; Anderegg, W.; Adams, H. D.

2017-12-01

The strength of the terrestrial carbon sink—dominated by forests—remains one of the greatest uncertainties in climate change modelling. How forests will respond to increased variability in temperature and precipitation is poorly understood, and experimental study to better inform global vegetation models in this area is needed. Necessary for achieving­­­­ this goal is an understanding of how increased temperatures and drought will affect landscape level distributions of plant species. Quantifying physiological thresholds representing a point of no return from drought stress, including thresholds in hydraulic function, is critical to this end. Recent theoretical, observational, and modelling research has converged upon a threshold of 60 percent loss of hydraulic conductivity at mortality (PLClethal). However, direct experimental determination of lethal points in conductivity and cavitation during drought is lacking. We quantified thresholds in hydraulic function in Loblolly pine, Pinus taeda, a commercially important timber species. In a greenhouse experiment, we exposed saplings (n = 96 total) to drought and rewatered treatment groups at variable levels of increasing water stress determined by pre-selected targets in pre-dawn water potential. Treatments also included a watered control with no drought, and drought with no rewatering. We measured physiological responses to water stress, including hydraulic conductivity, native PLC, water potential, foliar color, canopy die-back, and dark-adapted chlorophyll fluorescence. Following the rewatering treatment, we observed saplings for at least two months to determine which survived and which died. Using these data we calculated lethal physiological thresholds in water potential, directly measured PLC, and PLC inferred from water potential using a hydraulic vulnerability curve. We found that PLClethal inferred from water potential agreed with the 60% threshold suggested by previous research. However, directly measured PLC supported a much higher threshold. Beyond PLClethal, some trees survived by basal and epicormic re-sprouting, despite complete top-kill of existing foliage. Additional empirical study of multiple species to represent functional groups is needed to provide lethal thresholds for models presently in development.

Lethal mutagenesis: targeting the mutator phenotype in cancer.

PubMed

Fox, Edward J; Loeb, Lawrence A

2010-10-01

The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers. Copyright © 2010 Elsevier Ltd. All rights reserved.

Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer

PubMed Central

Tuohy, Vincent K.; Jaini, Ritika; Johnson, Justin M.; Loya, Matthew G.; Wilk, Dennis; Downs-Kelly, Erinn; Mazumder, Suparna

2016-01-01

We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC. PMID:27322324

Molecular Epidemiology Investigation of Obesity and Lethal Prostate Cancer

DTIC Science & Technology

2017-01-01

Final PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for Public...as an official Department of the Army position, policy or decision unless so designated by other documentation. 2 REPORT DOCUMENTATION PAGE Form...S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION

Baseline blood Pb levels of black-necked stilts on the upper Texas coast

USGS Publications Warehouse

Riecke, Thomas V.; Conway, Warren C.; Haukos, David A.; Moon, Jena A.; Comer, Christopher E.

2015-01-01

There are no known biological requirements for lead (Pb), and elevated Pb levels in birds can cause a variety of sub-lethal effects and mortality. Historic and current levels of Pb in mottled ducks (Anas fulvigula) suggest that environmental sources of Pb remain available on the upper Texas coast. Because of potential risks of Pb exposure among coexisting marsh birds, black-necked stilt (Himantopus mexicanus) blood Pb concentrations were measured during the breeding season. Almost 80 % (n = 120) of 152 sampled stilts exceeded the background threshold (>20 μg/dL) for Pb exposure. However, blood Pb concentrations did not vary by age or gender, and toxic or potentially lethal concentrations were rare (<5 %). Consistent, low-level blood Pb concentrations of black-necked stilts in this study suggest the presence of readily bioavailable sources of Pb, although potential impacts on local stilt populations remain unclear.

The staphylococcal enterotoxin (SE) family: SEB and siblings.

PubMed

Krakauer, Teresa; Stiles, Bradley G

2013-11-15

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s.

The staphylococcal enterotoxin (SE) family

PubMed Central

Krakauer, Teresa; Stiles, Bradley G

2013-01-01

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s. PMID:23959032

Daboia russellii and Naja kaouthia venom neutralization by lupeol acetate isolated from the root extract of Indian sarsaparilla Hemidesmus indicus R.Br.

PubMed

Chatterjee, Ipshita; Chakravarty, A K; Gomes, A

2006-06-15

The present study reports the isolation and purification of lupeol acetate from the methanolic root extract of Indian medicinal plant Hemidesmus indicus (L.) R.Br. (family: Asclepiadaceae) which could neutralize venom induced action of Daboia russellii and Naja kaouthia on experimental animals. Lupeol acetate could significantly neutralize lethality, haemorrhage, defibrinogenation, edema, PLA(2) activity induced by Daboia russellii venom. It also neutralized Naja kaouthia venom induced lethality, cardiotoxicity, neurotoxicity and respiratory changes in experimental animals. Lupeol acetate potentiated the protection by snake venom antiserum action against Daboia russellii venom induced lethality in male albino mice. Venom induced changes in lipid peroxidation and super oxide dismutase activity was antagonized by lupeol acetate. Snake venom neutralization by lupeol acetate and its possible mechanism of action has been discussed.

Role of the protective antigen octamer in the molecular mechanism of anthrax lethal toxin stabilization in plasma

PubMed Central

Kintzer, Alexander F.; Sterling, Harry J.; Tang, Iok I.; Abdul-Gader, Ali; Miles, Andrew J.; Wallace, B. A.; Williams, Evan R.; Krantz, Bryan A.

2010-01-01

Anthrax is caused by strains of Bacillus anthracis that produce two key virulence factors, anthrax toxin (Atx) and a poly-γ-D-glutamic acid capsule. Atx is comprised of three-proteins: protective antigen (PA) and two enzymes, lethal factor (LF) and edema factor (EF). To disrupt cell function, these components must assemble into holotoxin complexes, which contain either a ring-shaped homooctameric or homoheptameric PA oligomer bound to multiple copies of either LF and/or EF, producing lethal toxin (LT), edema toxin, or mixtures thereof. Once a host cell endocytoses these complexes, PA converts into a membrane-inserted channel that translocates LF and EF into the cytosol. LT may assemble on host cell surfaces or extracellularly in plasma. We show that under physiological conditions in bovine plasma that LT complexes containing heptameric PA aggregate and inactivate more readily than LT complexes containing octameric PA. LT complexes containing octameric PA possess enhanced stability, channel forming activity, and macrophage cytotoxicity relative to those containing heptameric PA. Under physiological conditions, multiple biophysical probes reveal that heptameric PA can prematurely adopt the channel conformation, but octameric PA complexes remain in their soluble prechannel configuration allowing them to resist aggregation and inactivation. We conclude that PA may form an octameric oligomeric state as a means to produce a more stable and active LT complex that may circulate freely in the blood. PMID:20433851

Impact of non-constant concentration exposure on lethality of inhaled hydrogen cyanide.

PubMed

Sweeney, Lisa M; Sommerville, Douglas R; Channel, Stephen R

2014-03-01

The ten Berge model, also known as the toxic load model, is an empirical approach in hazard assessment modeling for estimating the relationship between the inhalation toxicity of a chemical and the exposure duration. The toxic load (TL) is normally expressed as a function of vapor concentration (C) and duration (t), with TL equaling C(n) × t being a typical form. Hypothetically, any combination of concentration and time that yields the same "toxic load" will give a constant biological response. These formulas have been developed and tested using controlled, constant concentration animal studies, but the validity of applying these assumptions to time-varying concentration profiles has not been tested. Experiments were designed to test the validity of the model under conditions of non-constant acute exposure. Male Sprague-Dawley rats inhaled constant or pulsed concentrations of hydrogen cyanide (HCN) generated in a nose-only exposure system for 5, 15, or 30 min. The observed lethality of HCN for the 11 different C versus t profiles was used to evaluate the ability of the model to adequately describe the lethality of HCN under the conditions of non-constant inhalation exposure. The model was found to be applicable under the tested conditions, with the exception of the median lethality of very brief, high concentration, discontinuous exposures.

Lethal effect of electric fields on isolated ventricular myocytes.

PubMed

de Oliveira, Pedro Xavier; Bassani, Rosana Almada; Bassani, José Wilson Magalhães

2008-11-01

Defibrillator-type shocks may cause electric and contractile dysfunction. In this study, we determined the relationship between probability of lethal injury and electric field intensity (E in isolated rat ventricular myocytes, with emphasis on field orientation and stimulus waveform. This relationship was sigmoidal with irreversible injury for E > 50 V/cm . During both threshold and lethal stimulation, cells were twofold more sensitive to the field when it was applied longitudinally (versus transversally) to the cell major axis. For a given E, the estimated maximum variation of transmembrane potential (Delta V(max)) was greater for longitudinal stimuli, which might account for the greater sensitivity to the field. Cell death, however, occurred at lower maximum Delta V(max) values for transversal shocks. This might be explained by a less steep spatial decay of transmembrane potential predicted for transversal stimulation, which would possibly result in occurrence of electroporation in a larger membrane area. For the same stimulus duration, cells were less sensitive to field-induced injury when shocks were biphasic (versus monophasic). Ours results indicate that, although significant myocyte death may occur in the E range expected during clinical defibrillation, biphasic shocks are less likely to produce irreversible cell injury.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom

PubMed Central

Soni, Pranay; Bodakhe, Surendra H.

2014-01-01

Objective To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Methods Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. Results At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. Conclusions It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents. PMID:25183127

Cover Image, Volume 176A, Number 3, March 2018.

PubMed

Tamai, Kei; Tada, Katsuhiko; Takeuchi, Akihito; Nakamura, Makoto; Marunaka, Hidenori; Washio, Yosuke; Tanaka, Hiroyuki; Miya, Fuyuki; Okamoto, Nobuhiko; Kageyama, Misao

2018-03-01

The cover image, by Kei Tamai et al., is based on the Clinical Report Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome, DOI: 10.1002/ajmg.a.38598. © 2018 Wiley Periodicals, Inc.

Genetics Home Reference: platyspondylic lethal skeletal dysplasia, Torrance type

MedlinePlus

... type of collagen in the body. Instead of forming collagen molecules, the abnormal COL2A1 protein builds up ... Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S. Identification of COL2A1 mutations in ...

[Münchausen syndrome by proxy].

PubMed

Berent, Dominika; Florkowski, Antoni; Gałecki, Piotr

2010-01-01

Münchausen syndrome by proxy (MSBP), is a psychiatric disorder, a particular form of child abuse. An impaired emotional relationship exists mainly between the mother and her child. According to the variety of victims' symptoms, all medicine doctors may deal with this syndrome in every day clinical practice. Still insufficient knowledge about the syndrome and its' rare consideration in the differential diagnosis result in only severe, potentially lethal cases recognition. For many years the rest remains a source of a long-term physical and mental injuries in victims. About 30 years from the first attempt to precisely point the signalling symptoms for a proper diagnosis, we present the current knowledge on epidemiology, aetiology, diagnostic criteria, advised management and psychological portrait of the mother with the syndrome and her child, the syndrome's victim.

Treatment for Radiation-Induced Pulmonary Late Effects: Spoiled for Choice or Looking in the Wrong Direction?

PubMed Central

Williams, Jacqueline P.; Johnston, Carl J.; Finkelstein, Jacob N.

2010-01-01

Due to the radiosensitivity of the lung, toxic endpoints, in the form of radiation pneumonitis and pulmonary fibrosis, are relatively frequent outcomes following radiation treatment of thoracic neoplasms. Because of the potential lethal nature of these normal tissue reactions, they not only lead to quality-of-life issues in survivors, but also are deemed dose-limiting and thereby compromise treatment. The mitigation and treatment of lung normal tissue late effects has therefore been the goal of many investigations; however, the complexity of both the organ itself and its response to injury has resulted in little success. Nonetheless, current technology allows us to propose likely targets that are either currently being researched or should be considered in future studies. PMID:20583979

Acute toxicity of 353-nonylphenol and its metabolites for zebrafish embryos.

PubMed

Kammann, Ulrike; Vobach, Michael; Wosniok, Werner; Schäffer, Andreas; Telscher, Andreas

2009-03-01

Nonylphenol (NP) can be detected in the aquatic environment all over the world. It is applied as a technical mixture of isomers of which 353-NP is the most relevant both in terms of abundance (about 20% of total mass) and endocrine potential. 353-NP is metabolised in sewage sludge. The aims of the present study were to determine and to compare the acute toxicity of t-NP, 353-NP and its metabolites as well as to discuss if the toxicity of 353-NP changes during degradation. 353-NP and two of its metabolites were synthesised. The zebrafish embryo test was performed according to standard protocols. Several lethal and non-lethal endpoints during embryonal development were reported. NOEL, LOEL and EC50 were calculated. All tested compounds caused lethal as well as non-lethal malformations during embryo development. 353-NP showed a higher toxicity (EC50 for lethal endpoints 6.7 mg/L) compared to its metabolites 4-(3.5-dimethyl-3-heptyl)-2-nitrophenol (EC50 13.3 mg/L) and 4-(3,5-dimethyl-3-heptyl)-2-bromophenol (EC50 27.1 mg/L). In surface water, concentrations of NP are far below the NOEC identified by the zebrafish embryo test. However, in soils and sewage sludge, concentrations may reach or even exceed these concentrations. Therefore, sludge-treated sites close to surface waters should be analysed for NP and its metabolites in order to detect an unduly high contamination due to runoff events. The results of the present study point out that the toxicity of 353-NP probably declines during metabolisation in water, sediment and soil, but does not vanish since the major metabolites exhibit a clear toxic potential for zebrafish embryos. Metabolites of environmental pollutants should be included in the ecotoxicological test strategy for a proper risk assessment.

Chloroquine derivatives block the translocation pores and inhibit cellular entry of Clostridium botulinum C2 toxin and Bacillus anthracis lethal toxin.

PubMed

Kreidler, Anna-Maria; Benz, Roland; Barth, Holger

2017-03-01

The pathogenic bacteria Clostridium botulinum and Bacillus anthracis produce the binary protein toxins C2 and lethal toxin (LT), respectively. These toxins consist of a binding/transport (B 7 ) component that delivers the separate enzyme (A) component into the cytosol of target cells where it modifies its specific substrate and causes cell death. The B 7 components of C2 toxin and LT, C2IIa and PA 63 , respectively, are ring-shaped heptamers that bind to their cellular receptors and form complexes with their A components C2I and lethal factor (LF), respectively. After receptor-mediated endocytosis of the toxin complexes, C2IIa and PA 63 insert into the membranes of acidified endosomes and form trans-membrane pores through which C2I and LF translocate across endosomal membranes into the cytosol. C2IIa and PA 63 also form channels in planar bilayer membranes, and we used this approach earlier to identify chloroquine as a potent blocker of C2IIa and PA 63 pores. Here, a series of chloroquine derivatives was investigated to identify more efficient toxin inhibitors with less toxic side effects. Chloroquine, primaquine, quinacrine, and fluphenazine blocked C2IIa and PA 63 pores in planar lipid bilayers and in membranes of living epithelial cells and macrophages, thereby preventing the pH-dependent membrane transport of the A components into the cytosol and protecting cells from intoxication with C2 toxin and LT. These potent inhibitors of toxin entry underline the central role of the translocation pores for cellular uptake of binary bacterial toxins and as relevant drug targets, and might be lead compounds for novel pharmacological strategies against severe enteric diseases and anthrax.

Molecular mechanisms of the cytotoxicity of human α-lactalbumin made lethal to tumor cells (HAMLET) and other protein-oleic acid complexes.

PubMed

Nakamura, Takashi; Aizawa, Tomoyasu; Kariya, Ryusho; Okada, Seiji; Demura, Makoto; Kawano, Keiichi; Makabe, Koki; Kuwajima, Kunihiro

2013-05-17

Although HAMLET (human α-lactalbumin made lethal to tumor cells), a complex formed by human α-lactalbumin and oleic acid, has a unique apoptotic activity for the selective killing of tumor cells, the molecular mechanisms of expression of the HAMLET activity are not well understood. Therefore, we studied the molecular properties of HAMLET and its goat counterpart, GAMLET (goat α-lactalbumin made lethal to tumor cells), by pulse field gradient NMR and 920-MHz two-dimensional NMR techniques. We also examined the expression of HAMLET-like activities of complexes between oleic acid and other proteins that form a stable molten globule state. We observed that both HAMLET and GAMLET at pH 7.5 were heterogeneous, composed of the native protein, the monomeric molten globule-like state, and the oligomeric species. At pH 2.0 and 50 °C, HAMLET and GAMLET appeared in the monomeric state, and we identified the oleic acid-binding site in the complexes by two-dimensional NMR. Rather surprisingly, the binding site thus identified was markedly different between HAMLET and GAMLET. Furthermore, canine milk lysozyme, apo-myoglobin, and β2-microglobulin all formed the HAMLET-like complex with the anti-tumor activity, when the protein was treated with oleic acid under conditions in which their molten globule states were stable. From these results, we conclude that the protein portion of HAMLET, GAMLET, and the other HAMLET-like protein-oleic acid complexes is not the origin of their cytotoxicity to tumor cells and that the protein portion of these complexes plays a role in the delivery of cytotoxic oleic acid molecules into tumor cells across the cell membrane.

Molecular Mechanisms of the Cytotoxicity of Human α-Lactalbumin Made Lethal to Tumor Cells (HAMLET) and Other Protein-Oleic Acid Complexes*

PubMed Central

Nakamura, Takashi; Aizawa, Tomoyasu; Kariya, Ryusho; Okada, Seiji; Demura, Makoto; Kawano, Keiichi; Makabe, Koki; Kuwajima, Kunihiro

2013-01-01

Although HAMLET (human α-lactalbumin made lethal to tumor cells), a complex formed by human α-lactalbumin and oleic acid, has a unique apoptotic activity for the selective killing of tumor cells, the molecular mechanisms of expression of the HAMLET activity are not well understood. Therefore, we studied the molecular properties of HAMLET and its goat counterpart, GAMLET (goat α-lactalbumin made lethal to tumor cells), by pulse field gradient NMR and 920-MHz two-dimensional NMR techniques. We also examined the expression of HAMLET-like activities of complexes between oleic acid and other proteins that form a stable molten globule state. We observed that both HAMLET and GAMLET at pH 7.5 were heterogeneous, composed of the native protein, the monomeric molten globule-like state, and the oligomeric species. At pH 2.0 and 50 °C, HAMLET and GAMLET appeared in the monomeric state, and we identified the oleic acid-binding site in the complexes by two-dimensional NMR. Rather surprisingly, the binding site thus identified was markedly different between HAMLET and GAMLET. Furthermore, canine milk lysozyme, apo-myoglobin, and β2-microglobulin all formed the HAMLET-like complex with the anti-tumor activity, when the protein was treated with oleic acid under conditions in which their molten globule states were stable. From these results, we conclude that the protein portion of HAMLET, GAMLET, and the other HAMLET-like protein-oleic acid complexes is not the origin of their cytotoxicity to tumor cells and that the protein portion of these complexes plays a role in the delivery of cytotoxic oleic acid molecules into tumor cells across the cell membrane. PMID:23580643

Biological Effects of Directed Energy

NASA Astrophysics Data System (ADS)

Dayton, Thomas; Beason, Charles; Hitt, M. K.; Rogers, Walter; Cook, Michael

2002-11-01

This Final Report summarizes the biological effects research conducted by Veridian Engineering personnel under contract F41624-96-C-9009 in support of the Air Force Research Laboratory's Radio Frequency Radiation Branch from April 1997 to April 2002. Biological effects research and consultation were provided in five major areas: Active Denial System (also known as Vehicle Mounted Active Denial System), radio frequency radiation (RFR) health and safety, non-lethal weapon biological effects research, the newly formed Joint Non-Lethal Weapons Human Effects Center of Excellence, and Biotechnology. The report is organized by research efforts within the major research areas, providing title, objective, a brief description, relevance to the AF or DoD, funding, and products.

Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins

DOE PAGES

Kumar, Gyanendra; Swaminathan, Subramanyam

2015-03-01

Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are also potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, andmore » these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.« less

A Case Report of Cannabis Induced Hemoptysis

PubMed Central

Hashmi, Hafiz Rizwan Talib; Duncalf, Richard; Khaja, Misbahuddin

2016-01-01

Abstract As the principal route of marijuana use is by inhalation, potential harmful consequences on pulmonary structure and function can be anticipated. Here, we present a case of hemoptysis attributed to smoking cannabis in a 38-year-old man. The patient experienced an episode of hemoptysis and shortness of breath immediately after smoking marijuana. Chest radiograph and computed tomography (CT) scans of the chest showed bilateral diffuse ground-glass opacities. A fiber optic bronchoscopy confirmed bilateral diffuse bleeding from respiratory tract. Additional evaluation of hemoptysis indicated no infection or immunological responses. Urine toxicology was positive for cannabis. Chronic marijuana smoking causes visible and microscopic injury to the larger airways responsible for symptoms or chronic bronchitis. We review the beneficial and deleterious effects of marijuana and describe a case of significant hemoptysis attributed to smoking marijuana. In addition to other respiratory complications of marijuana use, physicians should educate their patients about this potentially lethal effect of marijuana smoking in the form of hemoptysis. PMID:27043693

Semiautomated cell-free conversion of prion protein: applications for high-throughput screening of potential antiprion drugs.

PubMed

Breydo, Leonid; Bocharova, Olga V; Baskakov, Ilia V

2005-04-01

Transmissible spongiform encephalitis (TSE) is a lethal illness with no known treatment. Conversion of the cellular prion protein (PrP(C)) into the infectious isoform (PrP(Sc)) is believed to be the central event in the development of this disease. Recombinant PrP (rPrP) protein folded into the amyloid conformation was shown to cause the transmissible form of prion disease in transgenic mice and can be used as a surrogate model for PrP(Sc). Here, we introduced a semiautomated assay of in vitro conversion of rPrP protein to the amyloid conformation. We have examined the effect of known inhibitors of prion propagation on this conversion and found good correlation between their activity in this assay and that in other in vitro assays. We thus propose that the conversion of rPrP to the amyloid isoform can serve as a high-throughput screen for possible inhibitors of PrP(Sc) formation and potential anti-TSE drugs.

Recent developments with metalloprotease inhibitor class of drug candidates for botulinum neurotoxins.

PubMed

Kumar, Gyanendra; Swaminathan, Subramanyam

2015-01-01

Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, and these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.

Embryonic lethality is not sufficient to explain hourglass-like conservation of vertebrate embryos.

PubMed

Uchida, Yui; Uesaka, Masahiro; Yamamoto, Takayoshi; Takeda, Hiroyuki; Irie, Naoki

2018-01-01

Understanding the general trends in developmental changes during animal evolution, which are often associated with morphological diversification, has long been a central issue in evolutionary developmental biology. Recent comparative transcriptomic studies revealed that gene expression profiles of mid-embryonic period tend to be more evolutionarily conserved than those in earlier or later periods. While the hourglass-like divergence of developmental processes has been demonstrated in a variety of animal groups such as vertebrates, arthropods, and nematodes, the exact mechanism leading to this mid-embryonic conservation remains to be clarified. One possibility is that the mid-embryonic period (pharyngula period in vertebrates) is highly prone to embryonic lethality, and the resulting negative selections lead to evolutionary conservation of this phase. Here, we tested this "mid-embryonic lethality hypothesis" by measuring the rate of lethal phenotypes of three different species of vertebrate embryos subjected to two kinds of perturbations: transient perturbations and genetic mutations. By subjecting zebrafish ( Danio rerio ), African clawed frog ( Xenopus laevis ), and chicken ( Gallus gallus ) embryos to transient perturbations, namely heat shock and inhibitor treatments during three developmental periods [early (represented by blastula and gastrula), pharyngula, and late], we found that the early stages showed the highest rate of lethal phenotypes in all three species. This result was corroborated by perturbation with genetic mutations. By tracking the survival rate of wild-type embryos and embryos with genetic mutations induced by UV irradiation in zebrafish and African clawed frogs, we found that the highest decrease in survival rate was at the early stages particularly around gastrulation in both these species. In opposition to the "mid-embryonic lethality hypothesis," our results consistently showed that the stage with the highest lethality was not around the conserved pharyngula period, but rather around the early period in all the vertebrate species tested. These results suggest that negative selection by embryonic lethality could not explain hourglass-like conservation of animal embryos. This highlights the potential contribution of alternative mechanisms such as the diversifying effect of positive selections against earlier and later stages, and developmental constraints which lead to conservation of mid-embryonic stages.

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

PubMed

Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

2015-01-01

There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

Strategic Influence: A Framework to Counter Violent Extremist Ideology

DTIC Science & Technology

2013-03-01

a result, non-lethal counterterrorism activities have “developed in a haphazard fashion without unitary direction or meaningful substance.”9 This...the critical capability is the network of likeminded individuals, which in some cases have formed franchise groups to the extremist social movement

9 CFR 430.1 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... poultry product that is in a form that is edible without additional preparation to achieve food safety and... Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE REGULATORY... product safe for human consumption. Examples of lethality treatments are cooking or the application of an...

Severe craniocerebral trauma with sequelae caused by Flash-Ball® shot, a less-lethal weapon: Report of one case and review of the literature.

PubMed

Hiquet, Jean; Gromb-Monnoyeur, Sophie

2016-07-01

The use of Flash-Ball® as a non-lethal weapon by several special units within the police and police forces started in France in 1995. Little literature is available concerning injuries caused by Flash-Ball® shooting. However, we report the case of a healthy 34-year-old male victim of a Flash-Ball® shooting during a riot following a sports event. This young man presented serious craniocerebral injuries with a left temporal fracture, moderate cerebral oedema, fronto-temporal haemorrhagic contusion along with an extra-dural hematoma and subarachnoid hemorrhage requiring neurological and rehabilitation care for two months leaving important sequelae. Although the risk is obviously lower than with firearms, Flash-Ball® is nonetheless potentially lethal and may cause serious physical injuries, particularly after a shot to the head. © The Author(s) 2015.

A 3-D QSAR-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS

EPA Science Inventory

Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

Baicalin inhibits the lethality of ricin in mice by inducing protein oligomerization.

PubMed

Dong, Jing; Zhang, Yong; Chen, Yutao; Niu, Xiaodi; Zhang, Yu; Li, Rui; Yang, Cheng; Wang, Quan; Li, Xuemei; Deng, Xuming

2015-05-15

Toxic ribosome-inactivating proteins abolish cell viability by inhibiting protein synthesis. Ricin, a member of these lethal proteins, is a potential bioterrorism agent. Despite the grave challenge posed by these toxins to public health, post-exposure treatment for intoxication caused by these agents currently is unavailable. In this study, we report the identification of baicalin extracted from Chinese herbal medicine as a compound capable of inhibiting the activity of ricin. More importantly, post-exposure treatment with baicalin significantly increased the survival of mice poisoned by ricin. We determined the mechanism of action of baicalin by solving the crystal structure of its complex with the A chain of ricin (RTA) at 2.2 Å resolution, which revealed that baicalin interacts with two RTA molecules at a novel binding site by hydrogen bond networks and electrostatic force interactions, suggesting its role as molecular glue of the RTA. Further biochemical and biophysical analyses validated the amino acids directly involved in binding the inhibitor, which is consistent with the hypothesis that baicalin exerts its inhibitory effects by inducing RTA to form oligomers in solution, a mechanism that is distinctly different from previously reported inhibitors. This work offers promising leads for the development of therapeutics against ricin and probably other ribosome-inactivating proteins. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate specific antigen-era: incidence and survival

PubMed Central

Richman, Erin L.; Kenfield, Stacey A.; Stampfer, Meir J.; Giovannucci, Edward L.; Chan, June M.

2011-01-01

Red and processed meat may increase risk of advanced prostate cancer. Data on post-diagnostic diet and prostate cancer are sparse, but post-diagnostic intake of poultry with skin and eggs may increase risk of disease progression. Therefore, we prospectively examined total, unprocessed, and processed red meat, poultry, and eggs in relation to risk of lethal prostate cancer (e.g. men without cancer at baseline who developed distant organ metastases or died from prostate cancer during follow-up) among 27, 607 men followed from 1994–2008. We also performed a case-only survival analysis to examine post-diagnostic consumption of these foods and risk of lethal prostate cancer among the 3,127 men initially diagnosed with non-metastatic prostate cancer during follow-up. In the incidence analysis, we observed 199 events during 306,715 person-years. Men who consumed 2.5 or more eggs per week had an 81% increased risk of lethal prostate cancer compared to men who consumed less than 0.5 eggs per week (HR: 1.81; 95% confidence interval (CI): 1.13, 2.89; p-trend: 0.01). In the case-only survival analysis, we observed 123 events during 19,354 person-years. There were suggestive, but not statistically significant, positive associations between post-diagnostic poultry (HR ≥3.5 vs. <1.5 servings per week: 1.69; 95%CI: 0.96, 2.99; p-trend: 0.07) and post-diagnostic processed red meat (HR ≥3 vs. <0.5 servings per week: 1.45; 95%CI: 0.73, 2.87; p-trend: 0.08) and risk of progression of localized prostate cancer to lethal disease. In conclusion, consumption of eggs may increase risk of developing a lethal-form of prostate cancer among healthy men. PMID:21930800

The Genome of a Tortoise Herpesvirus (Testudinid Herpesvirus 3) Has a Novel Structure and Contains a Large Region That Is Not Required for Replication In Vitro or Virulence In Vivo

PubMed Central

Gandar, Frédéric; Wilkie, Gavin S.; Gatherer, Derek; Kerr, Karen; Marlier, Didier; Diez, Marianne; Marschang, Rachel E.; Mast, Jan; Dewals, Benjamin G.

2015-01-01

ABSTRACT Testudinid herpesvirus 3 (TeHV-3) is the causative agent of a lethal disease affecting several tortoise species. The threat that this virus poses to endangered animals is focusing efforts on characterizing its properties, in order to enable the development of prophylactic methods. We have sequenced the genomes of the two most studied TeHV-3 strains (1976 and 4295). TeHV-3 strain 1976 has a novel genome structure and is most closely related to a turtle herpesvirus, thus supporting its classification into genus Scutavirus, subfamily Alphaherpesvirinae, family Herpesviridae. The sequence of strain 1976 also revealed viral counterparts of cellular interleukin-10 and semaphorin, which have not been described previously in members of subfamily Alphaherpesvirinae. TeHV-3 strain 4295 is a mixture of three forms (m1, m2, and M), in which, in comparison to strain 1976, the genomes exhibit large, partially overlapping deletions of 12.5 to 22.4 kb. Viral subclones representing these forms were isolated by limiting dilution assays, and each replicated in cell culture comparably to strain 1976. With the goal of testing the potential of the three forms as attenuated vaccine candidates, strain 4295 was inoculated intranasally into Hermann's tortoises (Testudo hermanni). All inoculated subjects died, and PCR analyses demonstrated the ability of the m2 and M forms to spread and invade the brain. In contrast, the m1 form was detected in none of the organs tested, suggesting its potential as the basis of an attenuated vaccine candidate. Our findings represent a major step toward characterizing TeHV-3 and developing prophylactic methods against it. IMPORTANCE Testudinid herpesvirus 3 (TeHV-3) causes a lethal disease in tortoises, several species of which are endangered. We have characterized the viral genome and used this information to take steps toward developing an attenuated vaccine. We have sequenced the genomes of two strains (1976 and 4295), compared their growth in vitro, and investigated the pathogenesis of strain 4295, which consists of three deletion mutants. The major findings are that (i) TeHV-3 has a novel genome structure, (ii) its closest relative is a turtle herpesvirus, (iii) it contains interleukin-10 and semaphorin genes (the first time these have been reported in an alphaherpesvirus), (iv) a sizeable region of the genome is not required for viral replication in vitro or virulence in vivo, and (v) one of the components of strain 4295, which has a deletion of 22.4 kb, exhibits properties indicating that it may serve as the starting point for an attenuated vaccine. PMID:26339050

Pathology of carcinoma in situ of the urinary bladder and related lesions.

PubMed

Farrow, G M

1992-01-01

In the United States, nearly all cases of bladder cancer are of the transitional cell type, and epidemiological evidence indicates that among these, approximately 80% present initially as more or less well-differentiated, superficial papillary neoplasms with a tendency for multifocal or diffuse involvement of the urothelial surface and/or recurrent tumor episodes, but with limited potential for invasive growth or a lethal outcome. Bladder tumors with lethal potential generally begin as poorly differentiated, sessile growths that are usually invasive at first diagnosis. Carcinoma in situ is a change that must be elicited among intact surface cells before progressive proliferation results in a tumor mass. Evidence for such an association is both temporal and spatial. Since most transitional cell carcinomas begin as well-differentiated tumors, i.e., resembling normal urothelium, recognition of early neoplastic alteration before a papillary structure forms is unlikely and most of the evidence is spatial based upon urothelial changes adjacent to papillary tumors. The morphologic definition of carcinoma in situ is arbitrary and generally defined as a total replacement of the urothelial surface by cells which bear morphologic features of carcinoma, but which lack architectural alteration other than an increase in the number of cell layers, i.e., a flat lesion. The Union Internationále Contra Cancer/American Joint Committee on Cancer (UICC/AJCC) staging scheme for bladder cancer distinguishes non-invasive papillary growths as Ta and carcinoma in situ as Tis. Because detection of carcinoma in situ, either by cytology or biopsy, depends upon recognizable malignant morphologic characteristics, studies of the lesion tend to be limited to the higher grade or more anaplastic examples.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model

PubMed Central

Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; de Lourdes Mora-García, María

2015-01-01

Background Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. Material/Methods Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. Results We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (p<0.05). This effect is similar to that of Plerixafor, and cells transplanted into lethally irradiated mice can restore hematopoiesis at higher percentages than mononuclear cells mobilized by Plerixafor (40% vs. 20%, respectively). Further, a secondary transplant rescued a separate group of irradiated mice from death, proving definitive evidence of hematopoietic reconstitution after hematopoietic stem cells transplantation. Data are presented as mean ± standard deviation. To determine significant differences between the data, one-way ANOVA and the Tukey test were used. Conclusions Collectively these results show the utility of sodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings. PMID:26409928

Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model.

PubMed

Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; Mora-García, María de Lourdes

2015-09-25

BACKGROUND Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. MATERIAL AND METHODS Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. RESULTS We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (p<0.05). This effect is similar to that of Plerixafor, and cells transplanted into lethally irradiated mice can restore hematopoiesis at higher percentages than mononuclear cells mobilized by Plerixafor (40% vs. 20%, respectively). Further, a secondary transplant rescued a separate group of irradiated mice from death, proving definitive evidence of hematopoietic reconstitution after hematopoietic stem cells transplantation. Data are presented as mean ± standard deviation. To determine significant differences between the data, one-way ANOVA and the Tukey test were used. CONCLUSIONS Collectively these results show the utility of sodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings.

Are High-Lethality Suicide Attempters With Bipolar Disorder a Distinct Phenotype?

PubMed Central

Oquendo, Maria A.; Carballo, Juan Jose; Rajouria, Namita; Currier, Dianne; Tin, Adrienne; Merville, Jessica; Galfalvy, Hanga C.; Sher, Leo; Grunebaum, Michael F.; Burke, Ainsley K.; Mann, J. John

2013-01-01

Because Bipolar Disorder (BD) individuals making highly lethal suicide attempts have greater injury burden and risk for suicide, early identification is critical. BD patients were classified as high- or low-lethality attempters. High-lethality attempts required inpatient medical treatment. Mixed effects logistic regression models and permutation analyses examined correlations between lethality, number, and order of attempts. High-lethality attempters reported greater suicidal intent and more previous attempts. Multiple attempters showed no pattern of incremental lethality increase with subsequent attempts, but individuals with early high-lethality attempts more often made high-lethality attempts later. A subset of high-lethality attempters make only high-lethality attempts. However, presence of previous low-lethality attempts does not indicate that risk for more lethal, possibly successful, attempts is reduced. PMID:19590998

PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas

PubMed Central

Czyż, Małgorzata; Toma, Monika; Gajos-Michniewicz, Anna; Majchrzak, Kinga; Hoser, Grazyna; Szemraj, Janusz; Nieborowska-Skorska, Margaret; Cheng, Phil; Gritsyuk, Daniel; Levesque, Mitchell; Dummer, Reinhard; Sliwinski, Tomasz; Skorski, Tomasz

2016-01-01

Cancer including melanoma may be “addicted” to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug. PMID:27705909

Teratogenic and toxic effects of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (W.Curt.:Fr.) P. Karst. (higher Basidiomycetes), on zebrafish embryo as model.

PubMed

Dulay, Rich Milton R; Kalaw, Sofronio P; Reyes, Renato G; Alfonso, Noel F; Eguchi, Fumio

2012-01-01

This paper highlights the teratogenic and toxic effects of Ganoderma lucidum (Lingzhi or Reishi mushroom) extract on zebrafish embryos. Hatchability, malformations, and lethality rate of zebrafish embryos were assessed to provide valuable information regarding the potential teratogenic activity of G. lucidum. Hatching was completed 48 h post treatment application (hpta) at 1% or lower concentrations of extract and embryo water. The hatching rate of embryos treated with 5% or higher concentrations was significantly lower (p> 0.05) than the control. Tail malformation was the most marked morphological abnormality in embryos at 72 hpta, which was obviously caused by 1% extract (55.56% tail malformation) and was observed in all embryos exposed to 5% of extract. Growth retardation was evident in embryos exposed to 5%, 10%, and 20%. However, lethal effect of extract of G. lucidum was dependent on dose and time of exposure. Mortality rates of embryos treated with 5% (44.44%) or higher concentrations of the extract was significantly higher (p > 0.05) than that of the control embryos at 72 hpta. These results suggest that G. lucidum extract has lethal and sub-lethal effects on zebrafish embryos.

Executive functions and social cognition in highly lethal self-injuring patients with borderline personality disorder.

PubMed

Williams, Gregory E; Daros, Alexander R; Graves, Bryanna; McMain, Shelley F; Links, Paul S; Ruocco, Anthony C

2015-04-01

Risk for potentially lethal self-injurious behavior in borderline personality disorder (BPD) may be associated with deficits in neuropsychological functions and social cognition. In particular, individuals with BPD engaging in more medically damaging self-injurious behaviors may have more severe executive function deficits and altered emotion perception as compared to patients engaging in less lethal acts. In the current study, 58 patients with BPD reporting a lifetime history of self-injurious behavior were administered neuropsychological measures of response inhibition, planning and problem-solving,and tests of facial emotion recognition and discrimination. Patients who engaged in more medically lethal self-injurious behaviors reported engaging in impulsive behaviors more frequently and displayed neuropsychological deficits in problem-solving and response inhibition. They were also less accurate in recognizing happy facial expressions and in discerning subtle differences in emotional intensity in sad facial expressions. These findings suggest that patients with BPD that engage in more physically damaging self-injurious behaviors may have greater difficulties with behavioral control and employ less efficient problem-solving strategies. Problems in facial emotion recognition and discrimination may contribute to interpersonal difficulties in patients with BPD who self-injure. (c) 2015 APA, all rights reserved).

Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens

PubMed Central

Christodoulou, Eleni G.; Yang, Hai; Lademann, Franziska; Pilarsky, Christian; Beyer, Andreas; Schroeder, Michael

2017-01-01

Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA. Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines. Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs. PMID:28415695

Profound microcephaly, primordial dwarfism with developmental brain malformations: a new syndrome.

PubMed

Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Saleem, Sahar N; Ahmed, Mahmoud K H; Issa, Mahmoud; Effat, Laila K; Kayed, Hisham F; Zaki, Maha S; Gaber, Khaled R

2012-08-01

We describe two sibs with a lethal form of profound congenital microcephaly, intrauterine and postnatal growth retardation, subtle skeletal changes, and poorly developed brain. The sibs had striking absent cranial vault with sloping of the forehead, large beaked nose, relatively large ears, and mandibular micro-retrognathia. Brain magnetic resonance imaging (MRI) revealed extremely simplified gyral pattern, large interhemispheric cyst and agenesis of corpus callosum, abnormally shaped hippocampus, and proportionately affected cerebellum and brainstem. In addition, fundus examination showed foveal hypoplasia with optic nerve atrophy. No abnormalities of the internal organs were found. This profound form of microcephaly was identified at 17 weeks gestation by ultrasound and fetal brain MRI helped in characterizing the developmental brain malformations in the second sib. Molecular analysis excluded mutations in potentially related genes such as RNU4ATAC, SLC25A19, and ASPM. These clinical and imaging findings are unlike that of any recognized severe forms of microcephaly which is believed to be a new microcephalic primordial dwarfism (MPD) with developmental brain malformations with most probably autosomal recessive inheritance based on consanguinity and similarly affected male and female sibs. Copyright © 2012 Wiley Periodicals, Inc.

Studies on the pathogenesis and survival of different culture forms of Listeria monocytogenes to pulsed UV-light irradiation after exposure to mild-food processing stresses.

PubMed

Bradley, Derek; McNeil, Brian; Laffey, John G; Rowan, Neil J

2012-06-01

The effects of mild conventional food-processing conditions on Listeria monocytogenes survival to pulsed UV (PUV) irradiation and virulence-associated characteristics were investigated. Specifically, this study describes the inability of 10 strains representative of 3 different culture forms or morphotypes of L. monocytogenes to adapt to normally lethal levels of PUV-irradiation after exposure to sub-lethal concentrations of salt (7.5% (w/v) NaCl for 1 h), acid (pH 5.5 for 1 h), heating (48 °C for 1 h) or PUV (UV dose 0.08 μJ/cm(2)). Findings showed that the order of increasing sensitivity of L. monocytogenes of non-adapted and stressed morphotypes to low pH (pH 3.5 for 5 h, adjusted with lactic), high salt (17.5% w/v NaCl for 5 h), heating (60 °C for 1 h) and PUV-irradiation (100 pulses at 7.2 J and 12.8 J, equivalent to UV doses of 2.7 and 8.4 μJ/cm(2) respectively) was typical wild-type smooth (S/WT), atypical filamentous rough (FR) and atypical multiple-cell-chain (MCR) variants. Exposure of L. monocytogenes cells to sub-lethal acid, salt or heating conditions resulted in similar or increased susceptibility to PUV treatments. Only prior exposure to mild heat stressing significantly enhanced invasion of Caco-2 cells, whereas subjection of L. monocytogenes cells to combined sub-lethal salt, acid and heating conditions produced the greatest reduction in invasiveness. Implications of these findings are discussed. This constitutes the first study to show that pre-exposure to mild conventional food-processing stresses enhances sensitivity of different culture morphotypes of L. monocytogenes to PUV, which is growing in popularity as an alternative or complementary approach for decontamination in the food environment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Non-thermal plasma jet without electrical shock for biomedical applications

NASA Astrophysics Data System (ADS)

Baik, Ku Youn; Kang, Han Lim; Kim, Junseong; Park, Shin Young; Bang, Ji Yun; Uhm, Han S.; Choi, Eun Ha; Cho, Guangsup

2013-10-01

A plasma jet without an electrical shock was generated through a Y-shaped tube in which voltages with opposite phases were applied to a pair of tubes. The plasma plume generated at the intersection had a plasma potential of a 60-90 V and high concentrations of reactive species sufficient to induce a high level of lethality on gram-negative bacteria on a tissue mimic. The selective lethality of bacteria on an epithelial-cell-containing tissue mimic could be modulated using oxidant and antioxidant chemicals, thereby leading to the possibility of a shock-reduced plasma jet for biomedical applications.

A chimeric measles virus with canine distemper envelope protects ferrets from lethal distemper challenge.

PubMed

Rouxel, Ronan Nicolas; Svitek, Nicholas; von Messling, Veronika

2009-08-06

CDV infects a broad range of carnivores, and over the past decades it has caused outbreaks in a variety of wild carnivore populations. Since the currently available live-attenuated vaccine is not sufficiently safe in these highly susceptible species, we produced a chimeric virus combining the replication complex of the measles Moraten vaccine strain with the envelope of a recent CDV wild type isolate. The resulting virus did not cause disease or immunosuppression in ferrets and conferred protection from challenge with a lethal wild type strain, demonstrating its potential value for wildlife conservation efforts.

Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor

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

Maize, Kimberly M.; Kurbanov, Elbek K.; Johnson, Rodney L.

2016-07-05

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.

Viral single-strand DNA induces p53-dependent apoptosis in human embryonic stem cells.

PubMed

Hirsch, Matthew L; Fagan, B Matthew; Dumitru, Raluca; Bower, Jacquelyn J; Yadav, Swati; Porteus, Matthew H; Pevny, Larysa H; Samulski, R Jude

2011-01-01

Human embryonic stem cells (hESCs) are primed for rapid apoptosis following mild forms of genotoxic stress. A natural form of such cellular stress occurs in response to recombinant adeno-associated virus (rAAV) single-strand DNA genomes, which exploit the host DNA damage response for replication and genome persistence. Herein, we discovered a unique DNA damage response induced by rAAV transduction specific to pluripotent hESCs. Within hours following rAAV transduction, host DNA damage signaling was elicited as measured by increased gamma-H2AX, ser15-p53 phosphorylation, and subsequent p53-dependent transcriptional activation. Nucleotide incorporation assays demonstrated that rAAV transduced cells accumulated in early S-phase followed by the induction of apoptosis. This lethal signaling sequalae required p53 in a manner independent of transcriptional induction of Puma, Bax and Bcl-2 and was not evident in cells differentiated towards a neural lineage. Consistent with a lethal DNA damage response induced upon rAAV transduction of hESCs, empty AAV protein capsids demonstrated no toxicity. In contrast, DNA microinjections demonstrated that the minimal AAV origin of replication and, in particular, a 40 nucleotide G-rich tetrad repeat sequence, was sufficient for hESC apoptosis. Our data support a model in which rAAV transduction of hESCs induces a p53-dependent lethal response that is elicited by a telomeric sequence within the AAV origin of replication.

Sub-lethal activity of small molecules from natural sources and their synthetic derivatives against biofilm forming nosocomial pathogens.

PubMed

Villa, Federica; Villa, Stefania; Gelain, Arianna; Cappitelli, Francesca

2013-01-01

Nowadays, the patient safety is seriously jeopardized by the emergence and spread of nosocomial pathogens in the form of biofilm that is resistant to traditional and affordable antimicrobials. Although advances in organic synthesis have extended the lifetime of classic antibiotics through synthetic modifications, the search of innovative antibiofilm compounds from natural sources can provide new templates, novel targets and unique mechanisms that should have advantages over known antimicrobial agents. Testing sub-lethal concentrations of crude extracts and/or isolated compounds from plants and microorganisms is critical to acting on mechanisms subtler than the killing activity, e.g. those influencing the multicellular behavior, offering an elegant way to develop novel antimicrobial-free antibiofilm strategies. Herein we discussed the search and biological activity of small molecules from natural sources and their synthetic derivatives able to modulate biofilm genesis of nosocomial pathogens through non-microbicidal mechanisms (sub-lethal concentrations). The present work offers an overview about the approaches applied to the discovery of lead small molecules including a) conventional drug design methods like screening of chemical compounds obtained from nature and b) computer- aided drug design approaches. Finally, a classification (not exhaustive but representative) based on the natural origin of small molecules and their synthetic derivatives was reported. The information presented in this review should be of interest to a broad range of disciplines and represents an effort to summarize experimental research and advances in this field.

Lethality of Sortase Depletion in Actinomyces oris Caused by Excessive Membrane Accumulation of a Surface Glycoprotein

PubMed Central

Wu, Chenggang; Huang, I-Hsiu; Chang, Chungyu; Reardon-Robinson, Melissa Elizabeth; Das, Asis; Ton-That, Hung

2014-01-01

Sortase, a cysteine-transpeptidase conserved in Gram-positive bacteria, anchors on the cell wall many surface proteins that facilitate bacterial pathogenesis and fitness. Genetic disruption of the housekeeping sortase in several Gram-positive pathogens reported thus far attenuates virulence, but not bacterial growth. Paradoxically, we discovered that depletion of the housekeeping sortase SrtA was lethal for Actinomyces oris; yet, all of its predicted cell wall-anchored protein substrates (AcaA-N) were individually dispensable for cell viability. Using Tn5-transposon mutagenesis to identify factors that upend lethality of srtA deletion, we uncovered a set of genetic suppressors harboring transposon insertions within genes of a locus encoding AcaC and a LytR-CpsA-Psr (LCP)-like protein. AcaC was shown to be highly glycosylated and dependent on LCP for its glycosylation. Upon SrtA depletion, the glycosylated form of AcaC, hereby renamed GspA, was accumulated in the membrane. Overexpression of GspA in a mutant lacking gspA and srtA was lethal; conversely, cells overexpressing a GspA mutant missing a membrane-localization domain were viable. The results reveal a unique glycosylation pathway in A. oris that is coupled to cell wall anchoring catalyzed by sortase SrtA. Significantly, this novel phenomenon of glyco-stress provides convenient cell-based assays for developing a new class of inhibitors against Gram-positive pathogens. PMID:25230351

Extracts of Renealmia alpinia (Rottb.) MAAS Protect against Lethality and Systemic Hemorrhage Induced by Bothrops asper Venom: Insights from a Model with Extract Administration before Venom Injection

PubMed Central

Patiño, Arley Camilo; Quintana, Juan Carlos; Gutiérrez, José María; Rucavado, Alexandra; Benjumea, Dora María; Pereañez, Jaime Andrés

2015-01-01

Renealmia alpinia (Rottb.) MAAS, obtained by micropropagation (in vitro) and wild forms have previously been shown to inhibit some toxic activities of Bothrops asper snake venom if preincubated before injection. In this study, assays were performed in a murine model in which extracts were administered for three days before venom injection. R. alpinia extracts inhibited lethal activity of B. asper venom injected by intraperitoneal route. Median Effective Dose (ED50) values were 36.6 ± 3.2 mg/kg and 31.7 ± 5.4 mg/kg (p > 0.05) for R. alpinia wild and in vitro extracts, respectively. At a dose of 75 mg/kg, both extracts totally inhibited the lethal activity of the venom. Moreover, this dose prolonged survival time of mice receiving a lethal dose of venom by the intravenous route. At 75 mg/kg, both extracts of R. alpinia reduced the extent of venom-induced pulmonary hemorrhage by 48.0% (in vitro extract) and 34.7% (wild extract), in agreement with histological observations of lung tissue. R. alpinia extracts also inhibited hemorrhage in heart and kidneys, as evidenced by a decrease in mg of hemoglobin/g of organ. These results suggest the possibility of using R. alpinia as a prophylactic agent in snakebite, a hypothesis that needs to be further explored. PMID:25941768

Extracts of Renealmia alpinia (Rottb.) MAAS Protect against Lethality and Systemic Hemorrhage Induced by Bothrops asper Venom: Insights from a Model with Extract Administration before Venom Injection.

PubMed

Patiño, Arley Camilo; Quintana, Juan Carlos; Gutiérrez, José María; Rucavado, Alexandra; Benjumea, Dora María; Pereañez, Jaime Andrés

2015-04-30

Renealmia alpinia (Rottb.) MAAS, obtained by micropropagation (in vitro) and wild forms have previously been shown to inhibit some toxic activities of Bothrops asper snake venom if preincubated before injection. In this study, assays were performed in a murine model in which extracts were administered for three days before venom injection. R. alpinia extracts inhibited lethal activity of B. asper venom injected by intraperitoneal route. Median Effective Dose (ED50) values were 36.6 ± 3.2 mg/kg and 31.7 ± 5.4 mg/kg (p > 0.05) for R. alpinia wild and in vitro extracts, respectively. At a dose of 75 mg/kg, both extracts totally inhibited the lethal activity of the venom. Moreover, this dose prolonged survival time of mice receiving a lethal dose of venom by the intravenous route. At 75 mg/kg, both extracts of R. alpinia reduced the extent of venom-induced pulmonary hemorrhage by 48.0% (in vitro extract) and 34.7% (wild extract), in agreement with histological observations of lung tissue. R. alpinia extracts also inhibited hemorrhage in heart and kidneys, as evidenced by a decrease in mg of hemoglobin/g of organ. These results suggest the possibility of using R. alpinia as a prophylactic agent in snakebite, a hypothesis that needs to be further explored.

Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.

PubMed

Yamada, Yuko; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakagawa, Yasuaki; Kuwabara, Yoshihiro; Minami, Takeya; Yamada, Chinatsu; Shibata, Junko; Nakao, Kazuhiro; Cho, Kosai; Arai, Yuji; Yasuno, Shinji; Nishikimi, Toshio; Ueshima, Kenji; Kamakura, Shiro; Nishida, Motohiro; Kiyonaka, Shigeki; Mori, Yasuo; Kimura, Takeshi; Kangawa, Kenji; Nakao, Kazuwa

2014-10-01

Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice.

PubMed

Moayeri, Mahtab; Tremblay, Jacqueline M; Debatis, Michelle; Dmitriev, Igor P; Kashentseva, Elena A; Yeh, Anthony J; Cheung, Gordon Y C; Curiel, David T; Leppla, Stephen; Shoemaker, Charles B

2016-01-06

Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Targeted Silencing of Anthrax Toxin Receptors Protects against Anthrax Toxins*

PubMed Central

Arévalo, Maria T.; Navarro, Ashley; Arico, Chenoa D.; Li, Junwei; Alkhatib, Omar; Chen, Shan; Diaz-Arévalo, Diana; Zeng, Mingtao

2014-01-01

Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax. PMID:24742682

Drugging the Cancers Addicted to DNA Repair.

PubMed

Nickoloff, Jac A; Jones, Dennie; Lee, Suk-Hee; Williamson, Elizabeth A; Hromas, Robert

2017-11-01

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects. © The Author 2017. Published by Oxford University Press.

[Pancreatic pathology in black Africans (excluding diabetes)].

PubMed

Sankalé, M

1984-01-01

Number of cases of pancreatitis obviously increases in african Black not so much acute forms but mainly chronic calcifying forms of which ethylism represents the main etiology. As in cancers and pancreatic cysts, symptomatology shows no particular characteristic in Negroes. Moreover, because some deficiencies in the sanitary network, lethality remains at a high level. A special form, principally identified in Kerala and Java, is met in some african areas: the juvenile tropical pancreatitis syndrom, with diabetes as main symptom, of which no explanation can be given up to now.

Country made scare gun vs. air gun--a comparative study of terminal ballistics using gelatine blocks.

PubMed

Hallikeri, Vinay R; Gouda, Hareesh S; Kadagoudar, Shivanand A

2012-01-10

Country made scare gun also called as bandook in the vernacular language designed with an intention of scaring away the menacing animals is not only unique and effective but also potentially lethal and has found wide spread usage in the rural parts of India. Here an attempt has been made to study the characteristic features such as physical dimensions, mechanism of action of this weapon and to compare its penetrating ability with that of air gun, whose potential lethality is a well-documented fact, using the ballistic gelatine blocks at various ranges. It is hoped that keeping the existence of such firearms in mind by the forensic experts might help to solve the unexplained and bizarre firearm injuries encountered in day to day practice. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome.

PubMed

Guemez-Gamboa, Alicia; Nguyen, Long N; Yang, Hongbo; Zaki, Maha S; Kara, Majdi; Ben-Omran, Tawfeg; Akizu, Naiara; Rosti, Rasim Ozgur; Rosti, Basak; Scott, Eric; Schroth, Jana; Copeland, Brett; Vaux, Keith K; Cazenave-Gassiot, Amaury; Quek, Debra Q Y; Wong, Bernice H; Tan, Bryan C; Wenk, Markus R; Gunel, Murat; Gabriel, Stacey; Chi, Neil C; Silver, David L; Gleeson, Joseph G

2015-07-01

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

Susceptibility of Blastomyces dermatitidis strains to products of oxidative metabolism.

PubMed

Sugar, A M; Chahal, R S; Brummer, E; Stevens, D A

1983-09-01

Three strains of Blastomyces dermatitidis which differ in their virulence for mice were exposed in their yeast form to various components of the peroxidase-hydrogen peroxide-halide system. Susceptibility to H2O2 alone correlated with virulence, with the most virulent strain (ATCC 26199) least susceptible (50% lethal dose, greater than 50 mM) and an avirulent strain (ATCC 26197) most susceptible (50% lethal dose less than 3.3 mM). A strain of intermediate virulence (ATCC 26198) was of intermediate susceptibility (50% lethal dose, 11.5 mM). The addition of a nontoxic concentration of KI (5 X 10(-4) M) did not increase H2O2 toxicity. However, the addition of either myeloperoxidase or horseradish peroxidase and KI markedly decreased the amount of H2O2 required to kill the organisms, with 100 +/- 0% of all strains killed at 5 X 10(-5) M H2O2 and 97 +/- 4, 100 +/- 0, and 94 +/- 8% of ATCC 26199, ATCC 26198, and ATCC 26197 killed, respectively, at 5 X 10(-6) M H2O2. Kinetic studies with H2O2 alone revealed a delayed onset of killing, but virtually 100% of organisms were killed by 120 min of exposure in all strains. By comparison, the peroxidase-hydrogen peroxide-halide system was 100% lethal for all strains at 1 min. The relatively high concentrations of H2O2 required to kill the yeast phase of B. dermatitidis suggest that H2O2 alone does not account for host resistance to the organism. However, the rapidly lethal effect of the peroxidase-hydrogen peroxide-halide system at physiologically relevant concentrations suggests that this may be one mechanism of host defense to B. dermatitidis.

Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations.

PubMed

Nakano, A; Pulkkinen, L; Murrell, D; Rico, J; Lucky, A W; Garzon, M; Stevens, C A; Robertson, S; Pfendner, E; Uitto, J

2001-05-01

Epidermolysis bullosa with pyloric atresia (EB-PA: OMIM 226730), also known as Carmi syndrome, is a rare autosomal recessive genodermatosis that manifests with neonatal mucocutaneous fragility associated with congenital pyloric atresia. The disease is frequently lethal within the first year, but nonlethal cases have been reported. Mutations in the genes encoding subunit polypeptides of the alpha 6 beta 4 integrin (ITGA6 and ITGB4) have been demonstrated in EB-PA patients. To extend the repertoire of mutations and to identify genotype-phenotype correlations, we examined seven new EB-PA families, four with lethal and three with nonlethal disease variants. DNA from patients was screened for mutations using heteroduplex analysis followed by nucleotide sequencing of PCR products spanning all beta 4 integrin-coding sequences. Mutation analysis disclosed 12 distinct mutations, 11 of them novel. Four mutations predicted a premature termination codon as a result of nonsense mutations or small out-of-frame insertions or deletions, whereas seven were missense mutations. This brings the total number of distinct ITGB4 mutations to 33. The mutation database indicates that premature termination codons are associated predominantly with the lethal EB-PA variants, whereas missense mutations are more prevalent in nonlethal forms. However, the consequences of the missense mutations are position dependent, and substitutions of highly conserved amino acids may have lethal consequences. In general, indirect immunofluorescence studies of affected skin revealed negative staining for beta 4 integrin in lethal cases and positive, but attenuated, staining in nonlethal cases and correlated with clinical phenotype. The data on specific mutations in EB-PA patients allows prenatal testing and preimplantation genetic diagnosis in families at risk.

Analysis of Lethality and Malformations During Zebrafish (Danio rerio) Development.

PubMed

Raghunath, Azhwar; Perumal, Ekambaram

2018-01-01

The versatility offered by zebrafish (Danio rerio) makes it a powerful and an attractive vertebrate model in developmental toxicity and teratogenicity assays. Apart from the newly introduced chemicals as drugs, xenobiotics also induce abnormal developmental abnormalities and congenital malformations in living organisms. Over the recent decades, zebrafish embryo/larva has emerged as a potential tool to test teratogenicity potential of these chemicals. Zebrafish responds to compounds as mammals do as they share similarities in their development, metabolism, physiology, and signaling pathways with that of mammals. The methodology used by the different scientists varies enormously in the zebrafish embryotoxicity test. In this chapter, we present methods to assess lethality and malformations during zebrafish development. We propose two major malformations scoring systems: binomial and relative morphological scoring systems to assess the malformations in zebrafish embryos/larvae. Based on the scoring of the malformations, the test compound can be classified as a teratogen or a nonteratogen and its teratogenic potential is evaluated.

Adjuvant effects and antiserum action potentiation by a (herbal) compound 2-hydroxy-4-methoxy benzoic acid isolated from the root extract of the Indian medicinal plant 'sarsaparilla' (Hemidesmus indicus R. Br.).

PubMed

Alam, M I; Gomes, A

1998-10-01

The adjuvant effect and antiserum potentiation of a compound 2-hydroxy-4-methoxy benzoic acid were explored in the present investigation. This compound, isolated and purified from the Indian medicinal plant Hemidesmus indicus R. Br, possessed antisnake venom activity. Rabbits immunized with Vipera russellii venom in the presence and absence of the compound along with Freund's complete adjuvant, produced a precipitating band in immunogel diffusion and immunogel electrophoresis. The venom neutralizing capacity of this antiserum showed positive adjuvant effects as evident by the higher neutralization capacity (lethal and hemorrhage) when compared with the antiserum raised with venom alone. The pure compound potentiated the lethal action neutralization of venom by commercial equine polyvalent snake venom antiserum in experimental models. These observations raised the possibility of the use of chemical antagonists (from herbs) against snake bite, which may provide a better protection in presence of antiserum, especially in the rural parts of India.

Clinical Effects and Lethal and Forensic Aspects of Propofol*

PubMed Central

Levy, Richard J.

2010-01-01

Propofol is a potent intravenous anesthetic agent that rapidly induces sedation and unconsciousness. The potential for propofol dependency, recreational use and abuse has only recently been recognized and several cases of accidental overdose and suicide have emerged. In addition, the first documented case of murder using propofol was reported a few months ago and a high profile case of suspected homicide with propofol is currently under investigation. A number of analytical methods have been employed to detect and quantify propofol concentrations in biological specimens. The reported propofol related deaths and post-mortem blood and tissue levels are reviewed. Importantly, limitations of propofol detection are discussed and future considerations are presented. Because propofol has the potential for diversion with lethal consequences, the forensic scientist must have a basic understanding of its clinical indications and uses, pharmacologic properties, and detection methods. In addition, medical institutions should develop systems to prevent and detect diversion of this potential drug of abuse. PMID:20950316

Delineating the requirements for spontaneous DNA damage resistance pathways in genome maintenance and viability in Saccharomyces cerevisiae.

PubMed

Morey, Natalie J; Doetsch, Paul W; Jinks-Robertson, Sue

2003-06-01

Cellular metabolic processes constantly generate reactive species that damage DNA. To counteract this relentless assault, cells have developed multiple pathways to resist damage. The base excision repair (BER) and nucleotide excision repair (NER) pathways remove damage whereas the recombination (REC) and postreplication repair (PRR) pathways bypass the damage, allowing deferred removal. Genetic studies in yeast indicate that these pathways can process a common spontaneous lesion(s), with mutational inactivation of any pathway increasing the burden on the remaining pathways. In this study, we examine the consequences of simultaneously compromising three or more of these pathways. Although the presence of a functional BER pathway alone is able to support haploid growth, retention of the NER, REC, or PRR pathway alone is not, indicating that BER is the key damage resistance pathway in yeast and may be responsible for the removal of the majority of either spontaneous DNA damage or specifically those lesions that are potentially lethal. In the diploid state, functional BER, NER, or REC alone can support growth, while PRR alone is insufficient for growth. In diploids, the presence of PRR alone may confer a lethal mutation load or, alternatively, PRR alone may be insufficient to deal with potentially lethal, replication-blocking lesions.

[Evaluation of the diagnostic usefulness for ultrasonographic and echocardiographic lethal markers in fetal pulmonary hypoplasia. Analysis of 11 cases].

PubMed

Kieszek, S; Kaczmarek, P; Czichos, E; Respondek, M

1996-07-01

Results of ultrasonographic and echocardiographic studies of 11 fetuses were analysed retrospectively in relation to their pulmonary hypoplasia. Congenital malformations, quality of hydramnios and echocardiographical measurements of fetal chest were estimated. The best symptoms of pulmonary hypoplasia were: oligo/ahydramnios, absence of fetal breathing movements and malformations in fetal chest cavity (diaphragmatic hernia, cardiomegaly, hydrothorax). Systemic malformations were present in each case. The measurements such as CC, CA, HA, (CA-HA) x 100/CA were not accurate enough and we did not find any statistical differences between the control and the studied group. Finding several factors predisposing to lung hypoplasia means that its lethal form may be present in fetus.

Botanicals for the prevention and treatment of cutaneous melanoma

PubMed Central

Syed, Deeba N.; Mukhtar, Hasan

2011-01-01

Summary Cutaneous melanoma, a cancer of melanocytes, when detected at later stages is arguably one of the most lethal cancers and the cause of more years of lost life than any other cancer among young adults. There is no standard therapy for advanced-stage melanoma and the median survival time for patients with metastatic melanoma is <1 yr. An urgent need for novel strategies against melanoma has directed research towards the development of new chemotherapeutic and biologic agents that can target the tumor by several different mechanisms. Recently, several dietary agents are being investigated for their role in the prevention and treatment of various forms of cancer and may represent the future modality of the treatment. Here, we have reviewed emerging data on botanicals that are showing promise for their potential inhibitory effect against cutaneous melanoma. PMID:21426532

Involvement of secondary metabolites in the pathogenesis of the American foulbrood of honey bees caused by Paenibacillus larvae.

PubMed

Müller, Sebastian; Garcia-Gonzalez, Eva; Genersch, Elke; Süssmuth, Roderich D

2015-06-01

The Gram-positive, spore-forming bacterium Paenibacillus larvae (P. larvae) is the causative agent of the epizootic American Foulbrood (AFB), a fatal brood disease of the western honey bee (Apis mellifera). AFB is one of the most destructive honey bee diseases since it is not only lethal for infected larvae but also for the diseased colonies. Due to the high impact of honey bees on ecology and economy this epizootic is a severe and pressing problem. Knowledge about virulence mechanisms and the underlying molecular mechanisms remain largely elusive. Recent genome sequencing of P. larvae revealed its potential to produce unknown secondary metabolites, like nonribosomal peptides and peptide-polyketide hybrids. This article highlights recent findings on secondary metabolites synthesized by P. larvae and discusses their role in virulence and pathogenicity towards the bee larvae.

Dermatitis herpetiformis: pathophysiology, clinical presentation, diagnosis and treatment*

PubMed Central

Clarindo, Marcos Vinícius; Possebon, Adriana Tomazzoni; Soligo, Emylle Marlene; Uyeda, Hirofumi; Ruaro, Roseli Terezinha; Empinotti, Julio Cesar

2014-01-01

Researches on DH have shown that it is not just a bullous skin disease, but a cutaneous-intestinal disorder caused by hypersensitivity to gluten. Exposure to gluten is the starting point of an inflammatory cascade capable of forming autoantibodies that are brought to the skin, where they are deposited, culminating in the formation of skin lesions. These lesions are vesico-bullous, pruritic, and localized especially on elbows, knees and buttocks, although atypical presentations can occur. Immunofluorescence of perilesional area is considered the gold standard for diagnosis, but serological tests help in cases where it is negative. Patients who follow glutenfree diets have better control of symptoms on the skin and intestine, as well as lower risks of progression to lymphoma. Dapsone remains the main drug for treatment, but it requires monitoring of possible side effects, some potentially lethal. PMID:25387490

Mechanism of Bacterial Inactivation by (+)-Limonene and Its Potential Use in Food Preservation Combined Processes

PubMed Central

Espina, Laura; Gelaw, Tilahun K.; de Lamo-Castellví, Sílvia; Pagán, Rafael; García-Gonzalo, Diego

2013-01-01

This work explores the bactericidal effect of (+)-limonene, the major constituent of citrus fruits' essential oils, against E. coli. The degree of E. coli BJ4 inactivation achieved by (+)-limonene was influenced by the pH of the treatment medium, being more bactericidal at pH 4.0 than at pH 7.0. Deletion of rpoS and exposure to a sub-lethal heat or an acid shock did not modify E. coli BJ4 resistance to (+)-limonene. However, exposure to a sub-lethal cold shock decreased its resistance to (+)-limonene. Although no sub-lethal injury was detected in the cell envelopes after exposure to (+)-limonene by the selective-plating technique, the uptake of propidium iodide by inactivated E. coli BJ4 cells pointed out these structures as important targets in the mechanism of action. Attenuated Total Reflectance Infrared Microspectroscopy (ATR-IRMS) allowed identification of altered E. coli BJ4 structures after (+)-limonene treatments as a function of the treatment pH: β-sheet proteins at pH 4.0 and phosphodiester bonds at pH 7.0. The increased sensitivity to (+)-limonene observed at pH 4.0 in an E. coli MC4100 lptD4213 mutant with an increased outer membrane permeability along with the identification of altered β-sheet proteins by ATR-IRMS indicated the importance of this structure in the mechanism of action of (+)-limonene. The study of mechanism of inactivation by (+)-limonene led to the design of a synergistic combined process with heat for the inactivation of the pathogen E. coli O157:H7 in fruit juices. These results show the potential of (+)-limonene in food preservation, either acting alone or in combination with lethal heat treatments. PMID:23424676

Mechanism of bacterial inactivation by (+)-limonene and its potential use in food preservation combined processes.

PubMed

Espina, Laura; Gelaw, Tilahun K; de Lamo-Castellví, Sílvia; Pagán, Rafael; García-Gonzalo, Diego

2013-01-01

This work explores the bactericidal effect of (+)-limonene, the major constituent of citrus fruits' essential oils, against E. coli. The degree of E. coli BJ4 inactivation achieved by (+)-limonene was influenced by the pH of the treatment medium, being more bactericidal at pH 4.0 than at pH 7.0. Deletion of rpoS and exposure to a sub-lethal heat or an acid shock did not modify E. coli BJ4 resistance to (+)-limonene. However, exposure to a sub-lethal cold shock decreased its resistance to (+)-limonene. Although no sub-lethal injury was detected in the cell envelopes after exposure to (+)-limonene by the selective-plating technique, the uptake of propidium iodide by inactivated E. coli BJ4 cells pointed out these structures as important targets in the mechanism of action. Attenuated Total Reflectance Infrared Microspectroscopy (ATR-IRMS) allowed identification of altered E. coli BJ4 structures after (+)-limonene treatments as a function of the treatment pH: β-sheet proteins at pH 4.0 and phosphodiester bonds at pH 7.0. The increased sensitivity to (+)-limonene observed at pH 4.0 in an E. coli MC4100 lptD4213 mutant with an increased outer membrane permeability along with the identification of altered β-sheet proteins by ATR-IRMS indicated the importance of this structure in the mechanism of action of (+)-limonene. The study of mechanism of inactivation by (+)-limonene led to the design of a synergistic combined process with heat for the inactivation of the pathogen E. coli O157:H7 in fruit juices. These results show the potential of (+)-limonene in food preservation, either acting alone or in combination with lethal heat treatments.

Phytochemistry, Brine shrimp lethality and mice acute oral toxicity studies on seed extracts of Vernonia anthelmintica.

PubMed

Jamil, Subia; Khan, Rafeeq Alam; Afroz, Syeda; Ahmed, Shadab

2016-11-01

Despite the widespread use of Vernonia anthelmintica seeds in traditional medicine, the need to establish the safety of the Vernonia anthelmintica is required to ascertain the safe use of this herbal medicine. The aim of the present study is to establish the acute toxicity profile of different extracts of Vernonia anthelmintica. Hexane and ethanol extract of Vernonia Anthelmintica has been studied for its brine shrimp lethality potential. Water decoction (WDVA), Hexane (HEVA) and Ethanol (EEVA) extracts of Vernonia anthelmintica has also been evaluated for their in-vivo acute oral toxicity in mice by Lorke's method. Phytochemistry of all three extracts was also evaluated for the presence of their secondary metabolites. All three extracts showed the presence of flavonoids and terpenoids, while alkaloids, tannins and fixed oils were present in HEVA and EEVA. Furthermore EEVA also showed presence of carbohydrates and HEVA also showed the presence of cardiac glycosides. Ethanol and hexane extracts of Vernonia anthelmintica showed a positive cytotoxicity in brine shrimp lethality test at 24 hours with LC50 104.16 (224.0-48.05)μg/ml and 216.11μg/ml (378.2-128.7) respectively as compared to standard drug etoposide LC50 7.46μg/ml. The oral LD50 for EEVA, HEVA and WDVA in mice by Lorke's method was greater than 5000mg/kg. The result of brine shrimp lethality test clearly exhibited the presence of bioactive compounds with cytotoxic potential; however seems to be safe for oral use since LD50 was higher than 5000mg/kg and thus safety of acute dosing in vivo practices is justified.

Leishmanization revisited: immunization with a naturally attenuated cutaneous Leishmania donovani isolate from Sri Lanka protects against visceral leishmaniasis.

PubMed

McCall, Laura-Isobel; Zhang, Wen-Wei; Ranasinghe, Shanlindra; Matlashewski, Greg

2013-02-27

Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa and associated with three main clinical presentations: cutaneous, mucocutaneous and visceral leishmaniasis. Visceral leishmaniasis is the second most lethal parasitic disease after malaria and there is so far no human vaccine. Leishmania donovani is a causative agent of visceral leishmaniasis in South East Asia and Eastern Africa. However, in Sri Lanka, L. donovani causes mainly cutaneous leishmaniasis, while visceral leishmaniasis is rare. We investigate here the possibility that the cutaneous form of L. donovani can provide immunological protection against the visceral form of the disease, as a potential explanation for why visceral leishmaniasis is rare in Sri Lanka. Subcutaneous immunization with a cutaneous clinical isolate from Sri Lanka was significantly protective against visceral leishmaniasis in BALB/c mice. Protection was associated with a mixed Th1/Th2 response. These results provide a possible rationale for the scarcity of visceral leishmaniasis in Sri Lanka and could guide leishmaniasis vaccine development efforts. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Saccharomyces boulardii CNCM I-745 strain shows protective effects against the B. anthracis LT toxin.

PubMed

Pontier-Bres, Rodolphe; Rampal, Patrick; Peyron, Jean-François; Munro, Patrick; Lemichez, Emmanuel; Czerucka, Dorota

2015-10-30

The probiotic yeast Saccharomyces boulardii (S. boulardii) has been prescribed for the prophylaxis and treatment of several infectious diarrheal diseases. Gastrointestinal anthrax causes fatal systemic disease. In the present study, we investigated the protective effects conferred by Saccharomyces boulardii CNCM I-745 strain on polarized T84 columnar epithelial cells intoxicated by the lethal toxin (LT) of Bacillus anthracis. Exposure of polarized T84 cells to LT affected cell monolayer integrity, modified the morphology of tight junctions and induced the formation of actin stress fibers. Overnight treatment of cells with S. boulardii before incubation with LT maintained the integrity of the monolayers, prevented morphological modification of tight junctions, restricted the effects of LT on actin remodeling and delayed LT-induced MEK-2 cleavage. Mechanistically, we demonstrated that in the presence of S. boulardii, the medium is depleted of both LF and PA sub-units of LT and the appearance of a cleaved form of PA. Our study highlights the potential of the S. boulardii CNCM I-745 strain as a prophylactic agent against the gastrointestinal form of anthrax.

The Saccharomyces boulardii CNCM I-745 Strain Shows Protective Effects against the B. anthracis LT Toxin

PubMed Central

Pontier-Bres, Rodolphe; Rampal, Patrick; Peyron, Jean-François; Munro, Patrick; Lemichez, Emmanuel; Czerucka, Dorota

2015-01-01

The probiotic yeast Saccharomyces boulardii (S. boulardii) has been prescribed for the prophylaxis and treatment of several infectious diarrheal diseases. Gastrointestinal anthrax causes fatal systemic disease. In the present study, we investigated the protective effects conferred by Saccharomyces boulardii CNCM I-745 strain on polarized T84 columnar epithelial cells intoxicated by the lethal toxin (LT) of Bacillus anthracis. Exposure of polarized T84 cells to LT affected cell monolayer integrity, modified the morphology of tight junctions and induced the formation of actin stress fibers. Overnight treatment of cells with S. boulardii before incubation with LT maintained the integrity of the monolayers, prevented morphological modification of tight junctions, restricted the effects of LT on actin remodeling and delayed LT-induced MEK-2 cleavage. Mechanistically, we demonstrated that in the presence of S. boulardii, the medium is depleted of both LF and PA sub-units of LT and the appearance of a cleaved form of PA. Our study highlights the potential of the S. boulardii CNCM I-745 strain as a prophylactic agent against the gastrointestinal form of anthrax. PMID:26529015

Habitat fragmentation caused by contaminants: Atrazine as a chemical barrier isolating fish populations.

PubMed

Araújo, Cristiano V M; Silva, Daniel C V R; Gomes, Luiz E T; Acayaba, Raphael D; Montagner, Cassiana C; Moreira-Santos, Matilde; Ribeiro, Rui; Pompêo, Marcelo L M

2018-02-01

Information on how atrazine can affect the spatial distribution of organisms is non-existent. As this effect has been observed for some other contaminants, we hypothesized that atrazine-containing leachates/discharges could trigger spatial avoidance by the fish Poecilia reticulata and form a chemical barrier isolating upstream and downstream populations. Firstly, guppies were exposed to an atrazine gradient in a non-forced exposure system, in which organisms moved freely among the concentrations, to assess their ability to avoid atrazine. Secondly, a chemical barrier formed by atrazine, separating two clean habitats (extremities of the non-forced system), was simulated to assess whether the presence of the contaminant could prevent guppies from migrating to the other side of the system. Fish were able to avoid atrazine contamination at environmentally relevant concentrations (0.02 μg L -1 ), below those described to cause sub-lethal effects. The AC 50 (atrazine concentration causing avoidance to 50% of the population) was 0.065 μg L -1 . The chemical barrier formed by atrazine at 150 μg L -1 (concentration that should produce an avoidance around 82%) caused a reduction in the migratory potential of the fish by 47%; while the chemical barrier at 1058 μg L -1 (concentration that produces torpidity) caused a reduction in the migratory potential of the fish by 91%. Contamination by atrazine, besides driving the spatial distribution of fish populations, has potential to act as a chemical barrier by isolating fish populations. This study includes a novel approach to be integrated in environmental risk assessment schemes to assess high-tier contamination effects such as habitat fragmentation and population displacement and isolation. Copyright © 2017 Elsevier Ltd. All rights reserved.

An H5N1-based matrix protein 2 ectodomain tetrameric peptide vaccine provides cross-protection against lethal infection with H7N9 influenza virus.

PubMed

Leung, Ho-Chuen; Chan, Chris Chung-Sing; Poon, Vincent Kwok-Man; Zhao, Han-Jun; Cheung, Chung-Yan; Ng, Fai; Huang, Jian-Dong; Zheng, Bo-Jian

2015-04-01

In March 2013, a patient infected with a novel avian influenza A H7N9 virus was reported in China. Since then, there have been 458 confirmed infection cases and 177 deaths. The virus contains several human-adapted markers, indicating that H7N9 has pandemic potential. The outbreak of this new influenza virus highlighted the need for the development of universal influenza vaccines. Previously, we demonstrated that a tetrameric peptide vaccine based on the matrix protein 2 ectodomain (M2e) of the H5N1 virus (H5N1-M2e) could protect mice from lethal infection with different clades of H5N1 and 2009 pandemic H1N1 influenza viruses. In this study, we investigated the cross-protection of H5N1-M2e against lethal infection with the new H7N9 virus. Although five amino acid differences existed at positions 13, 14, 18, 20, and 21 between M2e of H5N1 and H7N9, H5N1-M2e vaccination with either Freund's adjuvant or the Sigma adjuvant system (SAS) induced a high level of anti-M2e antibody, which cross-reacted with H7N9-M2e peptide. A mouse-adapted H7N9 strain, A/Anhui/01/2013m, was used for lethal challenge in animal experiments. H5N1-M2e vaccination provided potent cross-protection against lethal challenge of the H7N9 virus. Reduced viral replication and histopathological damage of mouse lungs were also observed in the vaccinated mice. Our results suggest that the tetrameric H5N1-M2e peptide vaccine could protect against different subtypes of influenza virus infections. Therefore, this vaccine may be an ideal candidate for developing a universal vaccine to prevent the reemergence of avian influenza A H7N9 virus and the emergence of potential novel reassortants of influenza virus.

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

Schmidt, Tobias; Bertermann, Rüdiger; Rusch, George M.

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a novel refrigerant intended for use in mobile air conditioning. It showed a low potential for toxicity in rodents studies with most NOAELs well above 10,000 ppm in guideline compliant toxicity studies. However, a developmental toxicity study in rabbits showed mortality at exposure levels of 5,500 ppm and above. No lethality was observed at exposure levels of 2,500 and 4,000 ppm. Nevertheless, increased subacute inflammatory heart lesions were observed in rabbits at all exposure levels. Since the lethality in pregnant animals may be due to altered biotransformation of HFO-1234yf and to evaluate the potential risk to pregnantmore » women facing a car crash, this study compared the acute toxicity and biotransformation of HFO-1234yf in male, female and pregnant female rabbits. Animals were exposed to 50,000 ppm and 100,000 ppm for 1 h. For metabolite identification by {sup 19}F NMR and LC/MS-MS, urine was collected for 48 h after inhalation exposure. In all samples, the predominant metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine. Since no major differences in urinary metabolite pattern were observed between the groups, only N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine excretion was quantified. No significant differences in recovery between non-pregnant (43.10 ± 22.35 μmol) and pregnant female (50.47 ± 19.72 μmol) rabbits were observed, male rabbits exposed to 100,000 ppm for one hour excreted 86.40 ± 38.87 μmol. Lethality and clinical signs of toxicity were not observed in any group. The results suggest that the lethality of HFO-1234yf in pregnant rabbits unlikely is due to changes in biotransformation patterns or capacity in pregnant rabbits. -- Highlights: ► No lethality and clinical signs were observed. ► No differences in metabolic pattern between pregnant and non-pregnant rabbits. ► Rapid and similar metabolite excretion in all groups. ► Very low amount of biotransformation in all groups (< 0.1%).« less

Induction of Immune Mediators in Glioma and Prostate Cancer Cells by Non-Lethal Photodynamic Therapy

PubMed Central

Kammerer, Robert; Buchner, Alexander; Palluch, Patrick; Pongratz, Thomas; Oboukhovskij, Konstantin; Beyer, Wolfgang; Johansson, Ann; Stepp, Herbert; Baumgartner, Reinhold; Zimmermann, Wolfgang

2011-01-01

Background Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. Methodology/Principal Findings Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. Conclusions Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways. PMID:21738796

Evaluating the lethal and pre-lethal effects of a range of fungi against adult Anopheles stephensi mosquitoes.

PubMed

Blanford, Simon; Jenkins, Nina E; Read, Andrew F; Thomas, Matthew B

2012-11-05

Insecticide resistance is seriously undermining efforts to eliminate malaria. In response, research on alternatives to the use of chemical insecticides against adult mosquito vectors has been increasing. Fungal entomopathogens formulated as biopesticides have received much attention and have shown considerable potential. This research has necessarily focused on relatively few fungal isolates in order to 'prove concept'. Further, most attention has been paid to examining fungal virulence (lethality) and not the other properties of fungal infection that might also contribute to reducing transmission potential. Here, a range of fungal isolates were screened to examine variation in virulence and how this relates to additional pre-lethal reductions in feeding propensity. The Asian malaria vector, Anopheles stephensi was exposed to 17 different isolates of entomopathogenic fungi belonging to species of Beauveria bassiana, Metarhizium anisopliae, Metarhizium acridum and Isaria farinosus. Each isolate was applied to a test substrate at a standard dose rate of 1×109 spores ml-1 and the mosquitoes exposed for six hours. Subsequently the insects were removed to mesh cages where survival was monitored over the next 14 days. During this incubation period the mosquitoes' propensity to feed was assayed for each isolate by offering a feeding stimulant at the side of the cage and recording the number probing. Fungal isolates showed a range of virulence to A. stephensi with some causing >80% mortality within 7 days, while others caused little increase in mortality relative to controls over the study period. Similarly, some isolates had a large impact on feeding propensity, causing >50% pre-lethal reductions in feeding rate, whereas other isolates had very little impact. There was clear correlation between fungal virulence and feeding reduction with virulence explaining nearly 70% of the variation in feeding reduction. However, there were some isolates where either feeding decline was not associated with high virulence, or virulence did not automatically prompt large declines in feeding. These results are discussed in the context of choosing optimum fungal isolates for biopesticide development.

Proposed modification to the specification for dry heat microbial reduction of spacecraft hardware for future US missions

NASA Astrophysics Data System (ADS)

James; Spry, A.; Beaudet, Robert; Schubert, Wayne

Dry heat microbial reduction (DHMR) is the primary technique used to reduce the microbial load of spacecraft and component parts to comply with planetary protection requirements. Often, manufacturing processes involve heating flight hardware to high temperatures for purposes other than planetary protection DHMR. At present, the existing specification in NASA document NPR8020.12C, describing the process lethality on B. atrophaeus (ATCC 9372) bacterial spores, does not allow for additional planetary protection bioburden reduction credit for processing outside a narrow temperature, time and humidity window. However, recent studies (Schubert et al., COSPAR 2008) from a comprehensive multi-year laboratory research effort have generated enhanced data sets on four aspects of the current specification: time and temperature combination effects, the effect that humidity has on spore lethality, the lethality for spores with exceptionally high thermal resistance (so called "hardies"), and the extended exposure requirement for encapsulated microorganisms. This paper describes proposed modifications to the specification, based on the data set generated in the referenced study. The proposed modifications are intended to broaden the scope of the current specification while still maintaining a confident conservative interpretation of the lethality of the DHMR process on microorganisms. Potential cost and schedule benefits to future missions utilizing the revised specification will be highlighted.

Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection.

PubMed

Qiu, Xiangguo; Fernando, Lisa; Melito, P Leno; Audet, Jonathan; Feldmann, Heinz; Kobinger, Gary; Alimonti, Judie B; Jones, Steven M

2012-01-01

Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 µg) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.

Prevention of Suicidal Behavior in Prisons

PubMed Central

2016-01-01

Abstract. Background: Worldwide, prisoners are at high risk of suicide. Research on near-lethal suicide attempts can provide important insights into risk and protective factors, and inform suicide prevention initiatives in prison. Aims: To synthesize findings of research on near-lethal attempts in prisons, and consider their implications for suicide prevention policies and practice, in the context of other research in custody and other settings. Method: We searched two bibliographic indexes for studies in any language on near-lethal and severe self-harm in prisoners, supplemented by targeted searches over the period 2000–2014. We extracted information on risk factors descriptively. Data were not meta-analyzed owing to heterogeneity of samples and methods. Results: We identified eight studies reporting associations between prisoner near-lethal attempts and specific factors. The latter included historical, prison-related, and clinical factors, including psychiatric morbidity and comorbidity, trauma, social isolation, and bullying. These factors were also identified as important in prisoners' own accounts of what may have contributed to their attempts (presented in four studies). Conclusion: Factors associated with prisoners' severe suicide attempts include a range of potentially modifiable clinical, psychosocial, and environmental factors. We make recommendations to address these factors in order to improve detection, management, and prevention of suicide risk in prisoners. PMID:27278569

Knockdown of genes in the Toll pathway reveals new lethal RNA interference targets for insect pest control.

PubMed

Bingsohn, L; Knorr, E; Billion, A; Narva, K E; Vilcinskas, A

2017-02-01

RNA interference (RNAi) is a promising alternative strategy for ecologically friendly pest management. However, the identification of RNAi candidate genes is challenging owing to the absence of laboratory strains and the seasonality of most pest species. Tribolium castaneum is a well-established model, with a strong and robust RNAi response, which can be used as a high-throughput screening platform to identify potential RNAi target genes. Recently, the cactus gene was identified as a sensitive RNAi target for pest control. To explore whether the spectrum of promising RNAi targets can be expanded beyond those found by random large-scale screening, to encompass others identified using targeted knowledge-based approaches, we constructed a Cactus interaction network. We tested nine genes in this network and found that the delivery of double-stranded RNA corresponding to fusilli and cactin showed lethal effects. The silencing of cactin resulted in 100% lethality at every developmental stage from the larva to the adult. The knockdown of pelle, Dorsal-related immunity factor and short gastrulation reduced or even prevented egg hatching in the next generation. The combination of such targets with lethal and parental RNAi effects can now be tested against different pest species in field studies. © 2016 The Royal Entomological Society.

Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer: Report From the 2015 Coffey-Holden Prostate Cancer Academy Meeting

PubMed Central

Miyahira, Andrea K.; Lang, Joshua M.; Den, Robert B.; Garraway, Isla P.; Lotan, Tamara L.; Ross, Ashley E.; Stoyanova, Tanya; Cho, Steve Y.; Simons, Jonathan W.; Pienta, Kenneth J.; Soule, Howard R.

2018-01-01

BACKGROUND The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: “Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer,” was held in La Jolla, California from June 25 to 28, 2015. METHODS The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. RESULTS The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. DISCUSSION This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. PMID:26477609

The Novel Application of Non-Lethal Citizen Science Tissue Sampling in Recreational Fisheries.

PubMed

Williams, Samuel M; Holmes, Bonnie J; Pepperell, Julian G

2015-01-01

Increasing fishing pressure and uncertainty surrounding recreational fishing catch and effort data promoted the development of alternative methods for conducting fisheries research. A pilot investigation was undertaken to engage the Australian game fishing community and promote the non-lethal collection of tissue samples from the black marlin Istiompax indica, a valuable recreational-only species in Australian waters, for the purpose of future genetic research. Recruitment of recreational anglers was achieved by publicizing the project in magazines, local newspapers, social media, blogs, websites and direct communication workshops at game fishing tournaments. The Game Fishing Association of Australia and the Queensland Game Fishing Association were also engaged to advertise the project and recruit participants with a focus on those anglers already involved in the tag-and-release of marlin. Participants of the program took small tissue samples using non-lethal methods which were stored for future genetic analysis. The program resulted in 165 samples from 49 participants across the known distribution of I. indica within Australian waters which was a sufficient number to facilitate a downstream population genetic analysis. The project demonstrated the potential for the development of citizen science sampling programs to collect tissue samples using non-lethal methods in order to achieve targeted research objects in recreationally caught species.

Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Lang, Joshua M; Den, Robert B; Garraway, Isla P; Lotan, Tamara L; Ross, Ashley E; Stoyanova, Tanya; Cho, Steve Y; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2016-02-01

The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: "Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer," was held in La Jolla, California from June 25 to 28, 2015. The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. © 2015 Wiley Periodicals, Inc.

Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

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

Yue, Dongli; Zhang, Zhen; Li, Jieyao

Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be seriallymore » passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. - Highlights: • Esophageal cancer sphere-forming cells possess cancer stem cell properties. • Sphere-forming cells enhance TGF-β1 pathway activity. • TGF-β 1 inhibitor suppresses the migration and invasion of sphere-forming cells.« less

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

PubMed

Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K; King, Carly J; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H; Coleman, Daniel J; Joshi, Sunil K; Kim, Dae-Hwan; Sampson, David A; Weinmann, Sheila; Kallakury, Bhaskar V S; Berry, Deborah L; Haque, Reina; Van Den Eeden, Stephen K; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M; Thomas, George V; Heiser, Laura M; Alumkal, Joshi J

2018-05-01

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis

PubMed Central

Wang, Zeneng; Roberts, Adam B.; Buffa, Jennifer A.; Levison, Bruce S.; Zhu, Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley, Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E.; Krajcik, Daniel; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

2016-01-01

SUMMARY Trimethylamine N-oxide (TMAO), a gut microbiota dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial trimethylamine (TMA) production, on diet-induced atherosclerosis. A structural analogue of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (eg intestinal contents, human feces) and reduce TMAO levels in mice fed a high choline or carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e−/− mice without alterations in circulating cholesterol levels. The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases. PMID:26687352

CHARACTERIZATION OF VIRULENCE OF Leptospira ISOLATES IN A HAMSTER MODEL

PubMed Central

Silva, Éverton F.; Santos, Cleiton S.; Athanazio, Daniel A.; Seyffert, Núbia; Seixas, Fabiana K.; Cerqueira, Gustavo M.; Fagundes, Michel Q.; Brod, Claudiomar S.; Reis, Mitermayer G.; Dellagostin, Odir A.; Ko, Albert I.

2008-01-01

Effort has been made to identify protective antigens in order to develop a recombinant vaccine against leptospirosis. Several attempts failed to conclusively demonstrate efficacy of vaccine candidates due to the lack of an appropriate model of lethal leptospirosis. The purposes of our study were: (i) to test the virulence of leptospiral isolates from Brazil, which are representative of important serogroups that cause disease in humans and animals; and (ii) to standardize the lethal dose 50% (LD50) for each of the virulent strains using a hamster (Mesocricetus auratus) model. Five of seven Brazilian isolates induced lethality in a hamster model, with inocula lower than 200 leptospires. Histopathological examination of infected animals showed typical lesions found in both natural and experimental leptospirosis. Results described here demonstrated the potential use of Brazilian isolates as highly virulent strains in challenge experiments using hamster as an appropriate animal model for leptospirosis. Furthermore these strains may be useful in heterologous challenge studies which aim to evaluate cross-protective responses induced by subunit vaccine candidates. PMID:18547690

Kunjin Virus Replicon-Based Vaccines Expressing Ebola Virus Glycoprotein GP Protect the Guinea Pig Against Lethal Ebola Virus Infection

PubMed Central

Reynard, O.; Mokhonov, V.; Mokhonova, E.; Leung, J.; Page, A.; Mateo, M.; Pyankova, O.; Georges-Courbot, M. C.; Raoul, H.; Khromykh, A. A.

2011-01-01

Pre- or postexposure treatments against the filoviral hemorrhagic fevers are currently not available for human use. We evaluated, in a guinea pig model, the immunogenic potential of Kunjin virus (KUN)–derived replicons as a vaccine candidate against Ebola virus (EBOV). Virus like particles (VLPs) containing KUN replicons expressing EBOV wild-type glycoprotein GP, membrane anchor-truncated GP (GP/Ctr), and mutated GP (D637L) with enhanced shedding capacity were generated and assayed for their protective efficacy. Immunization with KUN VLPs expressing full-length wild-type and D637L-mutated GPs but not membrane anchor–truncated GP induced dose-dependent protection against a challenge of a lethal dose of recombinant guinea pig-adapted EBOV. The surviving animals showed complete clearance of the virus. Our results demonstrate the potential for KUN replicon vectors as vaccine candidates against EBOV infection. PMID:21987742

Kratom: a dangerous player in the opioid crisis.

PubMed

Tayabali, Khadija; Bolzon, Colin; Foster, Paul; Patel, Janki; Kalim, Mohammad Omar

2018-01-01

Kratom use as a herbal supplement is on the rise in the United States, with reported medical outcomes and lethal effects suggesting a public health threat. Even though the Drug Enforcement Administration has included kratom on its drugs of concern list and the FDA has published a press release to identify it as an opioid with a potential for abuse, its therapeutic and side effects are still not well defined in the literature. Here, we present a case of a 32-year-old man with a history of kratom use who became acutely ill with a brief prodromal illness, followed by jaundice and elevated liver enzymes showing a cholestatic picture, and his successful treatment. In this case, we emphasize the need for awareness of kratom exposure as a key contributor in the expansion of the opioid crisis, with therapeutic benefits earned at the expense of potentially lethal side effects.

Fentanyl novel derivative-related deaths.

PubMed

Giorgetti, Arianna; Centola, Carmela; Giorgetti, Raffaele

2017-05-01

Fentanyl (FEN) is a potent, synthetic narcotic used as an anaesthetic and a pain reliever, but also illegally manufactured. For diversion purpose, it is being steadily modified to produce new analogous compounds and derivatives (FENS), categorised as novel psychoactive substances. While potential FEN abuse is already known, even in the absence of a clear lethal dosage, there is still a shortage of data on its derivatives. A literature review of FENS-related deaths was performed, to better understand potential damage and future perspectives of FEN congeners. Epidemiological data, pathological findings, administration routes, average concentrations and lethal doses, toxicological issues, trends in misuses, comparison among FENS, and possible explanation for FENS abuse are reviewed and discussed in depth. This study provides a medical-legal and toxicological assessment of this phenomenon in order to understand the role of illegal fentanyl and its congeners in deaths from FENS overdose. Copyright © 2017 John Wiley & Sons, Ltd.

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells.

PubMed

Telford, Bryony J; Chen, Augustine; Beetham, Henry; Frick, James; Brew, Tom P; Gould, Cathryn M; Single, Andrew; Godwin, Tanis; Simpson, Kaylene J; Guilford, Parry

2015-05-01

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. ©2015 American Association for Cancer Research.

Pilot-scale crossflow-microfiltration and pasturization to remove spores of Bacillus anthracis (Sterne) from milk

USDA-ARS?s Scientific Manuscript database

HTST pasteurization of milk is generally ineffective against spore-forming bacteria such as Bacillus anthracis (BA) but is lethal to its vegetative cells. Crossflow microfiltration (MF), using ceramic membranes with a pore diameter of 1.4 um, has been shown to physically remove somatic cells, vegeta...

From the lab - CancerSEEK: Blood Test Could Detect Cancer Earlier | NIH MedlinePlus the Magazine

MedlinePlus

... is supported by NIH, in a recent blog post. “CancerSEEK was able to detect most cases of eight different kinds of cancer, including some highly lethal forms that currently lack screening tests,” Dr. Collins said. The CancerSEEK trial tested breast, ...

Neutralization, by a monospecific Bothrops lanceolatus antivenom, of toxic activities induced by homologous and heterologous Bothírops snake venoms.

PubMed

Bogarín, G; Romero, M; Rojas, G; Lutsch, C; Casadamont, M; Lang, J; Otero, R; Gutiérrez, J M

1999-03-01

A monospecific Bothrops lanceolatus antivenom, currently used in Martinique, was tested for its efficacy in the neutralization of several toxic and enzymatic activities of the venoms of B. lanceolatus, B. atrox and B. asper. When tested by the i.p. route in mice, B. lanceolatus venom had an LD50 of 12.8 microg/g. In addition, it induced local tissue damage (hemorrhage, edema and myotoxicity) and showed indirect hemolytic activity, but was devoid of coagulant effect on human plasma in vitro and of defibrinating activity in mice. Antivenom was fully effective in the neutralization of lethal, hemorrhagic, edema-forming, myotoxic and indirect hemolytic effects of B. lanceolatus venom in assays involving preincubation of venom and antivenom. When tested against the venoms of B. asper and B. atrox, the antivenom completely neutralized the lethal, hemorrhagic, myotoxic and indirect hemolytic effects, and was partially effective in neutralizing edema-forming activity. In contrast, the antivenom was ineffective in the neutralization of in vitro coagulant and in vivo defibrinating effects induced by these two venoms.

D-enantiomeric peptides that eradicate wild-type and multi-drug resistant biofilms and protect against lethal Pseudomonas aeruginosa infections

PubMed Central

de la Fuente-Núñez, César; Reffuveille, Fany; Mansour, Sarah C.; Reckseidler-Zenteno, Shauna L.; Hernández, Diego; Brackman, Gilles; Coenye, Tom; Hancock, Robert E.W.

2015-01-01

SUMMARY In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active anti-biofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating pre-formed biofilms of seven species of wild-type and multiply antibiotic resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal P. aeruginosa infections, and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease resistant peptides produced here were more effective both in vitro and in vivo. PMID:25699603

Lethality of sortase depletion in Actinomyces oris caused by excessive membrane accumulation of a surface glycoprotein.

PubMed

Wu, Chenggang; Huang, I-Hsiu; Chang, Chungyu; Reardon-Robinson, Melissa Elizabeth; Das, Asis; Ton-That, Hung

2014-12-01

Sortase, a cysteine-transpeptidase conserved in Gram-positive bacteria, anchors on the cell wall many surface proteins that facilitate bacterial pathogenesis and fitness. Genetic disruption of the housekeeping sortase in several Gram-positive pathogens reported thus far attenuates virulence, but not bacterial growth. Paradoxically, we discovered that depletion of the housekeeping sortase SrtA was lethal for Actinomyces oris; yet, all of its predicted cell wall-anchored protein substrates (AcaA-N) were individually dispensable for cell viability. Using Tn5-transposon mutagenesis to identify factors that upend lethality of srtA deletion, we uncovered a set of genetic suppressors harbouring transposon insertions within genes of a locus encoding AcaC and a LytR-CpsA-Psr (LCP)-like protein. AcaC was shown to be highly glycosylated and dependent on LCP for its glycosylation. Upon SrtA depletion, the glycosylated form of AcaC, hereby renamed GspA, was accumulated in the membrane. Overexpression of GspA in a mutant lacking gspA and srtA was lethal; conversely, cells overexpressing a GspA mutant missing a membrane-localization domain were viable. The results reveal a unique glycosylation pathway in A. oris that is coupled to cell wall anchoring catalysed by sortase SrtA. Significantly, this novel phenomenon of glyco-stress provides convenient cell-based assays for developing a new class of inhibitors against Gram-positive pathogens. © 2014 John Wiley & Sons Ltd.

A Strong Loss-of-Function Mutation in RAN1 Results in Constitutive Activation of the Ethylene Response Pathway as Well as a Rosette-Lethal Phenotype

PubMed Central

Woeste, Keith E.; Kieber, Joseph J.

2000-01-01

A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resulted in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a competitive inhibitor of ethylene binding. In contrast to the previously identified ran1-1 and ran1-2 alleles that are morphologically indistinguishable from wild-type plants, this ran1-3 allele results in a rosette-lethal phenotype. The predicted protein encoded by the RAN1 gene is similar to the Wilson and Menkes disease proteins and yeast Ccc2 protein, which are integral membrane cation-transporting P-type ATPases involved in copper trafficking. Genetic epistasis analysis indicated that RAN1 acts upstream of mutations in the ethylene receptor gene family. However, the rosette-lethal phenotype of ran1-3 was not suppressed by ethylene-insensitive mutants, suggesting that this mutation also affects a non-ethylene-dependent pathway regulating cell expansion. The phenotype of ran1-3 mutants is similar to loss-of-function ethylene receptor mutants, suggesting that RAN1 may be required to form functional ethylene receptors. Furthermore, these results suggest that copper is required not only for ethylene binding but also for the signaling function of the ethylene receptors. PMID:10715329

A strong loss-of-function mutation in RAN1 results in constitutive activation of the ethylene response pathway as well as a rosette-lethal phenotype

NASA Technical Reports Server (NTRS)

Woeste, K. E.; Kieber, J. J.; Evans, M. L. (Principal Investigator)

2000-01-01

A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resulted in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a competitive inhibitor of ethylene binding. In contrast to the previously identified ran1-1 and ran1-2 alleles that are morphologically indistinguishable from wild-type plants, this ran1-3 allele results in a rosette-lethal phenotype. The predicted protein encoded by the RAN1 gene is similar to the Wilson and Menkes disease proteins and yeast Ccc2 protein, which are integral membrane cation-transporting P-type ATPases involved in copper trafficking. Genetic epistasis analysis indicated that RAN1 acts upstream of mutations in the ethylene receptor gene family. However, the rosette-lethal phenotype of ran1-3 was not suppressed by ethylene-insensitive mutants, suggesting that this mutation also affects a non-ethylene-dependent pathway regulating cell expansion. The phenotype of ran1-3 mutants is similar to loss-of-function ethylene receptor mutants, suggesting that RAN1 may be required to form functional ethylene receptors. Furthermore, these results suggest that copper is required not only for ethylene binding but also for the signaling function of the ethylene receptors.

Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome.

PubMed

McKie, Arthur B; Alsaedi, Atif; Vogt, Julie; Stuurman, Kyra E; Weiss, Marjan M; Shakeel, Hassan; Tee, Louise; Morgan, Neil V; Nikkels, Peter G J; van Haaften, Gijs; Park, Soo-Mi; van der Smagt, Jasper J; Bugiani, Marianna; Maher, Eamonn R

2014-12-05

Foetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes. After mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%. Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.

Non-Lethal Weapons Program

Science.gov Websites

), 26th Marine Expeditionary Unit (MEU), practice non-lethal control techniques during a non-lethal Skip to main content (Press Enter). Toggle navigation Non-Lethal Weapons Program Search Search JNLWP: Search Search JNLWP: Search Non-Lethal Weapons Program U.S. Department of Defense Non-Lethal

[Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991].

PubMed

Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G

1998-01-01

Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p < 0.000. Bladder tumours accounts in CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented.

Radioprotection by metals: Selenium

NASA Astrophysics Data System (ADS)

Weiss, J. F.; Srinivasan, V.; Kumar, K. S.; Landauer, M. R.

The need exists for compounds that will protect individuals from high-dose acute radiation exposure in space and for agents that might be less protective but less toxic and longer acting. Metals and metal derivatives provide a small degree of radioprotection (dose reduction factor <= 1.2 for animal survival after whole-body irradiation). Emphasis is placed here on the radioprotective potential of selenium (Se). Both the inorganic salt, sodium selenite, and the organic Se compound, selenomethionine, enhance the survival of irradiated mice (60Co, 0.2 Gy/min) when injected IP either before (-24 hr and -1 hr) or shortly after (+15 min) radiation exposure. When administered at equitoxic doses (one-fourth LD10; selenomethionine = 4.0 mg/kg Se, sodium selenite = 0.8 mg/kg Se), both drugs enhanced the 30-day survival of mice irradiated at 9 Gy. Survival after 10-Gy exposure was significantly increased only after selenomethionine treatment. An advantage of selenomethionine is lower lethal and behavioral toxicity (locomotor activity depression) compared to sodium selenite, when they are administered at equivalent doses of Se. Sodium selenite administered in combination with WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, enhances the radioprotective effect and reduces the lethal toxicity, but not the behavioral toxicity, of WR-2721. Other studies on radioprotection and protection against chemical carcinogens by different forms of Se are reviewed. As additional animal data and results from human chemoprevention trials become available, consideration also can be given to prolonged administration of Se compounds for protection against long-term radiation effects in space.

Lethal and mutagenic effects of ion beams and γ-rays in Aspergillus oryzae.

PubMed

Toyoshima, Yoshiyuki; Takahashi, Akemi; Tanaka, Hisaki; Watanabe, Jun; Mogi, Yoshinobu; Yamazaki, Tatsuo; Hamada, Ryoko; Iwashita, Kazuhiro; Satoh, Katsuya; Narumi, Issay

2012-12-01

Aspergillus oryzae is a fungus that is used widely in traditional Japanese fermentation industries. In this study, the lethal and mutagenic effects of different linear energy transfer (LET) radiation in freeze-dried conidia of A. oryzae were investigated. The lethal effect, which was evaluated by a 90% lethal dose, was dependent on the LET value of the ionizing radiation. The most lethal ionizing radiation among that tested was (12)C(5+) ion beams with an LET of 121keV/μm. The (12)C(5+) ion beams had a 3.6-times higher lethal effect than low-LET (0.2keV/μm) γ-rays. The mutagenic effect was evaluated by the frequency of selenate resistant mutants. (12)C(6+) ion beams with an LET of 86keV/μm were the most effective in inducing selenate resistance. The mutant frequency following exposure to (12)C(6+) ion beams increased with an increase in dose and reached 3.47×10(-3) at 700Gy. In the dose range from 0 to 700Gy, (12)C(5+) ion beams were the second most effective in inducing selenate resistance, the mutant frequency of which reached a maximum peak (1.67×10(-3)) at 400Gy. To elucidate the characteristics of mutation induced by ionizing radiation, mutations in the sulphate permease gene (sB) and ATP sulfurylase gene (sC) loci, the loss of function of which results in a selenate resistant phenotype, were compared between (12)C(5+) ion beams and γ-rays. We detected all types of transversions and transitions. For frameshifts, the frequency of a +1 frameshift was the highest in all cases. Although the incidence of deletions >2bp was generally low, deletions >20bp were characteristic for (12)C(5+) ion beams. γ-rays had a tendency to generate mutants carrying a multitude of mutations in the same locus. Both forms of radiation also induced genome-wide large-scale mutations including chromosome rearrangements and large deletions. These results provide new basic insights into the mutation breeding of A. oryzae using ionizing radiation. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Study of the Effects of Ultrasonic Waves on the Reproductive Integrity of Mammalian Cells Cultured in Vitro

NASA Technical Reports Server (NTRS)

Martins, B. I.

1971-01-01

The effects of monochromatic ultrasonic waves of 0.1, 0.5, 1.0, 2.0 and, 3.3 MHz frequency on the colony-forming ability of mammalian cells (M3-1,V79, Chang's and T-1) cultured in vitro have been studied to determine the nature of the action of ultrasonic energy on biological systems at the cellular level. The combined effect of ultrasound and X-rays has also been studied. It is concluded: (1) Ultrasonic irradiation causes both lethal and sublethal damage. (2) There is a threshold dose rate for lethal effects. (3) The effectiveness of ultrasonic waves in causing cell death probably depends on the frequency and the amplitude of the waves for a given cell line, indicating a possible resonance phenomenon.

Insights into the CuO nanoparticle ecotoxicity with suitable marine model species.

PubMed

Rotini, A; Gallo, A; Parlapiano, I; Berducci, M T; Boni, R; Tosti, E; Prato, E; Maggi, C; Cicero, A M; Migliore, L; Manfra, L

2018-01-01

Metal oxide nanoparticles, among them copper oxide nanoparticles (CuO NPs), are widely used in different applications (e.g. batteries, gas sensors, superconductors, plastics and metallic coatings), increasing their potential release in the environment. In aquatic matrix, the behavior of CuO NPs may strongly change, depending on their surface charge and some physical-chemical characteristics of the medium (e.g. ionic strength, salinity, pH and natural organic matter content). Ecotoxicity of CuO NPs to aquatic organisms was mainly studied on freshwater species, few tests being performed on marine biota. The aim of this study was to assess the toxicity of CuO NPs on suitable indicator species, belonging to the ecologically relevant level of consumers. The selected bioassays use reference protocols to identify Effect/Lethal Concentrations (E(L)C), by assessing lethal and sub-lethal endpoints. Mortality tests were performed on rotifer (Brachionus plicatilis), shrimp (Artemia franciscana) and copepod (Tigriopus fulvus). While moult release failure and fertilization rate were studied, as sub-lethal endpoints, on T. fulvus and sea urchin (Paracentrotus lividus), respectively. The size distribution and sedimentation rates of CuO NPs, together with the copper dissolution, were also analyzed in the exposure media. The CuO NP ecotoxicity assessment showed a concentration-dependent response for all species, indicating similar mortality for B. plicatilis (48hLC 50 = 16.94 ± 2.68mg/l) and T. fulvus (96hLC 50 = 12.35 ± 0.48mg/l), followed by A. franciscana (48hLC 50 = 64.55 ± 3.54mg/l). Comparable EC 50 values were also obtained for the sub-lethal endpoints in P. lividus (EC 50 = 2.28 ± 0.06mg/l) and T. fulvus (EC 50 = 2.38 ± 0.20mg/l). Copper salts showed higher toxicity than CuO NPs for all species, with common sensitivity trend as follows: P. lividus ≥ T. fulvus (sublethal endpoint) ≥ B. plicatilis >T. fulvus (lethal endpoint) >A. franciscana. CuO NP micrometric aggregates and high sedimentation rates were observed in the exposure media, with different particle size distributions depending on the medium. The copper dissolution was about 0.16% of the initial concentration, comparable to literature values. The integrated ecotoxicological-physicochemical approach was used to better describe CuO NP toxicity and behavior. In particular, the successful application of ecotoxicological reference protocols allowed to produce reliable L(E)C data useful to identify thresholds and assess potential environmental hazard due to NPs. Copyright © 2017 Elsevier Inc. All rights reserved.

The Combination of Cobinamide and Sulfanegen Is Highly Effective in Mouse Models of Cyanide Poisoning

PubMed Central

Chan, Adriano; Crankshaw, Daune L.; Monteil, Alexandre; Patterson, Steven E.; Nagasawa, Herbert T.; Briggs, Jackie E.; Kozocas, Joseph A.; Mahon, Sari B.; Brenner, Matthew; Pilz, Renate B.; Bigby, Timothy D.; Boss, Gerry R.

2013-01-01

SUMMARY Context Cyanide poisoning is a major contributor to death in smoke inhalation victims and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties. Objective We are developing two new cyanide antidotes—cobinamide, a vitamin B12 analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined. Materials and Methods We used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model. Results We found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone yielded 80 and 100% survival in the injection and inhalatiion models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote. Conclusion The combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning. PMID:21740135

A stratified analysis of the perioperative outcome of 17623 patients undergoing major head and neck cancer surgery in England over 10 years: Towards an Informatics-based Outcomes Surveillance Framework.

PubMed

Nouraei, S A R; Mace, A D; Middleton, S E; Hudovsky, A; Vaz, F; Moss, C; Ghufoor, K; Mendes, R; O'Flynn, P; Jallali, N; Clarke, P M; Darzi, A; Aylin, P

2017-02-01

To perform a national analysis of the perioperative outcome of major head and neck cancer surgery to develop a stratification strategy and outcomes assessment framework using hospital administrative data. A Hospital Episode Statistics N = near-all analysis. The English National Health Service. Local audit data were used to assess and triangulate the quality of the administrative dataset. Within the national dataset, cancer sites, morbidities, social deprivation, treatment, complications, and in-hospital mortality were recorded. Within local audit datasets, the accuracy of assigning newly-derived Cancer Site Strata and Resection Strata were 92.3% and 94.2%, respectively. Accuracy of morbidities assignment was 97%. Within the national dataset, we identified 17 623 major head and neck cancer resections between 2002 and 2012. There were 12 413 males and mean age at surgery was 63 ± 12 years. The commonest cancer site strata were oral cavity (42%) and larynx-hypopharynx (32%). The commonest resection site was the larynx (n = 4217), and 13 211 and 11 841 patients had neck dissection and flap-based reconstruction, respectively. There were prognostically significant baseline differences between patients with oromandibular and pharyngolaryngeal malignancy. Patients with pharyngolaryngeal malignancies had a greater burden of morbidities, lower socio-economic status, fewer primary resections, and a sixfold increased risk of undergoing their major resection during an emergency hospital admission. Mean length of stay was 25 days and each complication linearly increased it by 9.6 days. There were 609 (3.5%) in-hospital deaths and a basket of seven medical and three surgical complications significantly increased the risk of in-hospital death. At least one potentially lethal complication occurred in 26% of patients. The risk of in-hospital death in a patient with no potentially lethal complication was 1.1% and this increased to 6% with one potentially lethal complication, and to 15.1% if two potentially lethal complications occurred in one patient. Complex oral-pharyngeal resections and pharyngolaryngectomies had the highest risks of complications and mortality. Mortality following head and neck cancer surgery shows variation across different resection strata. We propose an Informatics-based Framework for Outcomes Surveillance (IFOS) in Head and Neck Surgery for perpetual quality assurance, using the local hospital coding data or its collated destination, the national administrative dataset. © 2016 John Wiley & Sons Ltd.

Medical Management of Acute Radiation Syndromes : Immunoprophylaxis by Antiradiation Vaccine

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey; Casey, Rachael; Kedar, Prasad

Introduction: Traditionally, the treatment of Acute Radiation Syndrome (ARS) includes supportive therapy, cytokine therapy, blood component transfusions and even stem cell transplantation. Recommendations for ARS treatment are based on clinical symptoms, laboratory results, radiation exposure doses and information received from medical examinations. However, the current medical management of ARS does not include immune prophylaxis based on antiradiation vaccines or immune therapy with hyperimmune antiradiation serum. Immuneprophylaxis of ARS could result from stimulating the immune system via immunization with small doses of radiation toxins (Specific Radiation Determinants-SRD) that possess significant immuno-stimulatory properties. Methods: Principles of immuno-toxicology were used to derive this method of immune prophylaxis. An antiradiation vaccine containing a mixture of Hematotoxic, Neurotoxic and Non-bacterial (GI) radiation toxins, underwent modification into a toxoid forms of the original SRD radiation toxins. The vaccine was administered to animals at different times prior to irradiation. The animals were subjected to lethal doses of radiation that induced different forms of ARS at LD 100/30. Survival rates and clinical symptoms were observed in both control and vaccine-treated animals. Results: Vaccination with non-toxic doses of Radiation toxoids induced immunity from the elaborated Specific Radiation Determinant (SRD) toxins. Neutralization of radiation toxins by specific antiradiation antibodies resulted in significantly improved clinical symptoms in the severe forms of ARS and observed survival rates of 60-80% in animals subjected to lethal doses of radiation expected to induce different forms of ARS at LD 100/30. The most effective vaccination schedule for the antiradiation vaccine consisted of repeated injections 24 and 34 days before irradiation. The vaccine remained effective for the next two years, although the specific immune memory probably persists for a much longer time period. Conclusion: The medical management of ARS by the application of an ARS-specific antiradiation vaccine resulted in significant increases of post-radiation survival rates, even in the absence of traditional ARS therapeutic treatments. The decreased mortality and improved clinical symptoms observed in animals treated with the antiradiation vaccine may lessen the burden of medical therapy and pharmaceuticals required for treatment. However, we hypothesize that a combination of the traditional treatment methods and specific immune prophylaxis by an antiradiation vaccine will potentially be even more effective than either alone.

Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder.

PubMed

Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew; Miller, Jeffrey M; Burke, Ainsley; Ogden, R Todd; Parsey, Ramin V; Mann, J John

2015-02-01

Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts.

Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder

PubMed Central

Sullivan, Gregory M.; Oquendo, Maria A.; Milak, Matthew; Miller, Jeffrey M.; Burke, Ainsley; Ogden, R. Todd; Parsey, Ramin V.; Mann, J. John

2015-01-01

IMPORTANCE Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin1A autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES To determine the relationships between brain serotonin1A binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin1A antagonist radiotracer carbon C 11 [11C]–labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin1A binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin1A BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin1A BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin1A BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin1A BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). CONCLUSIONS AND RELEVANCE Higher brainstem raphe serotonin1A BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin1A BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin1A BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts. PMID:25549105

Metal-Polycyclic Aromatic Hydrocarbon Mixture Toxicity in Hyalella azteca. 1. Response Surfaces and Isoboles To Measure Non-additive Mixture Toxicity and Ecological Risk.

PubMed

Gauthier, Patrick T; Norwood, Warren P; Prepas, Ellie E; Pyle, Greg G

2015-10-06

Mixtures of metals and polycyclic aromatic hydrocarbons (PAHs) occur ubiquitously in aquatic environments, yet relatively little is known regarding their potential to produce non-additive toxicity (i.e., antagonism or potentiation). A review of the lethality of metal-PAH mixtures in aquatic biota revealed that more-than-additive lethality is as common as strictly additive effects. Approaches to ecological risk assessment do not consider non-additive toxicity of metal-PAH mixtures. Forty-eight-hour water-only binary mixture toxicity experiments were conducted to determine the additive toxic nature of mixtures of Cu, Cd, V, or Ni with phenanthrene (PHE) or phenanthrenequinone (PHQ) using the aquatic amphipod Hyalella azteca. In cases where more-than-additive toxicity was observed, we calculated the possible mortality rates at Canada's environmental water quality guideline concentrations. We used a three-dimensional response surface isobole model-based approach to compare the observed co-toxicity in juvenile amphipods to predicted outcomes based on concentration addition or effects addition mixtures models. More-than-additive lethality was observed for all Cu-PHE, Cu-PHQ, and several Cd-PHE, Cd-PHQ, and Ni-PHE mixtures. Our analysis predicts Cu-PHE, Cu-PHQ, Cd-PHE, and Cd-PHQ mixtures at the Canadian Water Quality Guideline concentrations would produce 7.5%, 3.7%, 4.4% and 1.4% mortality, respectively.

Infectious and lethal doses of H5N1 highly pathogenic avian influenza virus for house sparrows (Passer domesticus) and rock pigeons (Columbia livia)

USDA-ARS?s Scientific Manuscript database

Terrestrial wild birds commonly associated with poultry farms have the potential to contribute to the spread of H5N1 highly pathogenic avian influenza virus within or between poultry facilities or between domesticated and wild bird populations. This potential, however, varies between species and is...

Inferring the distribution of mutational effects on fitness in Drosophila.

PubMed

Loewe, Laurence; Charlesworth, Brian

2006-09-22

The properties of the distribution of deleterious mutational effects on fitness (DDME) are of fundamental importance for evolutionary genetics. Since it is extremely difficult to determine the nature of this distribution, several methods using various assumptions about the DDME have been developed, for the purpose of parameter estimation. We apply a newly developed method to DNA sequence polymorphism data from two Drosophila species and compare estimates of the parameters of the distribution of the heterozygous fitness effects of amino acid mutations for several different distribution functions. The results exclude normal and gamma distributions, since these predict too few effectively lethal mutations and power-law distributions as a result of predicting too many lethals. Only the lognormal distribution appears to fit both the diversity data and the frequency of lethals. This DDME arises naturally in complex systems when independent factors contribute multiplicatively to an increase in fitness-reducing damage. Several important parameters, such as the fraction of effectively neutral non-synonymous mutations and the harmonic mean of non-neutral selection coefficients, are robust to the form of the DDME. Our results suggest that the majority of non-synonymous mutations in Drosophila are under effective purifying selection.

Lethal cellular changes induced by near ultraviolet radiation.

PubMed

Tyrrell, R M

1979-01-01

There is clear evidence that significant quantities of lesions are induced in DNA by near-UV radiation and that these lesions, although susceptible to repair, may lead to cell death because of the simultaneous disruption of DNA repair systems by the same wavelengths. No particular DNA lesion can be linked to cell death in wild type strains. However, there are good grounds for speculating that a type of near-UV lesion exists which is rapidly "fixed" as a lethal event in cells as a result of the oxygen-dependent disruption of repair. There is a strong indication that the relative ability of various near-UV wavelengths to sensitize cells to heat, chemicals or other radiations is directly related to their efficiency in disrupting DNA repair systems in general. Some important specific questions remain. For example, it is important to ask why breaks formed at 365 nm and 405 nm, although apparently requiring a pol dependent pathway for their repair, do not produce the predicted lethal biological action in the strains tested. In general terms it is hoped to provide more comprehensive physico-chemical data in support of, or contradicting, the proposed model.

Therapeutic use of recombinant human G-CSF (RHG-CSF) in a canine model of sublethal and lethal whole-body irradiation

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

Macvittie, T.J.; Monroy, R.L.; Patchen, M.L.

The short biologic half-life of the peripheral neutrophil (PMN) requires an active granulopoietic response to replenish functional PMSs and to remain a competent host defence in irradiated animals. Recombinant human G-CSF (rhG-CSF) was studied for its ability to modulate hemopoiesis in normal dogs as well as to decrease therapeutically the severity and duration of neutropenia in sublethally and lethally irradiated dogs. For the normal dog, subcutaneous administration of rhG-CSF induced neutrophilia within hours after the first injection; total PMSs continued to increase (with plateau phases) to mean peak values of 1000 per cent of baseline at the end of themore » treatment period (12-14 days). Bone-marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) increased significantly during treatment. For a sublethal 200 cGy dose, treatment with rhG-CSF for 14 consecutive days decreased the severity and shortened the duration of neutropenia and thrombocytopenia. The radiation-induced lethality of 60 per cent after a dose of 350 cGy was associated with marrow-derived GM-CFC survival of 1 per cent.« less

Sex chromosomes in land plants.

PubMed

Ming, Ray; Bendahmane, Abdelhafid; Renner, Susanne S

2011-01-01

Sex chromosomes in land plants can evolve as a consequence of close linkage between the two sex determination genes with complementary dominance required to establish stable dioecious populations, and they are found in at least 48 species across 20 families. The sex chromosomes in hepatics, mosses, and gymnosperms are morphologically heteromorphic. In angiosperms, heteromorphic sex chromosomes are found in at least 19 species from 4 families, while homomorphic sex chromosomes occur in 20 species from 13 families. The prevalence of the XY system found in 44 out of 48 species may reflect the predominance of the evolutionary pathway from gynodioecy towards dioecy. All dioecious species have the potential to evolve sex chromosomes, and reversions back from dioecy to various forms of monoecy, gynodioecy, or androdioecy have also occurred. Such reversals may occur especially during the early stages of sex chromosome evolution before the lethality of the YY (or WW) genotype is established.

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

Peglow, S.G.

We feel that the concept of intercepting a fractionated threat from a tactical ballistic missile is potentially feasible and would have very high payoff for the defense. Many other concepts have been suggested to solve this problem, although they have mostly been more futuristic approaches, e.g. aircrafty based lasers. We also believe that current technologies are not likely to be adequate for the expected types of very small submunition payloads, especially in the presence of relatively simple countermeasures. The MEDUSA concept, or its clones, may very well provide a vehicle for the study of less stressing threats, e.g. separating warheadsmore » and provide a lethality enhancement for non-deployed payloads. An opportunity also exists to investigate alternative technologies, such as the explosively-formed ``disk`` idea. The use of high-precision, limited field-of-view sensor-fuzed munitions is a subject of interest in other Defense Department programs and may have application to the important area of theater missile defense.« less

Antimicrobial activity of topically-applied soyaethyl morpholinium ethosulfate micelles against Staphylococcus species.

PubMed

Yang, Shih-Chun; Aljuffali, Ibrahim A; Sung, Calvin T; Lin, Chwan-Fwu; Fang, Jia-You

2016-03-01

Here we evaluated the antibacterial efficacy of soyaethyl morpholinium ethosulfate (SME) micelles as an inherent bactericide against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). The antimicrobial activity was examined by in vitro culture model and murine model of skin infection. Cationic micelles formed by benzalkonium chloride or cetylpyridinium chloride were used for comparison. The minimum inhibitory concentration and minimum bactericidal concentration against S. aureus and MRSA were 1.71-3.42 and 1.71-6.84 μg/ml, respectively. Topical administration of SME micelles significantly decreased the cutaneous infection and MRSA load in mice. The killing of bacteria was caused by direct cell wall/membrane rupture. SME micelles also penetrated into the bacteria to elicit a Fenton reaction and oxidative stress. SME micelles have potential as antimicrobial agents due to their lethal effect against S. aureus and MRSA with a low toxicity to mammalian cells.

Clinical study and numerical simulation of brain cancer dynamics under radiotherapy

NASA Astrophysics Data System (ADS)

Nawrocki, S.; Zubik-Kowal, B.

2015-05-01

We perform a clinical and numerical study of the progression of brain cancer tumor growth dynamics coupled with the effects of radiotherapy. We obtained clinical data from a sample of brain cancer patients undergoing radiotherapy and compare it to our numerical simulations to a mathematical model of brain tumor cell population growth influenced by radiation treatment. We model how the body biologically receives a physically delivered dose of radiation to the affected tumorous area in the form of a generalized LQ model, modified to account for the conversion process of sublethal lesions into lethal lesions at high radiation doses. We obtain good agreement between our clinical data and our numerical simulations of brain cancer progression given by the mathematical model, which couples tumor growth dynamics and the effect of irradiation. The correlation, spanning a wide dataset, demonstrates the potential of the mathematical model to describe the dynamics of brain tumor growth influenced by radiotherapy.

[Botulism disease].

PubMed

Marcus, Nir; Hourvitz, Ariel

2002-05-01

Botulism is caused by a neurotoxin produced from the anaerobic, spore forming bacteria--clostridium botulinum. The disease is usually caused by toxins type A, B and E. Since the disease was first recognized in the beginning of the nineteenth century as food poisoning, different forms of intoxication were described. Infantile botulism, wound botulism, infectious botulism and inadvertent botulism are all clinical syndromes caused by the same toxin. The attempt to use the botulinum toxin as biological warfare agent is well known. Recently the potential terrorist use of botulinum toxin has become a real concern. Botulism is characterized by its classic triad: 1) symmetric descending flaccid paralysis with prominent bulbar palsies 2) afebrile patient 3) clear sensorium. The paralysis usually begins in the cranial nerves where blurred vision, dysarthia and dysphagia are the initial complaints. Diagnosis is based on clinical findings, history of suspicious exposure and supportive ancillary testing to rule out other causes of neurologic dysfunction that mimic botulism such as the Guillain-Barre syndrome, Myasthenia Gravis or cerebrovascular stroke. Laboratory confirmation of suspected cases is usually delayed and treatment should begin before confirmation is completed. The treatment includes supportive care, and the administration of antitoxin which reduces mortality if given early. Since community and emergency room physicians may be the first to treat patients with any type of botulinum intoxication, they must know how to diagnose and treat this rare but potentially lethal disease.

Technical Guidance for Hazardous Analysis, Emergency Planning for Extremely Hazardous Substances

EPA Pesticide Factsheets

This current guide supplements NRT-1 by providing technical assistance to LEPCs to assess the lethal hazards related to potential airborne releases of extremely hazardous substances (EHSs) as designated under Section 302 of Title Ill of SARA.

Inactivation of Escherichia coli O157:H7 in biofilm on food-contact surfaces by sequential treatments of aqueous chlorine dioxide and drying.

PubMed

Bang, Jihyun; Hong, Ayoung; Kim, Hoikyung; Beuchat, Larry R; Rhee, Min Suk; Kim, Younghoon; Ryu, Jee-Hoon

2014-11-17

We investigated the efficacy of sequential treatments of aqueous chlorine and chlorine dioxide and drying in killing Escherichia coli O157:H7 in biofilms formed on stainless steel, glass, plastic, and wooden surfaces. Cells attached to and formed a biofilm on wooden surfaces at significantly (P ≤ 0.05) higher levels compared with other surface types. The lethal activities of sodium hypochlorite (NaOCl) and aqueous chlorine dioxide (ClO₂) against E. coli O157:H7 in a biofilm on various food-contact surfaces were compared. Chlorine dioxide generally showed greater lethal activity than NaOCl against E. coli O157:H7 in a biofilm on the same type of surface. The resistance of E. coli O157:H7 to both sanitizers increased in the order of wood>plastic>glass>stainless steel. The synergistic lethal effects of sequential ClO₂ and drying treatments on E. coli O157:H7 in a biofilm on wooden surfaces were evaluated. When wooden surfaces harboring E. coli O157:H7 biofilm were treated with ClO₂ (200 μg/ml, 10 min), rinsed with water, and subsequently dried at 43% relative humidity and 22 °C, the number of E. coli O157:H7 on the surface decreased by an additional 6.4 CFU/coupon within 6 h of drying. However, when the wooden surface was treated with water or NaOCl and dried under the same conditions, the pathogen decreased by only 0.4 or 1.0 log CFU/coupon, respectively, after 12 h of drying. This indicates that ClO₂ treatment of food-contact surfaces results in residual lethality to E. coli O157:H7 during the drying process. These observations will be useful when selecting an appropriate type of food-contact surfaces, determining a proper sanitizer for decontamination, and designing an effective sanitization program to eliminate E. coli O157:H7 on food-contact surfaces in food processing, distribution, and preparation environments. Copyright © 2014 Elsevier B.V. All rights reserved.

Studies on ’Macaca mulatta’ Infected with Rocky Mountain Spotted Fever

DTIC Science & Technology

1976-09-10

Mountain spotted fever (RMSF) rickettsiae. The LD50 in monkeys of the yolk-sac-grown seed stock was 10 to the 1.35th power plaque-forming units. Blood...acid glycoprotein, haptoglobin and albumin) were measured during a study in 16 male rhesus monkeys to determine the median lethal dose (LD50) of Rocky

[Generalized congenital fibromatosis (author's transl)].

PubMed

Larrègue, M; Poitou, C; Bressieux, J P; de Giacomoni, P; Vant, F

1977-05-01

About a spontaneously regressive case of osteo-cutaneous congenital fibromatosis, the authors describe the characteristics of the disease (32 observations). Although the majority of cases are sporadic, 3 familial observations are in favour of a dominant autosomal transmission of low penetrance. Study of the familial cases and analysis of the different localisations demonstrate the unicity of the so-called diffuse forms with visceral involvement and of the so-called generalized forms without visceral involvement congenital fibromatosis is characterized by several fibromas at birth: in two-thirds of the cases, it is a purely cutaneous or osteocutaneous form, which disappears spontaneously; in one third of the cases, it is a cutaneous or osteo-cutaneous form with lethal visceral involvement.

Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.

PubMed

Lilly, Elizabeth A; Ikeh, Melanie; Nash, Evelyn E; Fidel, Paul L; Noverr, Mairi C

2018-01-16

Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non- albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h due to robust local and systemic inflammation (sepsis). Surprisingly, inoculation with Candida dubliniensis or Candida glabrata with S. aureus resulted in minimal mortality, and rechallenge of these mice with lethal C. albicans / S. aureus (i.e., coninfection) resulted in >90% protection. The purpose of this study was to define requirements for C. dubliniensis / S. aureus -mediated protection and interrogate the mechanism of the protective response. Protection was conferred by C. dubliniensis alone or by killed C. dubliniensis plus live S. aureus S. aureus alone was not protective, and killed S. aureus compromised C. dubliniensis -induced protection. C. dubliniensis / S. aureus also protected against lethal challenge by NAC plus S. aureus and could protect for a long-term duration (60 days between primary challenge and C. albicans/S. aureus rechallenge). Unexpectedly, mice deficient in T and B cells (Rag-1 knockouts [KO]) survived both the initial C. dubliniensis/S. aureus challenge and the C. albicans/S. aureus rechallenge, indicating that adaptive immunity did not play a role. Similarly, mice depleted of macrophages prior to rechallenge were also protected. In contrast, protection was associated with high numbers of Gr-1 hi polymorphonuclear leukocytes (PMNLs) in peritoneal lavage fluid within 4 h of rechallenge, and in vivo depletion of Gr-1 + cells prior to rechallenge abrogated protection. These results suggest that Candida species can induce protection against a lethal C. albicans / S. aureus IAI that is mediated by PMNLs and postulated to be a unique form of trained innate immunity. IMPORTANCE Polymicrobial intra-abdominal infections are clinically devastating infections with high mortality rates, particularly those involving fungal pathogens, including Candida species. Even in patients receiving aggressive antimicrobial therapy, mortality rates remain unacceptably high. There are no available vaccines against IAI, which is complicated by the polymicrobial nature of the infection. IAI leads to lethal systemic inflammation (sepsis), which is difficult to target pharmacologically, as components of the inflammatory response are also needed to control the infection. Our studies demonstrate that prior inoculation with low-virulence Candida species provides strong protection against subsequent lethal infection with C. albicans and S. aureus Surprisingly, protection is long-lived but not mediated by adaptive (specific) immunity. Instead, protection is dependent on cells of the innate immune system (nonspecific immunity) and provides protection against other virulent Candida species. This discovery implies that a form of trained innate immunity may be clinically effective against polymicrobial IAI. Copyright © 2018 Lilly et al.

Comparing biomarker responses during thermal acclimation: A lethal vs non-lethal approach in a tropical reef clownfish.

PubMed

Madeira, Carolina; Madeira, Diana; Diniz, Mário S; Cabral, Henrique N; Vinagre, Catarina

2017-02-01

Knowledge of thermal stress biology for most tropical fish species in reef ecosystems under climate change is still quite limited. Thus, the objective of this study was to measure the time-course changes of thermal stress biomarkers in the commercially exploited coral reef fish Amphiprion ocellaris, during a laboratory simulated event of increased temperature. Heat shock protein 70kDa (Hsp70) and total ubiquitin (Ub) were determined in the muscle (lethal method) and in the fin (non-lethal alternative method) under two temperature treatments (control - 26°C and elevated temperature - 30°C) throughout one month with weekly samplings. Results suggest that biomarker basal levels are tissue-specific and influence the degree of response under temperature exposure. Responses were highly inducible in the muscle but not in fin tissue, indicating that the latter is not reliable for monitoring purposes. Thermal stress was observed in the muscle after one week of exposure (both biomarkers increased significantly) and Ub levels then decreased, suggesting the animals were able to acclimate by maintaining high levels of Hsp70 and through an effective protein turnover. In addition, the results show that mortality rates did not differ between treatments. This indicates that A. ocellaris is capable of displaying a plastic response to elevated temperature by adjusting the protein quality control system to protect cell functions, without decreasing survival. Thus, this coral reef fish species presents a significant acclimation potential under ocean warming scenarios of +4°C. Monitoring of thermal stress through a non-lethal method, fin-clipping, although desirable proved to be inadequate for this species. Copyright © 2016 Elsevier Inc. All rights reserved.

Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells

PubMed Central

Cardani, Amber; Boulton, Adam; Kim, Taeg S.; Braciale, Thomas J.

2017-01-01

The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. PMID:28085958

A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.

PubMed

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J; Wang, Ping; Sama, Andrew E; Wang, Haichao

2007-03-15

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.

A Cardiovascular Drug Rescues Mice from Lethal Sepsis by Selectively Attenuating a Late-Acting Proinflammatory Mediator, High Mobility Group Box 11

PubMed Central

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J.; Wang, Ping; Sama, Andrew E.; Wang, Haichao

2007-01-01

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10–25 μM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis. PMID:17339485

Role of T Cells and Gamma Interferon during Induction of Hypersensitivity to Lipopolysaccharide by Toxic Shock Syndrome Toxin 1 in Mice

PubMed Central

Dinges, Martin M.; Schlievert, Patrick M.

2001-01-01

The superantigenic function of toxic shock syndrome toxin 1 (TSST-1) is generally regarded as an important determinant of its lethal effects in humans or experimental animals. This study examined the role of superantigenicity in a BALB/c mouse model of lethal TSST-1-induced hypersensitivity to lipopolysaccharide (LPS). In this model, TSST-1 greatly potentiated both LPS-induced lethality, as well as LPS-induced serum tumor necrosis factor alpha (TNF-α) activity. Although BALB/c-SCID mice were resistant to these LPS enhancement effects of TSST-1, BALB/c-SCID mice reconstituted with T cells were completely susceptible to the enhancement effect of TSST-1 on LPS-induced serum TNF-α. Mice pretreated with cyclosporine (Cs) or neutralizing antibodies against gamma interferon (IFN-γ) did not develop lethal LPS hypersensitivity when injected with TSST-1, and these agents reduced the enhancement effect of TSST-1 on LPS-induced serum TNF-α by 99 and 85%, respectively. Cs pretreatment also completely inhibited the known capacity of TSST-1 to amplify LPS-induced levels of IFN-γ in serum. In contrast, mice given Cs after a priming injection of TSST-1, but before LPS, still exhibited lethal hypersensitivity to LPS. Cs given after TSST-1 also did not inhibit enhancement of LPS-induced serum TNF-α by TSST-1 but inhibited the enhancement effect of TSST-1 on LPS-induced serum IFN-γ by 50%. These experiments support the theory that TSST-1-induced hypersensitivity to LPS is mediated primarily by IFN-γ derived from superantigen-activated T cells. PMID:11179286

Dietary Lycopene, Angiogenesis, and Prostate Cancer: A Prospective Study in the Prostate-Specific Antigen Era

PubMed Central

2014-01-01

Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ2 tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; P trend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening. PMID:24463248

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus.

PubMed

Ogg, Monica; Jonsson, Colleen B; Camp, Jeremy V; Hooper, Jay W

2013-11-08

Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.

Cytotoxicity assays with fish cells as an alternative to the acute lethality test with fish.

PubMed

Segner, Helmut

2004-10-01

In ecotoxicology, in vitro assays with fish cells are currently applied for mechanistic studies, bioanalytical purposes and toxicity screening. This paper discusses the potential of cytotoxicity assays with fish cells to reduce, refine or replace acute lethality tests using fish. Basal cytotoxicity data obtained with fish cell lines or fish primary cell cultures show a reasonable to good correlation with lethality data from acute toxicity tests, with the exception of compounds that exert a specific mode of toxic action. Basal cytotoxicity data from fish cell lines also correlate well with cytotoxicity data from mammalian cell lines. However, both the piscine and mammalian in vitro assays are clearly less sensitive than the fish test. Therefore, in vivo LC50 values (concentrations of the test compounds that are lethal to 50% of the fish in the experiment within 96 hours) currently cannot be predicted from in vitro values. This in vitro-in vivo difference in sensitivity appears to be true for both fish cell lines and mammalian cell lines. Given the good in vitro-in vivo correlation in toxicity ranking, together with the clear-cut difference in sensitivity, the role of cytotoxicity assays in a tiered alternative testing strategy could be in priority setting in relation to toxic hazard and in the toxicity classification of chemicals and environmental samples.

Lethal and sub-lethal effects of five pesticides used in rice farming on the earthworm Eisenia fetida.

PubMed

Rico, Andreu; Sabater, Consuelo; Castillo, María-Ángeles

2016-05-01

The toxicity of five pesticides typically used in rice farming (trichlorfon, dimethoate, carbendazim, tebuconazole and prochloraz) was evaluated on different lethal and sub-lethal endpoints of the earthworm Eisenia fetida. The evaluated endpoints included: avoidance behaviour after an exposure period of 2 days; and mortality, weight loss, enzymatic activities (cholinesterase, lactate dehydrogenase and alkaline phosphatase) and histopathological effects after an exposure period of 14 days. Carbendazim was found to be highly toxic to E. fetida (LC50=2mg/kg d.w.), significantly reducing earthworm weight and showing an avoidance response at soil concentrations that are close to those predicted in rice-fields and in surrounding ecosystems. The insecticide dimethoate showed a moderate acute toxicity (LC50=28mg/kg d.w.), whereas the rest of tested pesticides showed low toxicity potential (LC50 values above 100mg/kg d.w.). For these pesticides, however, weight loss was identified as a sensitive endpoint, with NOEC values approximately 2 times or lower than the calculated LC10 values. The investigated effects on the enzymatic activities of E. fetida and the observed histopathological alterations (longitudinal and circular muscle lesions, edematous tissues, endothelial degeneration and necrosis) proved to be sensitive biomarkers to monitor pesticide contamination and are proposed as alternative measures to evaluate pesticide risks on agro-ecosystems. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of salinity on the upper lethal temperature tolerance of early-juvenile red drum.

PubMed

McDonald, Dusty; Bumguardner, Britt; Cason, Paul

2015-10-01

Previous work investigating the temperature tolerance of juvenile red drum ranging 18-50mm TL found evidence for positive size dependence (smaller fish less tolerant to higher temperatures) suggesting smaller size classes (<18mm TL) potentially may succumb to extreme summer water temperatures. Here, we explored the upper lethal temperature tolerance (ULT) in smaller-sized red drum which ranged from 10 to 20mm TL across multiple salinities to further understand the thermal limitations of this propagated game fish. In order to investigate the combined effect of temperature and salinity on ULT, temperature trials were conducted under three levels of salinity which commonly occur along the coast of Texas (25, 35, and 45ppt). The rate of temperature increase (+0.25°C/h) was designed to mimic a natural temperature increase of a summer day in Texas. We determined that the lethal temperature at 50% (LT50) did not differ between the three salinities examined statistically; median lethal temperature for individuals exposed to 25ppt ranged from 36.4 to 37.7°C, 35ppt ranged from 36.4 to 37.7°C, and 45ppt ranged from 36.1 to 37.4°C. Further, LT50 data obtained here for early-juvenile red drum did not differ from data of a similar experiment examining 25mm TL sized fish. Published by Elsevier Ltd.

Prevention and treatment of Clostridium perfringens epsilon toxin intoxication in mice with a neutralizing monoclonal antibody (c4D7) produced in Nicotiana benthamiana.

PubMed

Garcia, J P; Beingesser, J; Bohorov, O; Bohorova, N; Goodman, C; Kim, D; Pauly, M; Velasco, J; Whaley, K; Zeitlin, L; Roy, C J; Uzal, F A

2014-09-01

Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, is among the most lethal toxins known. ETX is a potential bioterrorism threat that was listed as a Category B agent by the U.S. Centers for Disease Control until 2012 and it still remains a toxin of interest for several government agencies. We produced a monoclonal antibody (MAb) against ETX (ETX MAb c4D7) in Nicotiana benthamiana and characterized its preventive and therapeutic efficacy in mice. The ETX preparation used was highly lethal for mice (LD50 = 1.6 μg/kg) and resulted in a mean time from inoculation to death of 18 and 180 min when administered intravenously or intraperitoneally, respectively. High lethal challenge resulted in dramatic increases of a variety of pro-inflammatory cytokines in serum, while lower, but still lethal doses, did not elicit such responses. ETX MAb c4D7 was highly effective prophylactically (ED50 = 0.3 mg/kg; ED100 = 0.8 mg/kg) and also provided protection when delivered 15-30 min post-ETX intoxication. These data suggest that ETX MAb c4D7 may have use as a pre- and post-exposure treatment for ETX intoxication. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fine-tuning synthesis of Yersinia pestis LcrV from runaway-like replication balanced-lethal plasmid in a Salmonella enterica serovar typhimurium vaccine induces protection against a lethal Y. pestis challenge in mice.

PubMed

Torres-Escobar, Ascención; Juárez-Rodríguez, María Dolores; Gunn, Bronwyn M; Branger, Christine G; Tinge, Steven A; Curtiss, Roy

2010-06-01

A balanced-lethal plasmid expression system that switches from low-copy-number to runaway-like high-copy-number replication (pYA4534) was constructed for the regulated delayed in vivo synthesis of heterologous antigens by vaccine strains. This is an antibiotic resistance-free maintenance system containing the asdA gene (essential for peptidoglycan synthesis) as a selectable marker to complement the lethal chromosomal DeltaasdA allele in live recombinant attenuated Salmonella vaccines (RASVs) such as Salmonella enterica serovar Typhimurium strain chi9447. pYA4534 harbors two origins of replication, pSC101 and pUC (low and high copy numbers, respectively). The pUC replication origin is controlled by a genetic switch formed by the operator/promoter of the P22 cro gene (O/P(cro)) (P(R)), which is negatively regulated by an arabinose-inducible P22 c2 gene located on both the plasmid and the chromosome (araC P(BAD) c2). The absence of arabinose, which is unavailable in vivo, triggers replication to a high-copy-number plasmid state. To validate these vector attributes, the Yersinia pestis virulence antigen LcrV was used to develop a vaccine against plague. An lcrV sequence encoding amino acids 131 to 326 (LcrV196) was optimized for expression in Salmonella, flanked with nucleotide sequences encoding the signal peptide (SS) and the carboxy-terminal domain (CT) of beta-lactamase, and cloned into pYA4534 under the control of the P(trc) promoter to generate plasmid pYA4535. Our results indicate that the live Salmonella vaccine strain chi9447 harboring pYA4535 efficiently stimulated a mixed Th1/Th2 immune response that protected mice against lethal challenge with Y. pestis strain CO92 introduced through either the intranasal or subcutaneous route.

Fine-Tuning Synthesis of Yersinia pestis LcrV from Runaway-Like Replication Balanced-Lethal Plasmid in a Salmonella enterica Serovar Typhimurium Vaccine Induces Protection against a Lethal Y. pestis Challenge in Mice▿

PubMed Central

Torres-Escobar, Ascención; Juárez-Rodríguez, María Dolores; Gunn, Bronwyn M.; Branger, Christine G.; Tinge, Steven A.; Curtiss, Roy

2010-01-01

A balanced-lethal plasmid expression system that switches from low-copy-number to runaway-like high-copy-number replication (pYA4534) was constructed for the regulated delayed in vivo synthesis of heterologous antigens by vaccine strains. This is an antibiotic resistance-free maintenance system containing the asdA gene (essential for peptidoglycan synthesis) as a selectable marker to complement the lethal chromosomal ΔasdA allele in live recombinant attenuated Salmonella vaccines (RASVs) such as Salmonella enterica serovar Typhimurium strain χ9447. pYA4534 harbors two origins of replication, pSC101 and pUC (low and high copy numbers, respectively). The pUC replication origin is controlled by a genetic switch formed by the operator/promoter of the P22 cro gene (O/Pcro) (PR), which is negatively regulated by an arabinose-inducible P22 c2 gene located on both the plasmid and the chromosome (araC PBAD c2). The absence of arabinose, which is unavailable in vivo, triggers replication to a high-copy-number plasmid state. To validate these vector attributes, the Yersinia pestis virulence antigen LcrV was used to develop a vaccine against plague. An lcrV sequence encoding amino acids 131 to 326 (LcrV196) was optimized for expression in Salmonella, flanked with nucleotide sequences encoding the signal peptide (SS) and the carboxy-terminal domain (CT) of β-lactamase, and cloned into pYA4534 under the control of the Ptrc promoter to generate plasmid pYA4535. Our results indicate that the live Salmonella vaccine strain χ9447 harboring pYA4535 efficiently stimulated a mixed Th1/Th2 immune response that protected mice against lethal challenge with Y. pestis strain CO92 introduced through either the intranasal or subcutaneous route. PMID:20308296

Integrative characterization of the venom of the coral snake Micrurus dumerilii (Elapidae) from Colombia: Proteome, toxicity, and cross-neutralization by antivenom.

PubMed

Rey-Suárez, Paola; Núñez, Vitelbina; Fernández, Julián; Lomonte, Bruno

2016-03-16

In Colombia, nearly 2.8% of the 4200 snakebite accidents recorded annually are inflicted by coral snakes (genus Micrurus). Micrurus dumerilii has a broad distribution in this country, especially in densely populated areas. The proteomic profile of its venom was here studied by a bottom-up approach combining RP-HPLC, SDS-PAGE and MALDI-TOF/TOF. Venom proteins were assigned to eleven families, the most abundant being phospholipases A2 (PLA2; 52.0%) and three-finger toxins (3FTx; 28.1%). This compositional profile shows that M. dumerilii venom belongs to the 'PLA2-rich' phenotype, in the recently proposed dichotomy for Micrurus venoms. Enzymatic and toxic venom activities correlated with protein family abundances. Whole venom induced a conspicuous myotoxic, cytotoxic and anticoagulant effect, and was mildly edematogenic and proteolytic, whereas it lacked hemorrhagic activity. Some 3FTxs and PLA2s reproduced the lethal effect of venom. A coral snake antivenom to Micrurus nigrocinctus demonstrated significant cross-recognition of M. dumerilii venom proteins, and accordingly, ability to neutralize its lethal effect. The combined compositional, functional, and immunological data here reported for M. dumerilii venom may contribute to a better understanding of these envenomings, and support the possible use of anti-M. nigrocinctus coral snake antivenom in their treatment. Coral snakes represent a highly diversified group of elapids in the New World, with nearly 70 species within the genus Micrurus. Owing to their scarce yields, the biochemical composition and toxic activities of coral snake venoms have been less well characterized than those of viperid species. In this work, an integrative view of the venom of M. dumerilii, a medically relevant coral snake from Colombia, was obtained by a combined proteomic, functional, and immunological approach. The venom contains proteins from at least eleven families, with a predominance of phospholipases A2 (PLA2), followed by three-finger toxins (3FTx). According to its compositional profile, M. dumerilii venom can be grouped with those of several Micrurus species from North and Central America that present a PLA2-predominant phenotype, to date it is the most southerly coral snake species to do so. Other coral snake species that a 'PLA2-rich' venom, M. dumerilii venom contains both components that form MitTx, a pain-inducing heterodimeric complex recently characterized from the venom of Micrurus tener, also present in Micrurus mosquitensis and M. nigrocinctus venoms. In addition to a lethal three-finger toxin, PLA2s participate in the toxicity of M. dumerilii venom, some of them displaying ability to induce cytolysis, muscle necrosis, and lethality to mice. An antivenom to M. nigrocinctus demonstrated significant cross-recognition of M. dumerilii venom proteins, and accordingly, ability to neutralize its lethal effect, being of potential therapeutic usefulness in these envenomings. Copyright © 2016 Elsevier B.V. All rights reserved.

CSF Analysis

MedlinePlus

... one or more hours to avoid a potential post-test headache. The lumbar puncture procedure usually takes less ... in CSF with laboratory tests such as molecular tests or culture. Parasitic meningitis or encephalitis are rare and can be lethal. One example is an infection caused by the free-living ...

The role of monamine oxidase inhibition in the acute toxicity of chlordimeform.

DOT National Transportation Integrated Search

1977-08-01

This paper presents data from experiments on male rats performed to determine whether drugs which interfere with central amine mechanisms would decrease the lethality of the acaricide chlordimeform (and thus be of potential value as antidotes for acc...

Comprehensive analysis of venom from the scorpion Centruroides tecomanus reveals compounds with antimicrobial, cytotoxic, and insecticidal activities.

PubMed

Valdez-Velazquéz, L L; Romero-Gutierrez, M T; Delgado-Enciso, I; Dobrovinskaya, O; Melnikov, V; Quintero-Hernández, V; Ceballos-Magaña, S G; Gaitan-Hinojosa, M A; Coronas, F I; Puebla-Perez, A M; Zamudio, F; De la Cruz-García, I; Vázquez-Vuelvas, O F; Soriano-Hernandez, A D; Possani, L D

2016-08-01

Centruroides tecomanus is a medically important scorpion of the state of Colima (Mexico). This communication reports the identification of venom components of this scorpion with biological activity over insects/crickets (Acheta domestica), crustaceans/fresh water shrimps (Cambarellus montezumae), and mammalians/mice (Mus musculus, strain CD1). It also describes the pharmacological effects on cell lines in culture (L5178Y cells, HeLa cells, HuTu cells and Jurkat E6-1 cells), as well as on several types of bacteria (see below). The soluble venom of this scorpion was fractionated by high-performance liquid chromatography (HPLC) and collected separately in twelve independent fractions collected over 60 min run (5 min time apart each other). The HPLC components of fraction VII were lethal to all three species used for assay. The IVth fraction had a toxic effect on freshwater shrimps. In this species, fractions VI, VII and VIII were all lethal. For crickets, fractions V and VI were toxic and fraction VII was lethal. In mouse, the lethal components were found in fraction VII, whereas fraction VIII was toxic, but not lethal, at the doses assayed. The molecular weight of peptides from the various group of fractions were identified by mass spectrometry determination. Components lethal to mice showed molecular weights from 7013 to 7487 Da. Two peptides were obtained in homogeneous form and shown to be lethal to the three species of animal used for assay. The soluble venom tested on L5178Y cell line survival was shown to be cytotoxic, at 10-100 μg/mL concentration, when compared to control murine splenocytes (p = 0.007). The soluble venom applied to Hela, Hutu and Jurkat cell lines did not show cytotoxic effects at these concentrations. On the contrary, it seems to have a proliferative effect. However the HPLC fractions I, III, VI and XII do have a cytotoxic effect on Jurkat E06-1 cells in culture at 200 μg/mL concentration. The antimicrobial activity of the venom fractions on Staphylococcus aureus (gram-positive), Escherichia coli, Pseudomonas aeruginosa y Salmonella spp (gram-negative) was measured, using the liquid inhibition growth system. The four strains of bacteria used were susceptible to fractions III and IV, affecting all four bacterial strains at concentrations below 5 μg/mL. Copyright © 2016 Elsevier Ltd. All rights reserved.

The absence of cruelty is not the presence of humanness: physicians and the death penalty in the United States.

PubMed

Zivot, Joel B

2012-12-03

The death penalty by lethal injection is a legal punishment in the United States. Sodium Thiopental, once used in the death penalty cocktail, is no longer available for use in the United States as a consequence of this association. Anesthesiologists possess knowledge of Sodium Thiopental and possible chemical alternatives. Further, lethal injection has the look and feel of a medical act thereby encouraging physician participation and comment. Concern has been raised that the death penalty by lethal injection, is cruel. Physicians are ethically directed to prevent cruelty within the doctor-patient relationship and ethically prohibited from participation in any component of the death penalty. The US Supreme Court ruled that the death penalty is not cruel per se and is not in conflict with the 8th amendment of the US constitution. If the death penalty is not cruel, it requires no further refinement. If, on the other hand, the death penalty is in fact cruel, physicians have no mandate outside of the doctor patient relationship to reduce cruelty. Any intervention in the name of cruelty reduction, in the setting of lethal injection, does not lead to a more humane form of punishment. If physicians contend that the death penalty can be botched, they wrongly direct that it can be improved. The death penalty cocktail, as a method to reduce suffering during execution, is an unverifiable claim. At best, anesthetics produce an outward appearance of calmness only and do not address suffering as a consequence of the anticipation of death on the part of the condemned.

The absence of cruelty is not the presence of humanness: physicians and the death penalty in the United States

PubMed Central

2012-01-01

The death penalty by lethal injection is a legal punishment in the United States. Sodium Thiopental, once used in the death penalty cocktail, is no longer available for use in the United States as a consequence of this association. Anesthesiologists possess knowledge of Sodium Thiopental and possible chemical alternatives. Further, lethal injection has the look and feel of a medical act thereby encouraging physician participation and comment. Concern has been raised that the death penalty by lethal injection, is cruel. Physicians are ethically directed to prevent cruelty within the doctor-patient relationship and ethically prohibited from participation in any component of the death penalty. The US Supreme Court ruled that the death penalty is not cruel per se and is not in conflict with the 8th amendment of the US constitution. If the death penalty is not cruel, it requires no further refinement. If, on the other hand, the death penalty is in fact cruel, physicians have no mandate outside of the doctor patient relationship to reduce cruelty. Any intervention in the name of cruelty reduction, in the setting of lethal injection, does not lead to a more humane form of punishment. If physicians contend that the death penalty can be botched, they wrongly direct that it can be improved. The death penalty cocktail, as a method to reduce suffering during execution, is an unverifiable claim. At best, anesthetics produce an outward appearance of calmness only and do not address suffering as a consequence of the anticipation of death on the part of the condemned. PMID:23199336

Network-centric decision architecture for financial or 1/f data models

NASA Astrophysics Data System (ADS)

Jaenisch, Holger M.; Handley, James W.; Massey, Stoney; Case, Carl T.; Songy, Claude G.

2002-12-01

This paper presents a decision architecture algorithm for training neural equation based networks to make autonomous multi-goal oriented, multi-class decisions. These architectures make decisions based on their individual goals and draw from the same network centric feature set. Traditionally, these architectures are comprised of neural networks that offer marginal performance due to lack of convergence of the training set. We present an approach for autonomously extracting sample points as I/O exemplars for generation of multi-branch, multi-node decision architectures populated by adaptively derived neural equations. To test the robustness of this architecture, open source data sets in the form of financial time series were used, requiring a three-class decision space analogous to the lethal, non-lethal, and clutter discrimination problem. This algorithm and the results of its application are presented here.

Exposure to Glycolytic Carbon Sources Reveals a Novel Layer of Regulation for the MalT Regulon

PubMed Central

Reimann, Sylvia A.; Wolfe, Alan J.

2011-01-01

Bacteria adapt to changing environments by means of tightly coordinated regulatory circuits. The use of synthetic lethality, a genetic phenomenon in which the combination of two nonlethal mutations causes cell death, facilitates identification and study of such circuitry. In this study, we show that the E. coli ompR malT con double mutant exhibits a synthetic lethal phenotype that is environmentally conditional. MalTcon, the constitutively active form of the maltose system regulator MalT, causes elevated expression of the outer membrane porin LamB, which leads to death in the absence of the osmoregulator OmpR. However, the presence and metabolism of glycolytic carbon sources, such as sorbitol, promotes viability and unveils a novel layer of regulation within the complex circuitry that controls maltose transport and metabolism. PMID:21912549

Exposure to Glycolytic Carbon Sources Reveals a Novel Layer of Regulation for the MalT Regulon.

PubMed

Reimann, Sylvia A; Wolfe, Alan J

2011-01-01

Bacteria adapt to changing environments by means of tightly coordinated regulatory circuits. The use of synthetic lethality, a genetic phenomenon in which the combination of two nonlethal mutations causes cell death, facilitates identification and study of such circuitry. In this study, we show that the E. coli ompR malT(con) double mutant exhibits a synthetic lethal phenotype that is environmentally conditional. MalT(con), the constitutively active form of the maltose system regulator MalT, causes elevated expression of the outer membrane porin LamB, which leads to death in the absence of the osmoregulator OmpR. However, the presence and metabolism of glycolytic carbon sources, such as sorbitol, promotes viability and unveils a novel layer of regulation within the complex circuitry that controls maltose transport and metabolism.

Microbial survival in deep space environment.

NASA Technical Reports Server (NTRS)

Silverman, G. J.

1971-01-01

Review of the knowledge available on the extent to which microorganisms (mainly microbial spores, vegetative cells, and fungi) are capable of surviving the environment of deep space, based on recent simulation experiments of deep space. A description of the experimental procedures used is followed by a discussion of deep space ecology, the behavior of microorganisms in ultrahigh vacuum, and factors influencing microbial survival. It is concluded that, so far, simulation experiments have proved far less lethal to microorganisms than to other forms of life. There are, however, wide gaps in the knowledge available, and no accurate predictions can as yet be made on the degree of lethality that might be incurred by a microbial population on a given mission. Therefore, sterilization of spacecraft surfaces is deemed necessary if induced panspermia (i.e., interplanetary life propagation) is to be avoided.

Protective Efficacy of Newcastle Disease Virus Expressing Soluble Trimeric Hemagglutinin against Highly Pathogenic H5N1 Influenza in Chickens and Mice

PubMed Central

Cornelissen, Lisette A. H. M.; de Leeuw, Olav S.; Tacken, Mirriam G.; Klos, Heleen C.; de Vries, Robert P.; de Boer-Luijtze, Els A.; van Zoelen-Bos, Diana J.; Rigter, Alan; Rottier, Peter J. M.; Moormann, Rob J. M.; de Haan, Cornelis A. M.

2012-01-01

Background Highly pathogenic avian influenza virus (HPAIV) causes a highly contagious often fatal disease in poultry, resulting in significant economic losses in the poultry industry. HPAIV H5N1 also poses a major public health threat as it can be transmitted directly from infected poultry to humans. One effective way to combat avian influenza with pandemic potential is through the vaccination of poultry. Several live vaccines based on attenuated Newcastle disease virus (NDV) that express influenza hemagglutinin (HA) have been developed to protect chickens or mammalian species against HPAIV. However, the zoonotic potential of NDV raises safety concerns regarding the use of live NDV recombinants, as the incorporation of a heterologous attachment protein may result in the generation of NDV with altered tropism and/or pathogenicity. Methodology/Principal Findings In the present study we generated recombinant NDVs expressing either full length, membrane-anchored HA of the H5 subtype (NDV-H5) or a soluble trimeric form thereof (NDV-sH53). A single intramuscular immunization with NDV-sH53 or NDV-H5 fully protected chickens against disease after a lethal challenge with H5N1 and reduced levels of virus shedding in tracheal and cloacal swabs. NDV-sH53 was less protective than NDV-H5 (50% vs 80% protection) when administered via the respiratory tract. The NDV-sH53 was ineffective in mice, regardless of whether administered oculonasally or intramuscularly. In this species, NDV-H5 induced protective immunity against HPAIV H5N1, but only after oculonasal administration, despite the poor H5-specific serum antibody response it elicited. Conclusions/Significance Although NDV expressing membrane anchored H5 in general provided better protection than its counterpart expressing soluble H5, chickens could be fully protected against a lethal challenge with H5N1 by using the latter NDV vector. This study thus provides proof of concept for the use of recombinant vector vaccines expressing a soluble form of a heterologous viral membrane protein. Such vectors may be advantageous as they preclude the incorporation of heterologous membrane proteins into the viral vector particles. PMID:22952980

Evaluation of photodynamic antimicrobial therapy (PACT) against promastigotes form of the Leishmania (Viannia) braziliensis: in vitro study

NASA Astrophysics Data System (ADS)

Barbosa, Artur F. S.; Sangiorgi, Bruno B.; Galdino, Suely L.; Pitta, Ivan R.; Barral Netto, Manoel; Correia, Neandder A.; Pinheiro, Antônio L. B.

2012-03-01

Leishmaniasis is a complex disease that affects more than 12 million people in 88 countries worldwide. Leishmania (Viannia) braziliensis is the most common species in the Americas and the most important causative agent of cutaneous and mucocutaneous leishmaniasis in Brazil. The therapeutic arsenal routinely employed to treat patients with leishmaniasis is limited and unsatisfactory. For cutaneous leishmaniasis, pentavalent antimonials are the first line therapeutic scheme recommended by the WHO. These compounds are highly toxic, poorly tolerated and their effectiveness highly variable. In this work, a technique with, so far, an unknown disadvantage is discussed. The aim of this study was to verify the effectiveness of PACT in vitro, as a new technique for the treatment of Leishmaniasis. For this, semiconductor laser (λ = 660nm, 40mW, 4.2J/cm2, CW) associated to phenothiazine's derivatives (5 and 10 μg/ml, TBO, Methylene Blue or Phenothiazine) on the promastigotes form of Leishmania braziliensis in a single session was used. Viability of the parasites was assessed in quadruplicates of each group. The samples were removed and analyzed in a hemocytometer 72h after PACT. We found an important decrease in the number of viable parasites on all treated groups in comparison to their controls. The results of present study showed significant percentage of lethality (above 95%) of the protocol. The 99.23% of lethality was achieved with 10 μg/ml of TBO. No lethality was seen on groups treated neither with laser nor with each compounds separately. The results are promising and indicative that the use of PACT may be a powerful treatment of leishmaniasis when compared to already available ones.

Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation

PubMed Central

Gregory, L. C.; Humayun, K. N.; Turton, J. P. G.; McCabe, M. J.; Rhodes, S. J.

2015-01-01

Background: LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. Objective/Hypothesis: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. Method: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. Results: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. Conclusion: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life. PMID:25871839

Knockdown of RNA interference pathway genes in western corn rootworm, Diabrotica virgifera virgifera, identifies no fitness costs associated with Argonaute 2 or Dicer-2.

PubMed

Camargo, Carolina; Wu, Ke; Fishilevich, Elane; Narva, Kenneth E; Siegfried, Blair D

2018-06-01

The use of transgenic crops that induce silencing of essential genes using double-stranded RNA (dsRNA) through RNA interference (RNAi) in western corn rootworm, Diabrotica virgifera virgifera, is likely to be an important component of new technologies for the control of this important corn pest. Previous studies have demonstrated that the dsRNA response in D. v. virgifera depends on the presence of RNAi pathway genes including Dicer-2 and Argonaute 2, and that downregulation of these genes limits the lethality of environmental dsRNA. A potential resistance mechanism to lethal dsRNA may involve loss of function of RNAi pathway genes. Howver, the potential for resistance to evolve may depend on whether these pathway genes have essential functions such that the loss of function of core proteins in the RNAi pathway will have fitness costs in D. v. virgifera. Fitness costs associated with potential resistance mechanisms have a central role in determining how resistance can evolve to RNAi technologies in western corn rootworm. We evaluated the effect of dsRNA and microRNA pathway gene knockdown on the development of D. v. virgifera larvae through short-term and long-term exposures to dsRNA for Dicer and Argonaute genes. Downregulation of Argonaute 2, Dicer-2, Dicer-1 did not significantly affect larval survivorship or development through short and long-term exposure to dsRNA. However, downregulation of Argonaute 1 reduced larval survivorship and delayed development. The implications of these results as they relate to D. v. virgifera resistance to lethal dsRNA are discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression

PubMed Central

Grillo-Hill, Bree K; Choi, Changhoon; Jimenez-Vidal, Maite; Barber, Diane L

2015-01-01

Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increase proliferation and migration as well as limit apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H+ efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive primary tumor cell lines with inhibiting H+ efflux. Synthetic lethality with reduced H+ efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off-target effects. DOI: http://dx.doi.org/10.7554/eLife.03270.001 PMID:25793441

Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster

PubMed Central

Hepburn, Dion D. D.; Xiao, Jiarong; Bindom, Sharell; Vincent, John B.; O'Donnell, Janis

2003-01-01

The nutritional dietary supplement chromium picolinate, [Cr(pic)3], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic)3] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic)3] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster. [Cr(pic)3], but not CrCl3, at levels of 260 μg Cr/kg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility. PMID:12649323

Effects of polystyrene microbeads in marine planktonic crustaceans.

PubMed

Gambardella, Chiara; Morgana, Silvia; Ferrando, Sara; Bramini, Mattia; Piazza, Veronica; Costa, Elisa; Garaventa, Francesca; Faimali, Marco

2017-11-01

Plastic debris accumulates in the marine environment, fragmenting into microplastics (MP), causing concern about their potential toxic effects when ingested by marine organisms. The aim of this study was to verify whether 0.1µm polystyrene beads are likely to trigger lethal and sub-lethal responses in marine planktonic crustaceans. MP build-up, mortality, swimming speed alteration and enzyme activity (cholinesterases, catalase) were investigated in the larval stages of Amphibalanus amphitrite barnacle and of Artemia franciscana brine shrimp exposed to a wide range of MP concentrations (from 0.001 to 10mgL -1 ) for 24 and 48h. The results show that MP were accumulated in crustaceans, without affecting mortality. Swimming activity was significantly altered in crustaceans exposed to high MP concentrations (> 1mgL -1 ) after 48h. Enzyme activities were significantly affected in all organisms exposed to all the above MP concentrations, indicating that neurotoxic effects and oxidative stress were induced after MP treatment. These findings provide new insight into sub-lethal MP effects on marine crustaceans. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of reduced risk pesticides for use in greenhouse vegetable production on Bombus impatiens (Hymenoptera: Apidae).

PubMed

Gradish, Angela E; Scott-Dupree, Cynthia D; Shipp, Les; Harris, C Ron; Ferguson, Gillian

2010-02-01

Bumble bees [Bombus impatiens (Cresson)] are widely used for supplemental pollination of greenhouse vegetables and are at risk of pesticide exposure while foraging. The objective of this study was to determine the lethal and sub-lethal effects of four insecticides (imidacloprid, abamectin, metaflumizone and chlorantraniliprole) and three fungicides (myclobutanil, potassium bicarbonate and cyprodinil + fludioxonil) used or with potential for use in Ontario greenhouse vegetable production to B. impatiens. Imidacloprid, abamectin, and metaflumizone were harmful to worker bees following direct contact, while chlorantraniliprole and all fungicides tested were harmless. Worker bees fed imidacloprid-contaminated pollen had shortened life spans and were unable to produce brood. Worker bees consumed less pollen contaminated with abamectin. Metaflumizone, chlorantraniliprole and all fungicides tested caused no sub-lethal effects in bumble bee micro-colonies. We conclude that the new reduced risk insecticides metaflumizone and chlorantraniliprole and the fungicides myclobutanil, potassium bicarbonate and cyprodinil + fludioxonil are safe for greenhouse use in the presence of bumble bees. This information can be used preserve greenhouse pollination programs while maintaining acceptable pest management.

Purification and biophysical characterization of the core protease domain of anthrax lethal factor

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

Gkazonis, Petros V.; Dalkas, Georgios A.; Chasapis, Christos T.

2010-06-04

Anthrax lethal toxin (LeTx) stands for the major virulence factor of the anthrax disease. It comprises a 90 kDa highly specific metalloprotease, the anthrax lethal factor (LF). LF possesses a catalytic Zn{sup 2+} binding site and is highly specific against MAPK kinases, thus representing the most potent native biomolecule to alter and inactivate MKK [MAPK (mitogen-activated protein kinase) kinases] signalling pathways. Given the importance of the interaction between LF and substrate for the development of anti-anthrax agents as well as the potential treatment of nascent tumours, the analysis of the structure and dynamic properties of the LF catalytic site aremore » essential to elucidate its enzymatic properties. Here we report the recombinant expression and purification of a C-terminal part of LF (LF{sub 672-776}) that harbours the enzyme's core protease domain. The biophysical characterization and backbone assignments ({sup 1}H, {sup 13}C, {sup 15}N) of the polypeptide revealed a stable, well folded structure even in the absence of Zn{sup 2+}, suitable for high resolution structural analysis by NMR.« less

Immobilized Hydrolytic Enzymes Exhibit Antibiofilm Activity Against Escherichia coli at Sub-Lethal Concentrations.

PubMed

Villa, Federica; Secundo, Francesco; Polo, Andrea; Cappitelli, Francesca

2015-07-01

The effects of two commercially available immobilized enzymes (namely the glycosidase pectinase and the protease subtilisin A) at sub-lethal concentrations were investigated in terms of their influence on biofilm genesis, on the composition of the biofilm matrix, and their antibiotic synergy against Escherichia coli biofilm, used as a model system of bacterial biofilms. The best antibiofilm performance of solid-supported hydrolases was obtained at the surface concentration of 0.022 and 0.095 U/cm(2) with a reduction of 1.2 and 2.3 log CFU/biofilm for pectinase and subtilisin, respectively. At these enzyme surface concentrations, the biocatalysts affected the structural composition of the biofilm matrix, impacting biofilm thickness. Finally, the immobilized hydrolases enhanced biofilm sensitivity to a clinically relevant concentration of the antibiotic ampicillin. At the final antibiotic concentration of 0.1 mg/ml, a reduction of 2 and 3.5 log10 units in presence of 0.022 Upectinase/cm(2) and 0.095 Usubtilisin/cm(2) was obtained, respectively, in comparison the antibiotic alone. Immobilized pectinase and subtilisin at sub-lethal concentrations demonstrated a great potential for antibiofilm applications.

Linking ciguatera poisoning to spatial ecology of fish: a novel approach to examining the distribution of biotoxin levels in the great barracuda by combining non-lethal blood sampling and biotelemetry.

PubMed

O'Toole, Amanda C; Dechraoui Bottein, Marie-Yasmine; Danylchuk, Andy J; Ramsdell, John S; Cooke, Steven J

2012-06-15

Ciguatera in humans is typically caused by the consumption of reef fish that have accumulated Ciguatoxins (CTXs) in their flesh. Over a six month period, we captured 38 wild adult great barracuda (Sphyraena barracuda), a species commonly associated with ciguatera in The Bahamas. We sampled three tissues (i.e., muscle, liver, and blood) and analysed them for the presence of ciguatoxins using a functional in vitro N2A bioassay. Detectable concentrations of ciguatoxins found in the three tissue types ranged from 2.51 to 211.74pg C-CTX-1 equivalents/g. Blood and liver toxin concentrations were positively correlated (ρ=0.86, P=0.003), indicating that, for the first time, blood sampling provides a non-lethal method of detecting ciguatoxin in wild fish. Non-lethal blood sampling also presents opportunities to couple this approach with biotelemetry and biologging techniques that enable the study of fish distribution and movement. To demonstrate the potential for linking ciguatoxin occurrence with barracuda spatial ecology, we also present a proof-of-concept case study where blood samples were obtained from 20 fish before releasing them with acoustic transmitters and tracking them in the coastal waters using a fixed acoustic telemetry array covering 44km(2). Fish that tested positive for CTX may have smaller home ranges than non-toxic fish (median distance travelled, U=2.21, P=0.03). Results presented from this study may help identify high risk areas and source-sink dynamics of toxins, potentially reducing the incidence and human health risk of ciguatera fish poisoning. Moreover, development of the non-lethal sampling approach and measurement of ciguatera from blood provide future opportunities to understand the mechanistic relationship between toxins and the spatial ecology of a broad range of marine fish species. Copyright © 2012 Elsevier B.V. All rights reserved.

Anti-NMDA Encephalitis: An Uncommon, Autoimmune Mediated Form of Encephalitis

PubMed Central

Azizyan, Avetis; Albrektson, Joshua R; Maya, Marcel M; Pressman, Barry D; Moser, Franklin

2014-01-01

We report an interesting case of a 19 year old female with findings on MRI suggestive of viral encephalitis. An extensive workup was negative for infectious causes and she was subsequently diagnosed with anti-NMDA encephalitis. Anti-NMDA encephalitis is a highly lethal but treatable form of autoimmune encephalitis that has recently been characterized. It is frequently found in young women and associated with an underlying teratoma. Although rare, this diagnosis should be considered in young females for whom a rapid onset of encephalitis cannot be explained by more common causes. PMID:25426239

Chronic Clostridium botulinum infections in farmers.

PubMed

Rodloff, Arne C; Krüger, Monika

2012-04-01

Although botulism is usually an acute, often lethal disease that is caused by the ingestion of botulinum neurotoxin, there are also recognized forms like infant botulism, wound botulism, or "botulism of undefined origin" that are characterized by the fact that Clostridium botulinum colonizes the host and produces its toxin in the host. Evidence is presented here that a disease in cattle and in human care takers of diseased animals that has evolved over the past two decades, may be a chronic, visceral form of C. botulinum infection. Copyright © 2012 Elsevier Ltd. All rights reserved.

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E.

PubMed

Jonard, Laurence; Feldmann, Delphine; Parsy, Christophe; Freitag, Sylvie; Sinico, Martine; Koval, Céleste; Grati, Mhamed; Couderc, Remy; Denoyelle, Françoise; Bodemer, Christine; Marlin, Sandrine; Hadj-Rabia, Smail

2008-01-01

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.

Requirement for erythroblast-macrophage protein (Emp) in definitive erythropoiesis.

PubMed

Soni, Shivani; Bala, Shashi; Hanspal, Manjit

2008-01-01

Emp, erythroblast-macrophage protein was initially identified as a mediator of erythroblast-macrophage interactions during erythroid differentiation. More recent studies have shown that targeted disruption of Emp leads to abnormal erythropoiesis in the fetal liver, and fetal demise. To further address the activity of Emp in the hematopoietic lineage in adult bone marrow, we conducted fetal liver HSC reconstitution assay. Emp null fetal liver cells were transplanted into lethally irradiated wild-type sibling mice, and assessed the erythropoietic activity. We found that Emp null cells rescued lethally irradiated mice with efficiency comparable to that of wild-type cells. However, the recipients of Emp null cells showed abnormal erythropoiesis as indicated by the presence of persistent anemia, extensive extramedullary erythropoiesis, and increased apoptosis of erythroid precursors. Extramedullary erythropoiesis suggests perturbed interactions between the Emp-deficient hematopoietic cells and the wild-type niche. Furthermore, in spleen colony-forming unit assays, proliferation rates of the Emp null cells were greater than those of the wild-type cells. Similarly, in vitro burst-forming unit-erythroid and colony-forming unit-erythroid assays showed increased erythroid colony numbers from Emp null livers. Morphologic examination showed that Emp null CFU-E-derived erythroblasts were immature compared to those derived from wild-type CFU-Es, suggesting that loss of Emp function in erythroid cells results in impaired proliferation and terminal differentiation. These results demonstrate that Emp plays a cell intrinsic role in the erythroid lineage.

Complex physiological traits as biomarkers of the sub-lethal toxicological effects of pollutant exposure in fishes.

PubMed

McKenzie, D J; Garofalo, E; Winter, M J; Ceradini, S; Verweij, F; Day, N; Hayes, R; van der Oost, R; Butler, P J; Chipman, J K; Taylor, E W

2007-11-29

Complex physiological traits, such as routine aerobic metabolic rate or exercise performance, are indicators of the functional integrity of fish that can reveal sub-lethal toxicological effects of aquatic pollutants. These traits have proved valuable in laboratory investigations of the sub-lethal effects of heavy metals, ammonia and various xenobiotics. It is not known, however, whether they can also function as biomarkers of the complex potential range of effects upon overall functional integrity caused by exposure to mixtures of chemicals in polluted natural environments. The current study used portable swimming respirometers to compare exercise performance and respiratory metabolism of fish exposed in cages for three weeks to either clean or polluted sites on three urban European river systems: the river Lambro, Milan, Italy; the rivers Blythe, Cole and Tame, Birmingham, UK; and the river Amstel, Amsterdam, The Netherlands. The UK and Italian rivers were variously polluted with high levels of both bioavailable heavy metals and organics, and the Amstel by mixtures of bioavailable organics at high concentrations. In both the UK and Italy, indigenous chub (Leuciscus cephalus) exposed to clean or polluted sites swam equally well in an initial performance test, but the chub from polluted sites could not repeat this performance after a brief recovery interval. These animals were unable to raise the metabolic rate and allocate oxygen towards exercise in the second trial, an effect confirmed in successive campaigns in Italy. Swimming performance was therefore a biomarker indicator of pollutant exposure in chub exposed at these sites. Exposure to polluted sites on the river Amstel did not affect the repeat swimming performance of cultured cloned carp (Cyprinus carpio), indicating either a species-specific tolerance or relative absence of heavy metals. However, measurements of oxygen uptake during swimming revealed increased rates of routine aerobic metabolism in both chub and carp at polluted sites in all of the rivers studied, indicating a sub-lethal metabolic loading effect. Therefore, the physiological traits of exercise performance and metabolic rate have potential as biomarkers of the overall sub-lethal toxic effects of exposure to complex mixtures of pollutants in rivers, and may also provide insight into why fish do not colonize some polluted environments.

Toxic properties of specific radiation determinant molecules, derived from radiated species

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Vecheslav; Kedar, Prasad; Casey, Rachael; Jones, Jeffrey

Introduction: High doses of radiation induce the formation of radiation toxins in the organs of irradiated mammals. After whole body irradiation, cellular macromolecules and cell walls are damaged as a result of long-lived radiation-induced free radicals, reactive oxygen species, and fast, charged particles of radiation. High doses of radiation induce breaks in the chemical bonds of macromolecules and cross-linking reactions via chemically active processes. These processes result in the creation of novel modified macromolecules that possess specific toxic and antigenic properties defined by the type and dose of irradiation by which they are generated. Radiation toxins isolated from the lymph of irradiated animals are classified as hematotoxic, neurotoxic, and enteric non-bacterial (GI) radiation toxins, and they play an important role in the development of hematopoietic, cerebrovascular, and gastrointestinal acute radiation syndromes (ARS). Seven distinct toxins derived from post-irradiated animals have been designated as Specific Radiation Determinants (SRD): SRD-1 (neurotoxic radiation toxin generated by the cerebrovascular form of ARS), SRD-3 (enteric non-bacterial radiation toxins generated by the gastrointestinal form of ARS), and SRD-4 (hematotoxic radiation toxins generated by the hematological, bone marrow form of ARS). SRD-4 is further subdivided into four groups depending on the severity of the ARS induced: SRD-4/1, mild ARS; SRD-4/2, moderate ARS; SRD-4/3, severe ARS; and SRD-4/4, extremely severe ARS. The seventh SRD, SRD-2 is a toxic extract derived from animals suffering from a fourth form of ARS, as described in European literature and produces toxicity primarily in the autonimic nervous system. These radiation toxins have been shown to be responsible for the induction of important pathophysiological, immunological, and biochemical reactions in ARS. Materials and Methods: These studies incorporated the use of statistically significant numbers of a variety of animals. Lymphatic fluid was collected from the thoracic ducts of bovine species exposed to lethal doses of gamma radiation, and the SRDs were separated by size exclusion gel filtration and high-performance liquid chromatography. We compared the toxicity of isolated radiation toxins in a variety of animals. The clinical characteristics of ARS induced by intravenous or intra-muscular injections of radiation toxins were observed. Results: In radiation-na¨ animals (rats, rabbits, and sheep), toxicity was defined ıve by observing the timing and rate of lethality following injections with extracted radiation toxins (SRDs). Preparations of SRD-1 were injected intra-muscularly in doses of 5 or 10 mg/kg body weight. We observed the development of cerebrovascular ARS with 100% lethality at 10-30 minutes after injection. Analysis of the toxicity of different forms of radiation toxins showed that cerebrovascular neurotoxins possess the highest toxicity compared with other forms of radiation toxins. The other SRD's were also injected into radiation-naive animals and observed for subsequent toxicity/lethality, with the other SRDs producing less virulent forms of ARS. However, both the SRD-2- and SRD-3-injected animals also suffered lethality between 2 and 30 days post-injection. Conclusions: We have observed that radiation toxins are transported from the cells and tissues of irradiated organisms to the interstitial blood and lymphatic fluids, and that this migration of radiation toxins occurs hours after irradiation. Upon analysis of the results of our research and literature sources, we postulate that radiation toxins arise from the radiation-induced chemical modification of macromolecules resident in cell membranes and other cellular structures. Furthermore, we postulate that these altered macromolecules are not processed by antigen processing cells, but instead bind to class II MHC molecules and TCR-beta chains. This causes nonspecific activation of T cells, pro-inflammatory agents such as cytokines and isozymes of phospholipase A2 and phospholipase C, and platelet-activating factor. Longer-term effects induced by the altered macromolecules include the activation of cytotoxic T cells, which induces cytolysis in radiation-damaged cells. Activated CD8+ T cells produce tumor necrosis factor-B and additional cytokines. By these mechanisms, we postulate that radiation toxins generate the pathophysiological reactions associated with acute radiation syndromes.

Close Call: Magic.

ERIC Educational Resources Information Center

Journal of Adventure Education and Outdoor Leadership, 1993

1993-01-01

Staff at a residential camp for high-risk youth dealt with campers eating potentially lethal hallucinogenic mushrooms by eliminating the mushrooms instead of confronting the group and thereby jeopardizing the relationship between staff and campers. Analyzes the situation and provides suggestions for handling similar incidents in the future. (LP)

Necrotizing fasciitis after internal fixation of fracture of femoral trochanteric☆☆☆

PubMed Central

Santos, Leandro Emílio Nascimento; Pires, Robinson Esteves Santos; Figueiredo, Leonardo Brandão; Soares, Eduardo Augusto Marques

2014-01-01

Necrotizing fasciitis is a rare and potentially lethal soft tissue infection. We report a case of trochanteric femur fracture in a patient who underwent fracture fixation and developed necrotizing fasciitis. A literature review on the topic will be addressed. PMID:26229777

Ecotoxicological effects of buprofezin on fecundity, growth, development, and predation of the wolf spider Pirata piratoides (Schenkel).

PubMed

Deng, Lingling; Xu, Muqi; Cao, Hong; Dai, Jiayin

2008-11-01

The toxicological effects of buprofezin, an insect growth regulator, on the fecundity, development, and pest control potential of the wolf spider Pirata piratoides (Schenkel) (Araneae: Lycosidae) were investigated in the laboratory. It was shown that buprofezin had low toxicity to P. piratoides and that the median lethal dosage (LD(50)) 48 h and 10% lethal dosage (LD(10)) after topical application for female spiders were 653 and 316 mg buprofezin/mg fresh weight of spider, respectively. Buprofezin significantly reduced the percent hatching of spiders' eggs but had only a slight effect on egg production. No negative effects on the development and growth were observed. However, spider predation rates were strongly affected: Insecticide-treated females predated on fewer prey than the controls, and their predation rate did not recover even 5 days after insecticide application. This indicated that their pest control potential might be influenced by buprofezin, and the use of buprofezin in biological control of insects is discussed.

Homicide Followed by Suicide: A Comparison with Homicide and Suicide

ERIC Educational Resources Information Center

Liem, Marieke; Nieuwbeerta, Paul

2010-01-01

Homicide-suicides are a rare yet very serious form of lethal violence which mainly occurs in partnerships and families. The extent to which homicide-suicide can be understood as being primarily a homicide or a suicide event, or rather a category of its own is examined. In total, 103 homicide-suicides were compared to 3,203 homicides and 17,751…

Homologous stress adaptation, antibiotic resistance, and biofilm forming ability of Salmonella enterica serovar Heidelberg (ATCC8326) on different food-contact surfaces following exposure to sub-lethal chlorine concentrations

USDA-ARS?s Scientific Manuscript database

Salmonella enterica serovar Heidelberg (American Type Culture Collection; ATCC 8326) was examined for the ability to adapt to the homologous stress of chlorine through exposure to increasing chlorine concentrations (25 ppm daily increments) in tryptic soy broth (TSB). The tested strain exhibited an ...

Yeast and Fungal Prions: Amyloid-Handling Systems, Amyloid Structure, and Prion Biology.

PubMed

Wickner, R B; Edskes, H K; Gorkovskiy, A; Bezsonov, E E; Stroobant, E E

2016-01-01

Yeast prions (infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. A single prion protein can become any of many distinct amyloid forms (called prion variants or strains), each of which is self-propagating, but with different biological properties (eg, lethal vs mild). The folded in-register parallel β sheet architecture of the yeast prion amyloids naturally suggests a mechanism by which prion variant information can be faithfully transmitted for many generations. The yeast prions rely on cellular chaperones for their propagation, but can be cured by various chaperone imbalances. The Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise. Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some are mild in their effects. Even the most mild forms of these prions are rare in the wild, indicating that they too are detrimental to yeast. The beneficial [Het-s] prion of Podospora anserina poses an important contrast in its structure, biology, and evolution to the yeast prions characterized thus far. Copyright © 2016 Elsevier Inc. All rights reserved.

A Japanese Encephalitis Virus Peptide Present on Johnson Grass Mosaic Virus-Like Particles Induces Virus-Neutralizing Antibodies and Protects Mice against Lethal Challenge

PubMed Central

Saini, Manisha; Vrati, Sudhanshu

2003-01-01

Protection against Japanese encephalitis virus (JEV) is antibody dependent, and neutralizing antibodies alone are sufficient to impart protection. Thus, we are aiming to develop a peptide-based vaccine against JEV by identifying JEV peptide sequences that could induce virus-neutralizing antibodies. Previously, we have synthesized large amounts of Johnson grass mosaic virus (JGMV) coat protein (CP) in Escherichia coli and have shown that it autoassembled to form virus-like particles (VLPs). The envelope (E) protein of JEV contains the virus-neutralization epitopes. Four peptides from different locations within JEV E protein were chosen, and these were fused to JGMV CP by recombinant DNA methods. The fusion protein autoassembled to form VLPs that could be purified by sucrose gradient centrifugation. Immunization of mice with the recombinant VLPs containing JEV peptide sequences induced anti-peptide and anti-JEV antibodies. A 27-amino-acid peptide containing amino acids 373 to 399 from JEV E protein, present on JGMV VLPs, induced virus-neutralizing antibodies. Importantly, these antibodies were obtained without the use of an adjuvant. The immunized mice showed significant protection against a lethal JEV challenge. PMID:12610124

Atypical myxomatosis--virus isolation, experimental infection of rabbits and restriction endonuclease analysis of the isolate.

PubMed

Psikal, I; Smíd, B; Rodák, L; Valícek, L; Bendová, J

2003-08-01

Atypical form of myxomatosis, which caused non-lethal and clinically mild disease in domestic rabbits 1 month after immunization with a commercially available vaccine MXT, is described. The isolated myxoma virus designated as Litovel 2 (Li-2) did not induce systemic disease following subcutaneous and intradermal applications in susceptible experimental rabbits but led to the immune response demonstrated by ELISA. No severe disease was induced in those Li-2 inoculated rabbits by challenge with the virulent strains Lausanne (Lu) or Sanar (SA), while the control animals showed nodular form of myxomatosis with lethal course of the illness. Restriction fragment length polymorphism (RFLP) of genomic DNA with KpnI and BamHI endonucleases was used for genetic characterization of the Li-2 isolate, the vaccine strain MXT and both virulent strains Lu and SA, respectively. In general, RFLP analysis has shown to be informative for inferring genetic relatedness between myxoma viruses. Based on restriction endonuclease DNA fragment size distribution, it was evident that the pathogenic strain SA is genetically related to the reference strain Lu and the isolate Li-2 is more related, but not identical, to the vaccination strain MXT.

Incomplete development of the spleen and the deformity in the chimeras between asplenic mutant (Dominant hemimelia) and normal mice.

PubMed

Suto, J; Wakayama, T; Imamura, K; Goto, S; Fukuta, K

1995-08-01

The semidominant gene Dh (Dominant hemimelia) induces skeletal and visceral abnormalities of various degrees and failure of the spleen in mice. The homozygous individual (Dh/Dh) seems to be lethal. The present experiment was designed to investigate the ability Dh cells to form a spleen and the genesis of the hind limb malformations by Dh/Dh and Dh/+ cells in chimeric mice. The Dh/Dh and Dh/+ embryos were produced in the F2 progeny of a cross between inbred strains of Dh/+ and DDD mice. They were aggregated with C3H/He or C57BL/6 embryos to make chimeras. Identification of Dh/Dh or Dh/+ embryos was carried out by Pep-3, and chimerism was analyzed by Gpi-1. Of 25 chimeras carrying the Dh gene, four mice formed a small spleen, two mice had a vestigial spleen, and the others no spleen. The tissues of the incompletely developed spleens were normal histologically and Dh cells were involved in the tissues of the spleen. In the chimeric mice, hindlimb malformation by the Dh gene was reduced in severity and the lethality of the homozygote (Dh/Dh) was rescued.

Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference.

PubMed

Geisbert, Thomas W; Hensley, Lisa E; Kagan, Elliott; Yu, Erik Zhaoying; Geisbert, Joan B; Daddario-DiCaprio, Kathleen; Fritz, Elizabeth A; Jahrling, Peter B; McClintock, Kevin; Phelps, Janet R; Lee, Amy C H; Judge, Adam; Jeffs, Lloyd B; MacLachlan, Ian

2006-06-15

Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent.

PubMed

Farese, Ann M; Brown, Cassandra R; Smith, Cassandra P; Gibbs, Allison M; Katz, Barry P; Johnson, Cynthia S; Prado, Karl L; MacVittie, Thomas J

2014-01-01

The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 h following total body irradiation in a non-human primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gy, (target lethal dose 50/60) delivered at 0.80 Gy min, using linear accelerator-derived 6 MV photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg d) or the control (5% dextrose in water) was administered subcutaneously daily through effect (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 h post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 h after irradiation, did not improve survival (2.5% increase, p = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure.

Ovulation and extra-ovarian origin of ovarian cancer

PubMed Central

Yang-Hartwich, Yang; Gurrea-Soteras, Marta; Sumi, Natalia; Joo, Won Duk; Holmberg, Jennie C.; Craveiro, Vinicius; Alvero, Ayesha B.; Mor, Gil

2014-01-01

The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies. PMID:25135607

Chimeric severe acute respiratory syndrome coronavirus (SARS-CoV) S glycoprotein and influenza matrix 1 efficiently form virus-like particles (VLPs) that protect mice against challenge with SARS-CoV

PubMed Central

Liu, Ye V.; Massare, Michael J.; Barnard, Dale L.; Kort, Thomas; Nathan, Margret; Wang, Lei; Smith, Gale

2011-01-01

SARS-CoV was the cause of the global pandemic in 2003 that infected over 8000 people in 8 months. Vaccines against SARS are still not available. We developed a novel method to produce high levels of a recombinant SARS virus-like particles (VLPs) vaccine containing the SARS spike (S) protein and the influenza M1 protein using the baculovirus insect cell expression system. These chimeric SARS VLPs have a similar size and morphology to the wild type SARS-CoV. We tested the immunogenicity and protective efficacy of purified chimeric SARS VLPs and full length SARS S protein vaccines in a mouse lethal challenge model. The SARS VLP vaccine, containing 0.8 μg of SARS S protein, completely protected mice from death when administered intramuscular (IM) or intranasal (IN) routes in the absence of an adjuvant. Likewise, the SARS VLP vaccine, containing 4 μg of S protein without adjuvant, reduced lung virus titer to below detectable level, protected mice from weight loss, and elicited a high level of neutralizing antibodies against SARS-CoV. Sf9 cell-produced full length purified SARS S protein was also an effective vaccine against SARS-CoV but only when co-administered IM with aluminum hydroxide. SARS-CoV VLPs are highly immunogenic and induce neutralizing antibodies and provide protection against lethal challenge. Sf9 cell-based VLP vaccines are a potential tool to provide protection against novel pandemic agents. PMID:21762752

Real-time quantitative reverse transcription-PCR analysis of expression stability of Aggregatibacter actinomycetemcomitans fimbria-associated gene in response to photodynamic therapy.

PubMed

Pourhajibagher, Maryam; Monzavi, Abbas; Chiniforush, Nasim; Monzavi, Mohammad Moein; Sobhani, Shaghayegh; Shahabi, Sima; Bahador, Abbas

2017-06-01

Aggregatibacter actinomycetemcomitans is an etiological agent of both chronic and aggressive periodontitis. Dissemination of A. actinomycetemcomitans from the oral cavity and initiation of systemic infections has led to new approaches for treatment being needed. In this study, a series of experiments presented investigated the effect of methylene blue (MB)-mediated antimicrobial photodynamic therapy (aPDT) on cell viability and expression of fimbria-associated gene (rcpA) in A. actinomycetemcomitans. To determine the dose-depended effects of aPDT, A. actinomycetemcomitans ATCC 33384 strain photosensitized with MB was irradiated with diode laser following bacterial viability measurements. Cell-surviving assay and expression ratio of rcpA were assessed by colony forming unit and real-time quantitative reverse transcription-PCR (qRT-PCR) assays, respectively. In the current study, MB-mediated aPDT using 100μg/mL showed significant reduction in A. actinomycetemcomitans growth when compared to the control (P<0.05). Sub-lethal dose of aPDT against A. actinomycetemcomitans was 25μg/mL MB at fluency of 93.75J/cm 2 . Sub-lethal dose of aPDT could lead to about four-fold suppression of expression of rcpA. High doses of MB-mediated aPDT could potentially exhibit antimicrobial activity, and the expression of rcpA as an important virulence factor of this strain is reduced in cells surviving aPDT with MB. So, aPDT can be a valuable tool for the treatment of A. actinomycetemcomitans infections. Copyright © 2017 Elsevier B.V. All rights reserved.

Mass Spectrometric Detection of Bacterial Protein Toxins and Their Enzymatic Activity.

PubMed

Kalb, Suzanne R; Boyer, Anne E; Barr, John R

2015-08-31

Mass spectrometry has recently become a powerful technique for bacterial identification. Mass spectrometry approaches generally rely upon introduction of the bacteria into a matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometer with mass spectrometric recognition of proteins specific to that organism that form a reliable fingerprint. With some bacteria, such as Bacillus anthracis and Clostridium botulinum, the health threat posed by these organisms is not the organism itself, but rather the protein toxins produced by the organisms. One such example is botulinum neurotoxin (BoNT), a potent neurotoxin produced by C. botulinum. There are seven known serotypes of BoNT, A-G, and many of the serotypes can be further differentiated into toxin variants, which are up to 99.9% identical in some cases. Mass spectrometric proteomic techniques have been established to differentiate the serotype or toxin variant of BoNT produced by varied strains of C. botulinum. Detection of potent biological toxins requires high analytical sensitivity and mass spectrometry based methods have been developed to determine the enzymatic activity of BoNT and the anthrax lethal toxins produced by B. anthracis. This enzymatic activity, unique for each toxin, is assessed with detection of the toxin-induced cleavage of strategically designed peptide substrates by MALDI-TOF mass spectrometry offering unparalleled specificity. Furthermore, activity assays allow for the assessment of the biological activity of a toxin and its potential health risk. Such methods have become important diagnostics for botulism and anthrax. Here, we review mass spectrometry based methods for the enzymatic activity of BoNT and the anthrax lethal factor toxin.

Mass Spectrometric Detection of Bacterial Protein Toxins and Their Enzymatic Activity

PubMed Central

Kalb, Suzanne R.; Boyer, Anne E.; Barr, John R.

2015-01-01

Mass spectrometry has recently become a powerful technique for bacterial identification. Mass spectrometry approaches generally rely upon introduction of the bacteria into a matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometer with mass spectrometric recognition of proteins specific to that organism that form a reliable fingerprint. With some bacteria, such as Bacillus anthracis and Clostridium botulinum, the health threat posed by these organisms is not the organism itself, but rather the protein toxins produced by the organisms. One such example is botulinum neurotoxin (BoNT), a potent neurotoxin produced by C. botulinum. There are seven known serotypes of BoNT, A–G, and many of the serotypes can be further differentiated into toxin variants, which are up to 99.9% identical in some cases. Mass spectrometric proteomic techniques have been established to differentiate the serotype or toxin variant of BoNT produced by varied strains of C. botulinum. Detection of potent biological toxins requires high analytical sensitivity and mass spectrometry based methods have been developed to determine the enzymatic activity of BoNT and the anthrax lethal toxins produced by B. anthracis. This enzymatic activity, unique for each toxin, is assessed with detection of the toxin-induced cleavage of strategically designed peptide substrates by MALDI-TOF mass spectrometry offering unparalleled specificity. Furthermore, activity assays allow for the assessment of the biological activity of a toxin and its potential health risk. Such methods have become important diagnostics for botulism and anthrax. Here, we review mass spectrometry based methods for the enzymatic activity of BoNT and the anthrax lethal factor toxin. PMID:26404376

Synthetic Lethal Networks for Precision Oncology: Promises and Pitfalls.

PubMed

Shen, John Paul; Ideker, Trey

2018-06-19

Synthetic lethal interactions, in which the simultaneous loss-of-function of two genes produces a lethal phenotype, are being explored as a means to therapeutically exploit cancer-specific vulnerabilities and expand the scope of precision oncology. Currently, three FDA approved drugs work by targeting the synthetic lethal interaction between BRCA1/2 and PARP. This review examines additional efforts to discover networks of synthetic lethal interactions and discusses both challenges and opportunities regarding the translation of new synthetic lethal interactions into the clinic. Copyright © 2018. Published by Elsevier Ltd.

The effect of hyperthermia on the radiation response of crypt cells in mouse jejunum

NASA Technical Reports Server (NTRS)

Wilson, J. D.

1978-01-01

The effect of hyperthermia and/or gamma-radiation on the survival of intestinal crypt cells was studied in BDF sub 1 mice using a microcolony assay. Hyperthermia treatments, which in themselves caused no detectable cell lethality, inhibited the capacity of crypt cells to repair sublethal radiation damage. In addition, heat applied either before or after single radiation exposures potentiated lethal damage to crypt cells; the degree of enhancement was dependent on the time interval between treatments. At the levels of heating employed, DNA synthesis in the intestinal epithelium was significantly reduced immediately following exposure, but returned rapidly to normal levels. No further disturbances in cellular kinetics were observed for up to 10 days after heating.

Fatal combination of moclobemide overdose and whisky.

PubMed

Bleumink, G S; van Vliet, A C M; van der Tholen, A; Stricker, B H Ch

2003-03-01

The antidepressant moclobemide (Aurorix) is a reversible inhibitor of monoamine oxidase-A. Pure moclobemide overdose is considered to be relatively safe. Mixed drug overdoses including moclobemide are potentially lethal, especially when serotonergical drugs are involved. So far, only one fatality due to moclobemide mono-overdose has been reported. We report here on a fatality following the ingestion of a moclobemide overdose in combination with half a bottle of whisky. Although dietary restrictions during moclobemide therapy are not considered necessary, the combination of large quantities of moclobemide and tyramine-containing products seems to be lethal, probably because monoamine oxidase-A selectivity is overwhelmed after massive overdoses. Since there is no specific antidote and treatment is only symptomatic, the severity of an overdose with moclobemide must not be underestimated.

Relative toxicity testing of spacecraft materials. 2: Aircraft materials

NASA Technical Reports Server (NTRS)

Lawrence, W. H.

1980-01-01

The relative toxicity of thermodegradation (pyrolysis/combustion) products of aircraft materials was studied. Two approaches were taken to assess the biological activity of the pyrolysis/combustion products of these materials: (1) determine the acute lethality to rats from inhalation of these pyrolysates and (2) examine the tendency for sublethal exposure to the pyrolysates to disrupt behavioral (shock avoidance) performance of exposed rats. The ralative importance of lethality vs. behavioral effects in selection of a material may be dictated by whether or not individuals potentially exposed to such products, would have an opportunity to escape if they were behaviorally capable of doing so. If so, the second parameter would assume greater importance, but if not the first parameter may be of much greater importance in selecting materials.

Differential expression of the lethal gene Luteus-Pa in cacao of the Parinari series.

PubMed

Rehem, B C; Almeida, A-A F; Figueiredo, G S F; Gesteira, A S; Santos, S C; Corrêa, R X; Yamada, M M; Valle, R R

2016-02-22

The recessive lethal character Luteus-Pa is found in cacao (Theobroma cacao) genotypes of the Parinari series (Pa) and is characterized by expression of leaf chlorosis and seedling death. Several genotypes of the Pa series are bearers of the gene responsible for the expression of the Luteus-Pa character, which can be used as a tool for determining relationships between genotypes of this group. To evaluate this phenomenon, we analyzed the differential expression of genes between mutant seedlings and wild-type hybrid Pa 30 x 169 seedlings, with the aim of elucidating the possible lethal mechanisms of the homozygous recessive character Luteus-Pa. Plant material was harvested from leaves of wild and mutant seedlings at different periods to construct a subtractive library and perform quantitative analysis using real-time PCR. The 649 sequences obtained from the subtractive library had an average length of 500 bp, forming 409 contigs. The probable proteins encoded were grouped into 10 functional categories. Data from ESTs identified genes associated with Rubisco, peroxidases, and other proteins and enzymes related to carbon assimilation, respiration, and photosystem 2. Mutant seedlings were characterized by synthesizing defective PsbO and PsbA proteins, which were overexpressed from 15 to 20 days after seedling emergence.

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

PubMed Central

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

2008-01-01

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

Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

PubMed Central

Wilson, Robert; Geyer, Stefan H.; Reissig, Lukas; Rose, Julia; Szumska, Dorota; Hardman, Emily; Prin, Fabrice; McGuire, Christina; Ramirez-Solis, Ramiro; White, Jacqui; Galli, Antonella; Tudor, Catherine; Tuck, Elizabeth; Mazzeo, Cecilia Icoresi; Smith, James C.; Robertson, Elizabeth; Adams, David J.; Mohun, Timothy; Weninger, Wolfgang J.

2017-01-01

Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all mutant embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve. Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates. PMID:27996060

Acute, Sub-lethal Cyanide Poisoning in Mice is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination

PubMed Central

Cambal, Leah K.; Swanson, Megan R.; Yuan, Quan; Weitz, Andrew C.; Li, Hui-Hua; Pitt, Bruce R.; Pearce, Linda L.; Peterson, Jim

2011-01-01

Sodium nitrite alone is shown to ameliorate sub-lethal cyanide toxicity in mice when given from ~1 hour before until 20 minutes after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication. PMID:21534623

Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development

EPA Science Inventory

Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, s...

Suicide Risk Response: Enhancing Patient Safety Through Development of Effective Institutional Policies

DTIC Science & Technology

2004-01-01

potentially lethal self harm ). The CWG recognized the importance of having well-defined policies for response to suicidal TIDES and WAVES patients, and...calculates responses and automatically triggers the suicidality protocol 3.1 3 Spontaneous mention of suicide, self - harm , or persistent thoughts

Cold hardiness of Helicoverpa zea (Lepidoptera: Noctuidae) pupae

Treesearch

A.C. Morey; W.D. Hutchison; R.C. Venette; E.C. Burkness

2012-01-01

An insect's cold hardiness affects its potential to overwinter and outbreak in different geographic regions. In this study, we characterized the response of Helicoverpa zea (Boddie) pupae to low temperatures by using controlled laboratory measurements of supercooling point (SCP), lower lethal temperature (LT50), and lower...

Effects of Culling on Leptospira interrogans Carriage by Rats

PubMed Central

Byers, Kaylee A.; Donovan, Christina M.; Bidulka, Julie J.; Stephen, Craig; Patrick, David M.; Himsworth, Chelsea G.

2018-01-01

We found that lethal, urban rat control is associated with a significant increase in the odds that surviving rats carry Leptospira interrogans. Our results suggest that human interventions have the potential to affect and even increase the prevalence of zoonotic pathogens within rat populations. PMID:29350160

JUVENILE AMPHIBIANS DO NOT AVOID POTENTIALLY LETHAL LEVELS OF UREA ON SOIL SUBSTRATE. (U915529)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Larvicidal potential of ethanolic extracts of dried fruits of three species of peppercorns against different instars of an indian strain of dengue fever mosquito, Aedes aegypti L. (Diptera: Culicidae).

PubMed

Kumar, Sarita; Warikoo, Radhika; Wahab, Naim

2010-09-01

Larvicidal bioassay was carried out in the laboratory to assess the potential of ethanolic extracts of dried fruits of three species of peppercorns: Long pepper, Piper longum L., Black pepper, Piper nigrum, and White pepper, Piper nigrum against the different instars of field-collected Indian strain of dengue fever mosquito (Aedes aegypti L.). The investigations established the larvicidal potential of all the varieties of pepper fruits against Ae. aegypti. Against early fourth instar, the ethanolic extracts of Black and White P. nigrum proved to be 30-40% less toxic than the extracts of P. longum, whereas against third instars, white pepper extracts exhibited 7% more efficacy than that of black pepper and 47% more toxicity than that of long pepper. The results also revealed that the extracts of all the three pepper species were 11-25 times more toxic against the third instar larvae as compared to the early fourth instars. The lethal concentration, 50% (LC(50)) values obtained with ethanolic extracts of P. longum, White P. nigrum and Black P. nigrum against early fourth instar larvae were 0.248, 0.356, and 0.405 ppm, respectively, and the lethal concentration, 90% (LC(90)) values were 0.605, 0.758, and 0.801 ppm, respectively. Whereas against third instar larvae, the LC(50) values recorded with three extracts were 0.022, 0.015, and 0.016 ppm and the LC(90) values recorded were 0.054, 0.034, and 0.046 ppm, respectively. The larvae treated with all the pepper species showed initial abnormal behavior in their motion followed by excitation, convulsions, and paralysis, leading to 100% kill indicating delayed larval toxicity and effects of the extracts on the neuromuscular system. Observations of morphological alterations on treated larvae under light microscopy revealed that most organs, except anal papillae, had a normal structural appearance as that of controls. The structural deformation in the form of shrinkage in the internal membrane exhibited by anal papillae suggests the anal papillae as the probable action sites of the pepper extracts. The potential of peppercorns as new types of larvicides for the control of mosquitoes are explored.

The Protective Antigen Component of Anthrax Toxin Forms Functional Octameric Complexes

PubMed Central

Kintzer, Alexander F.; Thoren, Katie L.; Sterling, Harry J.; Dong, Ken C.; Feld, Geoffrey K.; Tang, Iok I.; Zhang, Teri T.; Williams, Evan R.; Berger, James M.; Krantz, Bryan A.

2009-01-01

The assembly of bacterial toxins and virulence factors is critical to their function, but the regulation of assembly during infection has not been studied. We begin to address this question using anthrax toxin as a model. The protective antigen (PA) component of the toxin assembles into ring-shaped homooligomers that bind the two other enzyme components of the toxin, lethal factor (LF) and edema factor (EF), to form toxic complexes. To disrupt the host, these toxic complexes are endocytosed, such that the PA oligomer forms a membrane-spanning channel that LF and EF translocate through to enter the cytosol. We show using single-channel electrophysiology that PA channels contain two populations of conductance states, which correspond with two different PA pre-channel oligomers observed by electron microscopy—the well-described heptamer and a novel octamer. Mass spectrometry demonstrates that the PA octamer binds four LFs, and assembly routes leading to the octamer are populated with even-numbered, dimeric and tetrameric, PA intermediates. Both heptameric and octameric PA complexes can translocate LF and EF with similar rates and efficiencies. Here we also report a 3.2-Å crystal structure of the PA octamer. The octamer comprises ∼20−30% of the oligomers on cells, but outside of the cell, the octamer is more stable than the heptamer under physiological pH. Thus the PA octamer is a physiological, stable, and active assembly state capable of forming lethal toxins that may withstand the hostile conditions encountered in the bloodstream. This assembly mechanism may provide a novel means to control cytotoxicity. PMID:19627991

MASM, a Matrine Derivative, Offers Radioprotection by Modulating Lethal Total-Body Irradiation-Induced Multiple Signaling Pathways in Wistar Rats.

PubMed

Li, Jianzhong; Xu, Jing; Lu, Yiming; Qiu, Lei; Xu, Weiheng; Lu, Bin; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

2016-05-17

Matrine is an alkaloid extracted from Sophora flavescens Ait and has many biological activities, such as anti-inflammatory, antitumor, anti-fibrosis, and immunosuppressive properties. In our previous studies, the matrine derivative MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis. In this study, we mainly investigated its protection against lethal total-body irradiation (TBI) in rats. Administration of MASM reduced the radiation sickness characteristics and increased the 30-day survival of rats before or after lethal TBI. Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI. Pretreatment with MASM prevented differential expression of 53% (765 genes) of 1445 differentially expressed genes induced by TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and mitogen-activated protein kinase (MAPK) pathways. Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI, suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways, such as multiple MAPK pathways. Therefore, MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.

Filgrastim Improves Survival in Lethally Irradiated Nonhuman Primates

PubMed Central

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

2015-01-01

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

Green tea extract-induced lethal toxicity in fasted but not in nonfasted dogs.

PubMed

Wu, Kuei-Meng; Yao, Jiaqin; Boring, Daniel

2011-02-01

Recent chronic toxicity studies performed on green tea extracts in fasted dogs have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Key findings included necrosis of hepatic cells, gastrointestinal epithelia and renal tubules, atrophy of reproductive organs, atrophy and necrosis of hematopoietic tissues, and associated hematological changes. The polyphenol cachetins (a mixture of primarily epigallocatechin gallate [≥55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied. Conduct of the study in nonfasted dogs under the same testing conditions and dose levels showed unremarkable results. Assuming both studies were valid, at the identified no observed adverse effect levels (NOAEL) of each study, systemic exposures (based on area under the curve [AUC]) were actually lower in fasted than nonfasted dogs, suggesting that fasting may have rendered the target organ systems potentially more vulnerable to the effects of green tea extract. The toxicity mechanisms that produced lethality are not known, but the results are scientifically intriguing. Because tea drinking has become more popular in the United States and abroad, the mode of action and site of action of green tea extract-induced lethal toxicities during fasting and the role of other phytochemical components of Folia Camellia sinensis (including nonpolyphenol fractions, which are often consumed when whole-leaf products are presented) warrant further investigation.

Differential sensitivity of developmental stages of the South American toad to a fungicide based on fludioxonil and metalaxyl-M.

PubMed

Svartz, Gabriela; Acquaroni, Mercedes; Pérez Coll, Cristina

2018-06-07

Agricultural fungicide application in Argentina has increased twice since 2008, with Maxim® XL (2.5% fludioxonil +1% metalaxyl-M) as one of the most used fungicide formulation. The toxicity of this pesticide on Rhinella arenarum was assessed by means of continuous (from embryo and larval development) and 24-h pulse exposure standardized bioassays. Lethality was concentration- and exposure time-dependent. Maxim® XL caused a progressive lethal effect along the bioassays with higher toxicity on embryos than larvae, obtaining 50% lethal concentrations at 96, 336, and 504 h of 10.85, 2.89, and 1.71 mg/L for embryos, and 43.94, 11.79, and 5.76 mg/L for larvae respectively. Lethal 504-h no observed effect concentration values for embryos and larvae were 1 and 2.5 mg/L respectively. A stage-dependent toxicity of Maxim® XL was also demonstrated within the embryo development, with early stages more sensitive than the later ones, and blastula as the most sensitive developmental stage. The risk quotients obtained for chronic risk assessment determined a potential threat for the survival and continuity of R. arenarum populations under these conditions. The results indicate that the levels of the fungicide reaching amphibian habitats could be risky for the early development of this amphibian species. This study also emphasizes the necessity to evaluate the chronic effects of fungicides in pesticide risk assessment.

The Effect of Oseltamivir on the Disease Progression of Lethal Influenza A Virus Infection: Plasma Cytokine and miRNA Responses in a Mouse Model

PubMed Central

Chockalingam, Ashok K.; Hamed, Salaheldin; Goodwin, David G.; Rosenzweig, Barry A.; Pang, Eric; Boyne II, Michael T.

2016-01-01

Lethal influenza A virus infection leads to acute lung injury and possibly lethal complications. There has been a continuous effort to identify the possible predictors of disease severity. Unlike earlier studies, where biomarkers were analyzed on certain time points or days after infection, in this study biomarkers were evaluated over the entire course of infection. Circulating proinflammatory cytokines and/or miRNAs that track with the onset and progression of lethal A/Puerto Rico/8/34 (PR8) influenza A virus infection and their response to oseltamivir treatment were investigated up to 10 days after infection. Changes in plasma cytokines (IL-1β, IL-10, IL-12p70, IL-6, KC, TNF-α, and IFN-γ) and several candidate miRNAs were profiled. Among the cytokines analyzed, IL-6 and KC/GRO cytokines appeared to correlate with peak viral titer. Over the selected 48 miRNAs profiled, certain miRNAs were up- or downregulated in a manner that was dependent on the oseltamivir treatment and disease severity. Our findings suggest that IL-6 and KC/GRO cytokines can be a potential disease severity biomarker and/or marker for the progression/remission of infection. Further studies to explore other cytokines, miRNAs, and lung injury proteins in serum with different subtypes of influenza A viruses with varying disease severity may provide new insight into other unique biomarkers. PMID:27110056

Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids.

PubMed

Gable, Robert S

2007-01-01

To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. A systematic literature search, supplemented by interviews with ceremony participants. No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.

Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.

PubMed

Clermont, Pier-Luc; Crea, Francesco; Chiang, Yan Ting; Lin, Dong; Zhang, Amy; Wang, James Z L; Parolia, Abhijit; Wu, Rebecca; Xue, Hui; Wang, Yuwei; Ding, Jiarui; Thu, Kelsie L; Lam, Wan L; Shah, Sohrab P; Collins, Colin C; Wang, Yuzhuo; Helgason, Cheryl D

2016-01-01

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

A modular and optimized single marker system for generating Trypanosoma brucei cell lines expressing T7 RNA polymerase and the tetracycline repressor.

PubMed

Poon, S K; Peacock, L; Gibson, W; Gull, K; Kelly, S

2012-02-01

Here, we present a simple modular extendable vector system for introducing the T7 RNA polymerase and tetracycline repressor genes into Trypanosoma brucei. This novel system exploits developments in our understanding of gene expression and genome organization to produce a streamlined plasmid optimized for high levels of expression of the introduced transgenes. We demonstrate the utility of this novel system in bloodstream and procyclic forms of Trypanosoma brucei, including the genome strain TREU927/4. We validate these cell lines using a variety of inducible experiments that recapture previously published lethal and non-lethal phenotypes. We further demonstrate the utility of the single marker (SmOx) TREU927/4 cell line for in vivo experiments in the tsetse fly and provide a set of plasmids that enable both whole-fly and salivary gland-specific inducible expression of transgenes.

A modular and optimized single marker system for generating Trypanosoma brucei cell lines expressing T7 RNA polymerase and the tetracycline repressor

PubMed Central

Poon, S. K.; Peacock, L.; Gibson, W.; Gull, K.; Kelly, S.

2012-01-01

Here, we present a simple modular extendable vector system for introducing the T7 RNA polymerase and tetracycline repressor genes into Trypanosoma brucei. This novel system exploits developments in our understanding of gene expression and genome organization to produce a streamlined plasmid optimized for high levels of expression of the introduced transgenes. We demonstrate the utility of this novel system in bloodstream and procyclic forms of Trypanosoma brucei, including the genome strain TREU927/4. We validate these cell lines using a variety of inducible experiments that recapture previously published lethal and non-lethal phenotypes. We further demonstrate the utility of the single marker (SmOx) TREU927/4 cell line for in vivo experiments in the tsetse fly and provide a set of plasmids that enable both whole-fly and salivary gland-specific inducible expression of transgenes. PMID:22645659

[The plague].

PubMed

Carniel, Elisabeth

2002-08-01

The plague has been one of the most devastating diseases of human history. Despite major advances in diagnosis, prevention, and treatment, it has not been possible to eradicate this infection. Plague is still active in Africa, in Asia and in the Americas, and is classified as a currently re-emerging disease. The plague is mainly a disease of rodents, which is transmitted by fleabites. Humans develop two main clinical forms: bubonic plague (following bites of infected fleas, lethal in 50-70% of the cases in less than a week if an appropriate treatment is not started rapidly), and pneumonic plague (after inhalation of infected droplets, lethal in less than three days in 100% of cases without immediate treatment). Y. pestis, the causative agent of plague, is usually sensitive to most antibiotics, but the first multi-resistant strain was recently described. No efficient and safe vaccines are currently available. The plague bacillus is one of the few organisms that could be used for biological warfare.

Separation/divorce sexual assault in rural Ohio: survivors' perceptions.

PubMed

DeKeseredy, Walter S; Schwartz, Martin D

2008-01-01

Since the 1970s, many studies have enhanced a social scientific understanding of the lethal and non-lethal physical abuse of women during and after separation and divorce, but less than a handful have examined sexual assaults on rural women who want to leave, are trying to leave, or who have left spouses or live-in male partners. Further, none of the work done so far on this problem has examined the role of collective efficacy. The results presented here help fill these research gaps and call into question the common assumption that there is more collective control on criminal behavior in rural settings. Moreover, our exploratory qualitative data show that collective efficacy can take many shapes and forms, and often what is perceived as the "common good" may actually be behaviors and discourses that threaten the health and well-being of women seeking freedom from abusive male partners.

Human cooperation by lethal group competition.

PubMed

Egas, Martijn; Kats, Ralph; van der Sar, Xander; Reuben, Ernesto; Sabelis, Maurice W

2013-01-01

Why humans are prone to cooperate puzzles biologists, psychologists and economists alike. Between-group conflict has been hypothesized to drive within-group cooperation. However, such conflicts did not have lasting effects in laboratory experiments, because they were about luxury goods, not needed for survival ("looting"). Here, we find within-group cooperation to last when between-group conflict is implemented as "all-out war" (eliminating the weakest groups). Human subjects invested in helping group members to avoid having the lowest collective pay-off, whereas they failed to cooperate in control treatments with random group elimination or with no subdivision in groups. When the game was repeated, experience was found to promote helping. Thus, not within-group interactions alone, not random group elimination, but pay-off-dependent group elimination was found to drive within-group cooperation in our experiment. We suggest that some forms of human cooperation are maintained by multi-level selection: reciprocity within groups and lethal competition among groups acting together.

Complementation Studies of Bacteriophage λ O Amber Mutants by Allelic Forms of O Expressed from Plasmid, and O-P Interaction Phenotypes.

PubMed

Hayes, Sidney; Rajamanickam, Karthic; Hayes, Connie

2018-04-05

λ genes O and P are required for replication initiation from the bacteriophage λ origin site, ori λ, located within gene O . Questions have persisted for years about whether O-defects can indeed be complemented in trans . We show the effect of original null mutations in O and the influence of four origin mutations (three are in-frame deletions and one is a point mutation) on complementation. This is the first demonstration that O proteins with internal deletions can complement for O activity, and that expression of the N-terminal portion of gene P can completely prevent O complementation. We show that O-P co-expression can limit the lethal effect of P on cell growth. We explore the influence of the contiguous small RNA OOP on O complementation and P-lethality.

EVALUATING THE PREDICTIVE VALIDITY OF SUICIDAL INTENT AND MEDICAL LETHALITY IN YOUTH

PubMed Central

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (Mage at hospitalization = 14.83; 51% female; 80% Caucasian) were characterized using the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson-Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. Results Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. Conclusions Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should only be considered as predictors within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to previous attempts. PMID:22250854

Placenta Defects and Embryonic Lethality Resulting from Disruption of Mouse Hydroxysteroid (17-β) Dehydrogenase 2 Gene

PubMed Central

Rantakari, Pia; Strauss, Leena; Kiviranta, Riku; Lagerbohm, Heidi; Paviala, Jenni; Holopainen, Irma; Vainio, Seppo; Pakarinen, Pirjo; Poutanen, Matti

2008-01-01

Hydroxysteroid (17-β) dehydrogenase 2 (HSD17B2) is a member of aldo-keto reductase superfamily, known to catalyze the inactivation of 17β-hydroxysteroids to less active 17-keto forms and catalyze the conversion of 20α-hydroxyprogesterone to progesterone in vitro. To examine the role of HSD17B2 in vivo, we generated mice deficient in Hsd17b2 [HSD17B2 knockout (KO)] by a targeted gene disruption in embryonic stem cells. From the homozygous mice carrying the disrupted Hsd17b2, 70% showed embryonic lethality appearing at the age of embryonic d 11.5 onward. The embryonic lethality was associated with reduced placental size measured at embryonic d 17.5. The HSD17B2KO mice placentas presented with structural abnormalities in all three major layers: the decidua, spongiotrophoblast, and labyrinth. Most notable was the disruption of the spongiotrophoblast and labyrinthine layers, together with liquid-filled cysts in the junctional region and the basal layer. Treatments with an antiestrogen or progesterone did not rescue the embryonic lethality or the placenta defect in the homozygous mice. In hybrid background used, 24% of HSD17B2KO mice survived through the fetal period but were born growth retarded and displayed a phenotype in the brain with enlargement of ventricles, abnormal laminar organization, and increased cellular density in the cortex. Furthermore, the HSD17B2KO mice had unilateral renal degeneration, the affected kidney frequently appearing as a fluid-filled sac. Our results provide evidence for a role for HSD17B2 enzyme in the cellular organization of the mouse placenta. PMID:18048640

Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening.

PubMed

Adams, David; Baldock, Richard; Bhattacharya, Shoumo; Copp, Andrew J; Dickinson, Mary; Greene, Nicholas D E; Henkelman, Mark; Justice, Monica; Mohun, Timothy; Murray, Stephen A; Pauws, Erwin; Raess, Michael; Rossant, Janet; Weaver, Tom; West, David

2013-05-01

Identifying genes that are important for embryo development is a crucial first step towards understanding their many functions in driving the ordered growth, differentiation and organogenesis of embryos. It can also shed light on the origins of developmental disease and congenital abnormalities. Current international efforts to examine gene function in the mouse provide a unique opportunity to pinpoint genes that are involved in embryogenesis, owing to the emergence of embryonic lethal knockout mutants. Through internationally coordinated efforts, the International Knockout Mouse Consortium (IKMC) has generated a public resource of mouse knockout strains and, in April 2012, the International Mouse Phenotyping Consortium (IMPC), supported by the EU InfraCoMP programme, convened a workshop to discuss developing a phenotyping pipeline for the investigation of embryonic lethal knockout lines. This workshop brought together over 100 scientists, from 13 countries, who are working in the academic and commercial research sectors, including experts and opinion leaders in the fields of embryology, animal imaging, data capture, quality control and annotation, high-throughput mouse production, phenotyping, and reporter gene analysis. This article summarises the outcome of the workshop, including (1) the vital scientific importance of phenotyping embryonic lethal mouse strains for basic and translational research; (2) a common framework to harmonise international efforts within this context; (3) the types of phenotyping that are likely to be most appropriate for systematic use, with a focus on 3D embryo imaging; (4) the importance of centralising data in a standardised form to facilitate data mining; and (5) the development of online tools to allow open access to and dissemination of the phenotyping data.

In Vitro Stretch Injury Induces Time- and Severity-Dependent Alterations of STEP Phosphorylation and Proteolysis in Neurons

PubMed Central

Mesfin, Mahlet N.; von Reyn, Catherine R.; Mott, Rosalind E.; Putt, Mary E.

2012-01-01

Abstract Striatal-enriched tyrosine phosphatase (STEP) has been identified as a component of physiological and pathophysiological signaling pathways mediated by N-methyl-d-aspartate (NMDA) receptor/calcineurin/calpain activation. Activation of these pathways produces a subsequent change in STEP isoform expression or activation via dephosphorylation. In this study, we evaluated changes in STEP phosphorylation and proteolysis in dissociated cortical neurons after sublethal and lethal mechanical injury using an in vitro stretch injury device. Sublethal stretch injury produces minimal changes in STEP phosphorylation at early time points, and increased STEP phosphorylation at 24 h that is blocked by the NMDA-receptor antagonist APV, the calcineurin-inhibitor FK506, and the sodium channel blocker tetrodotoxin. Lethal stretch injury produces rapid STEP dephosphorylation via NR2B-containing NMDA receptors, but not calcineurin, and a subsequent biphasic phosphorylation pattern. STEP61 expression progressively increases after sublethal stretch with no change in calpain-mediated STEP33 formation, while lethal stretch injury results in STEP33 formation via a NR2B-containing NMDA receptor pathway within 1 h of injury. Blocking calpain activation in the initial 30 min after stretch injury increases the ratio of active STEP in cells and blocks STEP33 formation, suggesting that STEP is an early substrate of calpain after mechanical injury. There is a strong correlation between the amount of STEP33 formed and the degree of cell death observed after lethal stretch injury. In summary, these data demonstrate that previously characterized pathways of STEP regulation via the NMDA receptor are generally conserved in mechanical injury, and suggest that calpain-mediated cleavage of STEP33 should be further examined as an early marker of neuronal fate after stretch injury. PMID:22435660

AMBIENT SOLAR UV RADIATION CAUSES MORTALITY IN LARVAE OF THREE SPECIES OF RANA

EPA Science Inventory

Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

Lethal trap trees: a potential option for emerald ash borer (Agrilus planipennis Fairmaire) management

Treesearch

Deborah G McCullough; Therese M. Poland; Phillip A. Lewis

2015-01-01

BACKGROUND: Economic and ecological impacts of ash (Fraxinus spp.) mortality resulting from emerald ash borer (EAB) (Agrilus planipennis Fairmaire) invasion are severe in forested, residential and urban areas. Management options include girdling ash trees to attract ovipositing adult beetles and then destroying infested trees...

Adolescents' Misperceptions of the Dangerousness of Acetaminophen in Overdose.

ERIC Educational Resources Information Center

Harris, Hope Elaine; Myers, Wade C.

1997-01-01

Assesses the generality and strength of nonclinical youths' (N=569) perceptions of the harmfulness and lethality of acetaminophen in overdose. Findings indicate that adolescents have ready access to acetaminophen and use it in suicide attempts but underestimate its potential for toxicity, lacking knowledge regarding side effects of overdose. (RJM)

Reconsidering the Relationship between Alcohol and Lethal Violence

ERIC Educational Resources Information Center

Phillips, Scott; Matusko, Jacqueline; Tomasovic, Elizabeth

2007-01-01

Prior event-based research regarding the relationship between alcohol and violence suffers from important limitations, including the absence of a comparison group, an inappropriate comparison group, or a comparison group that could be considered appropriate but does not control for potential confounders. To overcome such limitations, we use a…

The Clinical Management and Prevention of Pica: A Retrospective Follow-Up of 41 Individuals with Intellectual Disabilities and Pica

ERIC Educational Resources Information Center

Williams, Don E.; Kirkpatrick-Sanchez, Sharon; Enzinna, Christie; Dunn, Jacqueline; Borden-Karasack, Deborah

2009-01-01

Background: Pica is a very dangerous form of self-injurious behaviour because one occurrence can be lethal. Dealing successfully with dangerous pica in a large institution requires a high level of administrative support. It cannot be relegated to each psychologist to write a programme. A written behaviour programme is only one component of…

Hafnium-Based Bulk Metallic Glasses for Kinetic Energy Penetrators

DTIC Science & Technology

2004-12-01

uranium -based (DU) and tungsten- nickel -iron (W-Ni-Fe) composite kinetic energy (KE) munitions is primarily ascribed to their high densities (U: ρ...based on an invariant point identified in the hafnium- copper- nickel ternary system. They are denser than zirconium-based glass-forming compositions...depleted- uranium penetrators. 1. INTRODUCTION 1.1 Criterion for Effective Kinetic Energy Penetrator Performance The lethality of depleted

Cell therapies for Chagas disease.

PubMed

Carvalho, Adriana Bastos; Goldenberg, Regina Coeli Dos Santos; Campos de Carvalho, Antonio Carlos

2017-11-01

In this review of cell therapies in Chagas disease, we cover aspects related to the disease, its treatment and world demographics, before proceeding to describe the preclinical and clinical trials performed using cell therapies in the search for an alternative therapy for the most severe and lethal form of this disease, chronic chagasic cardiomyopathy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Chemical, Biochemical, and Genetic Approaches to Arsenic Metabolism" -An overview of arsenic metabolism and toxicity- A series of five papers to appear together in Current Protocols in Toxicology

EPA Science Inventory

The toxic properties of arsenic (As) were recognized long before Albertus Magnus in the 13th century prepared its elemental form (Buchanan, 1962). Its use as a poison has played lethal and decisive roles in domestic and dynastic intrigues throughout history (Cullen, 2008). Inorga...

Examining Merkel Cell Polyomavirus Minor Capsid Proteins | Center for Cancer Research

Cancer.gov

Merkel cell polyomavirus (MCV or MCPyV) is a recently discovered member of the viral family Polyomaviridae. It is a skin-dwelling polyomavirus species that appears to cause a rare but highly lethal form of skin cancer called Merkel cell carcinoma (MCC). Despite MCC being uncommon, chronic MCV infection of human skin is widespread, and most infected people have no known

Preventing abusive head trauma resulting from a failure of normal interaction between infants and their caregivers.

PubMed

Barr, Ronald G

2012-10-16

Head trauma from abuse, including shaken baby syndrome, is a devastating and potentially lethal form of infant physical abuse first recognized in the early 1970s. What has been less recognized is the role of the early increase in crying in otherwise normal infants in the first few months of life as a trigger for the abuse. In part, this is because infant crying, especially prolonged unsoothable crying, has been interpreted clinically as something wrong with the infant, the infant's caregiver, or the interactions between them. Here, we review an alternative developmental interpretation, namely, that the early increase in crying is a typical behavioral development in normal infants and usually does not reflect anything wrong or abnormal. We also review evidence indicating that this normal crying pattern is the most common trigger for abusive head trauma (AHT). Together, these findings point to a conceptualization of AHT as the consequence of a failure in an otherwise common, iterative, and developmentally normal infant-caregiver interaction. They also imply that there is a window of opportunity for prevention of AHT, and potentially other forms of infant abuse, through a public health primary universal prevention strategy aimed at changing knowledge and behaviors of caregivers and society in general concerning normal development of infants and the significance of early increased infant crying. If effective, there may be important implications for prevention of infant abuse nationally and internationally.

Conventional Therapy and Promising Plant-Derived Compounds Against Trypanosomatid Parasites

PubMed Central

Alviano, Daniela Sales; Barreto, Anna Léa Silva; Dias, Felipe de Almeida; Rodrigues, Igor de Almeida; Rosa, Maria do Socorro dos Santos; Alviano, Celuta Sales; Soares, Rosangela Maria de Araújo

2012-01-01

Leishmaniasis and trypanosomiasis are two neglected and potentially lethal diseases that affect mostly the poor and marginal populations of developing countries around the world and consequently have an important impact on public health. Clinical manifestations such as cutaneous, mucocutaneous, and visceral disorders are the most frequent forms of leishmaniasis, a group of diseases caused by several Leishmania spp. American trypanosomiasis, or Chagas disease, is caused by Trypanosoma cruzi, a parasite that causes progressive damage to different organs, particularly the heart, esophagus, and lower intestine. African trypanosomiasis, or sleeping sickness, is caused by Trypanosoma brucei and is characterized by first presenting as an acute form that affects blood clotting and then becoming a chronic meningoencephalitis. The limited number, low efficacy, and side effects of conventional anti-leishmania and anti-trypanosomal drugs and the resistance developed by parasites are the major factors responsible for the growth in mortality rates. Recent research focused on plants has shown an ingenious way to obtain a solid and potentially rich source of drug candidates against various infectious diseases. Bioactive phytocompounds present in the crude extracts and essential oils of medicinal plants are components of an important strategy linked to the discovery of new medicines. These compounds have proven to be a good source of therapeutic agents for the treatment of leishmaniasis and trypanosomiasis. This work highlights some chemotherapeutic agents while emphasizing the importance of plants as a source of new and powerful drugs against these widespread diseases. PMID:22888328

Preventing abusive head trauma resulting from a failure of normal interaction between infants and their caregivers

PubMed Central

Barr, Ronald G.

2012-01-01

Head trauma from abuse, including shaken baby syndrome, is a devastating and potentially lethal form of infant physical abuse first recognized in the early 1970s. What has been less recognized is the role of the early increase in crying in otherwise normal infants in the first few months of life as a trigger for the abuse. In part, this is because infant crying, especially prolonged unsoothable crying, has been interpreted clinically as something wrong with the infant, the infant’s caregiver, or the interactions between them. Here, we review an alternative developmental interpretation, namely, that the early increase in crying is a typical behavioral development in normal infants and usually does not reflect anything wrong or abnormal. We also review evidence indicating that this normal crying pattern is the most common trigger for abusive head trauma (AHT). Together, these findings point to a conceptualization of AHT as the consequence of a failure in an otherwise common, iterative, and developmentally normal infant–caregiver interaction. They also imply that there is a window of opportunity for prevention of AHT, and potentially other forms of infant abuse, through a public health primary universal prevention strategy aimed at changing knowledge and behaviors of caregivers and society in general concerning normal development of infants and the significance of early increased infant crying. If effective, there may be important implications for prevention of infant abuse nationally and internationally. PMID:23045677

Lethality of Rendang packaged in multilayer retortable pouch with sterilization process

NASA Astrophysics Data System (ADS)

Praharasti, A. S.; Kusumaningrum, A.; Frediansyah, A.; Nurhikmat, A.; Khasanah, Y.; Suprapedi

2017-01-01

Retort Pouch had become a choice to preserve foods nowadays, besides the used of the can. Both had their own advantages, and Retort Pouch became more popular for the reason of cheaper and easier to recycle. General Method usually used to estimate the lethality of commercial heat sterilization process. Lethality value wa s used for evaluating the efficacy of the thermal process. This study aimed to find whether different layers of pouch materials affect the lethality value and to find differences lethality in two types of multilayer retort pouch, PET/Aluminum Foil/Nylon/RCPP and PET/Nylon/Modified Aluminum/CPP. The result showed that the different layer arrangement was resulted different Sterilization Value (SV). PET/Nylon/Modified Aluminum/CPP had better heat penetration, implied by the higher value of lethality. PET/Nylon/Modified Aluminum/CPP had the lethality value of 6,24 minutes, whereas the lethality value of PET/Aluminum Foil/Nylon/RCPP was 3,54 minutes.

Huffing air conditioner fluid: a cool way to die?

PubMed

Phatak, Darshan R; Walterscheid, Jeffrey

2012-03-01

"Huffing," the form of substance abuse involving inhalants, is growing in popularity because of the ease and availability of chemical inhalants in many household products. The purpose in huffing is to achieve euphoria when the chemicals in question interact with the central nervous system in combination with oxygen displacement. The abuser is lulled into a false sense of safety despite the well-documented potential for lethal cardiac arrhythmia and the effects of chronic inhalant abuse, including multisystem organ failure, and brain damage. Huffing air conditioner fluid is a growing problem given the accessibility to outdoor units and their fluid components, such as difluorochloromethane(chlorodifluoromethane, Freon), and we have classified multiple cases of accidental death due to the toxicity of difluorochloromethane. Given the ubiquity of these devices and the vast lack of gating or security devices, they make an inviting target for inhalant abusers. Acute huffing fatalities have distinct findings that are present at the scene, given the position of the decedent and proximity to the air conditioner unit. The purpose of the autopsy in these cases is to exclude other potential causes of death and to procure specimens for toxicological analysis.

Miscoding and mutagenic properties of 8-oxoguanine and abasic sites: Ubiquitous lesions in damaged DNA

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

Grollman, A.P.; Takeshita, Masaru

1995-12-31

More than twenty oxidatively-damaged bases, including 8-oxoguanine, have been found to occur in genomic DNA. Some of these lesions block DNA replication and are potentially lethal; others generate mutations which can initiate carcinogenesis and promote cellular aging. In this report, the authors focus attention on the mutagenicity and repair of 8-oxoguanine. Kasai and Nishimura`s discovery that hydroxyl radicals react with guanine residues in DNA to form 8-oxoguanine and the development of sensitive methods for the detection and quantitation of this modified base led to the observation that approximately 1 in 10{sup 5} guanine residues in mammalian DNA are oxidized atmore » the C-8 position. DNA containing 8-oxoguanine and synthetic analogs of the abasic site have been used to investigate the miscoding and mutagenic potential of these ubiquitous lesions. Studies in the laboratory were facilitated by the development of solid state synthetic methods by which these lesions could be introduced at defined positions in DNA. In this paper, the authors review studies in which 8-oxoguanine and abasic sites have been used in model systems to explore various early events in the replication of selectively damaged DNA.« less

Vesicular glutamate transporter VGLUT1 has a role in hippocampal long-term potentiation and spatial reversal learning.

PubMed

Balschun, Detlef; Moechars, Diederik; Callaerts-Vegh, Zsuzsanna; Vermaercke, Ben; Van Acker, Nathalie; Andries, Luc; D'Hooge, Rudi

2010-03-01

Vesicular glutamate transporters 1 and 2 (VGLUT1, VGLUT2) show largely complementary distribution in the mature rodent brain and tend to segregate to synapses with different physiological properties. In the hippocampus, VGLUT1 is the dominate subtype in adult animals, whereas VGLUT2 is transiently expressed during early postnatal development. We generated and characterized VGLUT1 knockout mice in order to examine the functional contribution of this transporter to hippocampal synaptic plasticity and hippocampus-dependent spatial learning. Because complete deletion of VGLUT1 resulted in postnatal lethality, we used heterozygous animals for analysis. Here, we report that deletion of VGLUT1 resulted in impaired hippocampal long-term potentiation (LTP) in the CA1 region in vitro. In contrast, heterozygous VGLUT2 mice that were investigated for comparison did not show any changes in LTP. The reduced ability of VGLUT1-deficient mice to express LTP was accompanied by a specific deficit in spatial reversal learning in the water maze. Our data suggest a functional role of VGLUT1 in forms of hippocampal synaptic plasticity that are required to adapt and modify acquired spatial maps to external stimuli and changes.

Understanding Change: Sigismund Von Schlichting and the Operational Level of War

DTIC Science & Technology

1989-05-10

Day-, we see the relationship between mass arT ie- lethal weapons and the emergence of both a nw form c,’ co:mrtat (which we now call ALI+tragStakt ik...war wa_,sa - science , and that wi su-f+icient Plannino the eet c a mp a: Qn could be aoresc-1 arnd arranac wi th somethi~.ng mathematical certainty. In...clearly that the technological changes of the 19th CentUry had created a new form of the military art --what we now call the ooerat2.~nal art . His

Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

PubMed

Soloff, Paul; White, Richard; Diwadkar, Vaibhav A

2014-06-30

Impulsivity and aggressiveness are trait dispositions associated with the vulnerability to suicidal behavior across diagnoses. They are associated with structural and functional abnormalities in brain networks involved in regulation of mood, impulse and behavior. They are also core characteristics of borderline personality disorder (BPD), a disorder defined, in part, by recurrent suicidal behavior. We assessed the relationships between personality traits, brain structure and lethality of suicide attempts in 51 BPD attempters using multiple regression analyses on structural MRI data. BPD was diagnosed by the Diagnostic Interview for Borderline Patients-revised, impulsivity by the Barratt Impulsiveness Scale (BIS), aggression by the Brown-Goodwin Lifetime History of Aggression (LHA), and high lethality by a score of 4 or more on the Lethality Rating Scale (LRS). Sixteen High Lethality attempters were compared to 35 Low Lethality attempters, with no significant differences noted in gender, co-morbidity, childhood abuse, BIS or LHA scores. Degree of medical lethality (LRS) was negatively related to gray matter volumes across multiple fronto-temporal-limbic regions. Effects of impulsivity and aggression on gray matter volumes discriminated High from Low Lethality attempters and differed markedly within lethality groups. Lethality of suicide attempts in BPD may be related to the mediation of these personality traits by specific neural networks. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Developmental toxicity and risk assessment of nonylphenol to the South American toad, Rhinella arenarum.

PubMed

Mariel, Aronzon Carolina; Alejandra, Babay Paola; Silvia, Pérez Coll Cristina

2014-09-01

The toxicity of Nonylphenol, an emerging pollutant, on the common South American toad Rhinella arenarum was stage and time dependent, thus Median Lethal Concentrations (LC50) for acute (96h), short-term chronic (168h) and chronic exposure (336h) were 1.06; 0.96 and 0.17mgNP/L from embryonic period (S.4), whereas for exposure from larvae (S.25), LC50 remained constant at 0.37mgNP/L from 96h to 168h, decreasing to 0.11mgNP/L at 336h. NOEC-168h for exposure from embryos was 0.025mgNP/L. The Teratogenic Potential (NOEC-lethality/NOEC-sublethal effects) was 23 times higher than the threshold value, indicating a high risk for embryos to be malformed in absence of significant lethality and representing a threat for the species conservation. By comparing with other amphibians, the early development of R. arenarum was very sensitive to NP. The results highlight the relevance of extending the exposure time and look for the most sensitive stage in order to perform the bioassays for conservation purposes. Copyright © 2014 Elsevier B.V. All rights reserved.

Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

PubMed Central

Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara; Podszywalow-Bartnicka, Paulina; Maifrede, Silvia; Di Marcantonio, Daniela; Bolton-Gillespie, Elisabeth; Cramer-Morales, Kimberly; Lee, Jaewong; Li, Min; Slupianek, Artur; Gritsyuk, Daniel; Cerny-Reiterer, Sabine; Seferynska, Ilona; Bullinger, Lars; Gorbunova, Vera; Piwocka, Katarzyna; Valent, Peter; Civin, Curt I.; Muschen, Markus; Dick, John E.; Wang, Jean C.Y.; Bhatia, Smita; Bhatia, Ravi; Eppert, Kolja; Minden, Mark D.; Sykes, Stephen M.

2017-01-01

Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase–mediated (DNA-PK–mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK–deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK–deficient quiescent leukemia cells and BRCA/DNA-PK–deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients. PMID:28481221

Inhibition of anthrax lethal factor by ssDNA aptamers.

PubMed

Lahousse, Mieke; Park, Hae-Chul; Lee, Sang-Choon; Ha, Na-Reum; Jung, In-Pil; Schlesinger, Sara R; Shackelford, Kaylin; Yoon, Moon-Young; Kim, Sung-Kun

2018-05-15

Anthrax is caused by Bacillus anthracis, a bacterium that is able to secrete the toxins protective antigen, edema factor and lethal factor. Due to the high level of secretion from the bacteria and its severe virulence, lethal factor (LF) has been sought as a biomarker for detecting bacterial infection and as an effective target to neutralize toxicity. In this study, we found three aptamers, and binding affinity was determined by fluorescently labeled aptamers. One of the aptamers exhibited high affinity, with a K d value of 11.0 ± 2.7 nM, along with low cross reactivity relative to bovine serum albumin and protective antigen. The therapeutic functionality of the aptamer was examined by assessing the inhibition of LF protease activity against a mitogen-activated protein kinase kinase. The aptamer appears to be an effective inhibitor of LF with an IC 50 value of 15 ± 1.5 μM and approximately 85% cell viability, suggesting that this aptamer provides a potential clue for not only development of a sensitive diagnostic device of B. anthracis infection but also the design of novel inhibitors of LF. Copyright © 2018 Elsevier Inc. All rights reserved.

hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

PubMed

Nogawa, Hisashi; Kawai, Tomoyuki

2014-10-15

Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

Synergistic Antibacterial and Anti-Inflammatory Activity of Temporin A and Modified Temporin B In Vivo

PubMed Central

Capparelli, Rosanna; Romanelli, Alessandra; Iannaccone, Marco; Nocerino, Nunzia; Ripa, Raffaella; Pensato, Soccorsa; Pedone, Carlo; Iannelli, Domenico

2009-01-01

Temporins are antimicrobial peptides secreted by the granular glands of the European red frog (Rana temporaria). They are 10–14 amino acid long polypeptides active prevalently against gram positive bacteria. This study shows that a synthetic temporin B analogue (TB-YK), acquires the capacity to act in synergism with temporin A and to exert antimicrobial and anti-inflammatory activity in vivo against gram positive and gram negative bacteria. Administration of 3.4 mg/Kg of temporin A (TA)+1.6 mg/Kg TB-YK, given to individual mice concurrently with a lethal dose of bacteria (gram positive or negative), rescued 100% of the animals. More importantly, the same doses of temporins, administered one week after experimental infection with a sub lethal dose of bacteria, sterilized 100% of the animals within 3–6 days. Also, it is described an animal model based on the use of sub lethal doses of bacteria, which closely mimics bacterial infection in humans. The model offers the possibility to test in a preclinical setting the true potential of TA and TB-YK in combination as antimicrobial and anti-inflammatory agents. PMID:19784377

DNA vaccines targeting heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E induce potent humoral and cellular immunity and provide protection from lethal toxin challenge.

PubMed

Scott, Veronica L; Villarreal, Daniel O; Hutnick, Natalie A; Walters, Jewell N; Ragwan, Edwin; Bdeir, Khalil; Yan, Jian; Sardesai, Niranjan Y; Finnefrock, Adam C; Casimiro, Danilo R; Weiner, David B

2015-01-01

Botulinum neurotoxins (BoNTs) are deadly, toxic proteins produced by the bacterium Clostridium botulinum that can cause significant diseases in humans. The use of the toxic substances as potential bioweapons has raised concerns by the Centers for Disease Control and Prevention and the United States Military. Currently, there is no licensed vaccine to prevent botulinum intoxication. Here we present an immunogenicity study to evaluate the efficacy of novel monovalent vaccines and a trivalent cocktail DNA vaccine targeting the heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E. These synthetic DNA vaccines induced robust humoral and polyfunctional CD4(+) T-cell responses which fully protected animals against lethal challenge after just 2 immunizations. In addition, naïve animals administered immunized sera mixed with the lethal neurotoxin were 100% protected against intoxication. The data demonstrate the protective efficacy induced by a combinative synthetic DNA vaccine approach. This study has importance for the development of vaccines that provide protective immunity against C. botulinum neurotoxins and other toxins.

Three homicides with darts tainted with succinylcholine: autopsy and toxicology.

PubMed

Xing, Jingjun; Li, Wenhe; Tong, Fang; Liang, Yue; He, Guanglong; Zhou, Yiwu

2016-11-01

In emergency departments, intoxication with the muscle relaxant succinylcholine (SUX) often leads to a potentially lethal respiratory paralysis or other deleterious side effects. However, homicide cases with SUX poisoning are very rare because the toxic or lethal concentration ranges of SUX have not yet been determined. We described three uncommon homicide cases due to acute poisoning by darts contaminated with SUX. All the victims died quickly (less than 30 min) after being shot by an especially designed dart gun. Succinylmonocholine (SMC), a metabolite of SUX, was used as a marker to detect the latter. HPLC-MS/MS analysis demonstrated the presence of SUX in the droplet residues of the darts and SMC in the blood and urine in all cases. SMC concentrations of 0.45, 14.0, and 17.9 ng/ml were detected in the victims' blood and 259.0 ng/ml in the urine from the third case. The main pathological changes consisted of hemorrhage of the injured soft tissues, visceral congestion, severe pulmonary edema, and multifocal petechial hemorrhage of the heart and lungs. Taken together, the findings supported a diagnosis of fatal SUX poisoning. Futhermore, our study provided a reference for the lethal concentrations of SUX poisoning.

Experimental Respiratory Infection of Marmosets (Callithrix jacchus) With Ebola Virus Kikwit.

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Nunez, Alejandro; Salguero, Francisco J; Lever, Mark S

2015-10-01

Ebola virus (EBOV) causes a highly infectious and lethal hemorrhagic fever in primates with high fatality rates during outbreaks and EBOV may be exploited as a potential biothreat pathogen. There is therefore a need to develop and license appropriate medical countermeasures against this virus. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess vaccines or therapies against EBOV disease (EVD), initial susceptibility, lethality and pathogenesis studies were performed. Low doses of EBOV-Kikwit, between 4 and 27 times the 50% tissue culture infectious dose, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to EVD between 6 and 8 days after challenge. Typical signs of EVD were observed. Pathogenesis studies revealed that virus was isolated from the lungs of animals beginning on day 3 after challenge and from the liver, spleen and blood beginning on day 5. The most striking features were observed in animals that succumbed to infection, including high viral titers in all organs, increased levels of liver function enzymes and blood clotting times, decreased levels of platelets, multifocal moderate to severe hepatitis, and perivascular edema. © Crown copyright 2015.

Post-exposure treatment of non-human primates lethally infected with Ebola virus with EBOTAb, a purified ovine IgG product.

PubMed

Dowall, Stuart D; Jacquot, Frédéric; Landon, John; Rayner, Emma; Hall, Graham; Carbonnelle, Caroline; Raoul, Hervé; Pannetier, Delphine; Cameron, Ian; Coxon, Ruth; Al Abdulla, Ibrahim; Hewson, Roger; Carroll, Miles W

2017-06-22

Despite sporadic outbreaks of Ebola virus (EBOV) over the last 4 decades and the recent public health emergency in West Africa, there are still no approved vaccines or therapeutics for the treatment of acute EBOV disease (EVD). In response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed EBOTAb. After promising results in the guinea pig model of EBOV infection, EBOTAb was tested in the cynomolgus macaque non-human primate model of lethal EBOV infection. To ensure stringent therapeutic testing conditions to replicate likely clinical usage, EBOTAb was first delivered 1, 2 or 3 days post-challenge with a lethal dose of EBOV. Results showed a protective effect of EBOTAb given post-exposurally, with survival rates decreasing with increasing time after challenge. Viremia results demonstrated that EBOTAb resulted in a decreased circulation of EBOV in the bloodstream. Additionally, assay of liver enzymes and histology analysis of local tissues identified differences between EBOTAb-treated and untreated groups. The results presented demonstrate that EBOTAb conferred protection against EBOV when given post-exposure and should be explored and developed further as a potential intervention strategy for future outbreaks, which are likely to occur.

Toxicity and bioconcentration evaluation of RDX and HMX using sheepshead minnows in water exposures.

PubMed

Lotufo, Guilherme R; Gibson, Alfreda B; Yoo, J Leslie

2010-10-01

Lethal effects of the explosives RDX and HMX were assessed using ten-day water exposures to juvenile sheepshead minnows (Cyprinodon variegatus). For RDX, maximum mortality occurred during the first two days of exposure with a 10-d median lethal concentration (LC50) of 9.9 mg L(-1). The RDX 10-d median lethal residue (LR50) was 9.6 mg kg(-1) (34.9 μmol kg(-1)) wet weight (ww), the first RDX critical body residue reported for fish. Previous investigations reported that RDX body residues in marine amphipods up to 96 μmol kg(-1) ww and in marine mussels up to 86 μmol kg(-1) ww failed to result in significant mortality. The highest HMX concentration tested, corresponding to its apparent solubility limit in seawater (2.0 mg L(-1)), and the associated mean body residue (3 mg kg(-1) or 14 μmol kg(-1) ww) resulted in no significant mortality for exposed minnows. The mean 10-d bioconcentration factors for RDX (0.6-0.9 L kg(-1)) and HMX (0.3-1.6 L kg(-1)) were typically lower than 1, reflecting the low bioaccumulative potential for these compounds. Published by Elsevier Inc.

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

Park, Hyejin; Yoon, Min-Sik; Ryu, Kwon-Yul, E-mail: kyryu@uos.ac.kr

Highlights: •Proliferation capacity of Ubc{sup −/−} FLCs was reduced during culture in vitro. •Ubc is required for proliferation of both hepatocytes and bipotent FLEPCs. •Bipotent FLEPCs exhibit highest Ubc transcription and proliferation capacity. •Cell types responsible for Ubc{sup −/−} fetal liver developmental defect were identified. -- Abstract: We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoieticmore » system. We confirmed that Ubc{sup −/−} embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc{sup −/−} cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid-gestation lethality of Ubc{sup −/−} embryos.« less

Production of high titre antibody response against Russell's viper venom in mice immunized with ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine.

PubMed

Shenoy, P A; Nipate, S S; Sonpetkar, J M; Salvi, N C; Waghmare, A B; Chaudhari, P D

2014-01-15

Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. The aim of the study was to assess the production of antibody response against Russell's viper venom in mice after prophylactic immunization with ethanolic extract of fruits of Piper longum L. and piperine. The mice sera were tested for the presence of antibodies against Russell's viper venom by in vitro lethality neutralization assay and in vivo lethality neutralization assay. Polyvalent anti-snake venom serum (antivenom) manufactured by Haffkine Bio-Pharmaceutical Corporation Ltd. was used as standard. Further confirmation of presence of antibodies against the venom in sera of mice immunized with PLE and piperine was done using indirect enzyme-linked immunosorbent assay (ELISA) and double immunodiffusion test. Treatment with PLE-treated mice serum and piperine-treated mice serum was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay. ELISA testing indicated that there were significantly high (p<0.01) levels of cross reactions between the PLE and piperine treated mice serum and the venom antigens. In double immunodiffusion test, a white band was observed between the two wells of antigen and antibodies for both the PLE-treated and piperine-treated mice serum. Thus it can be concluded that immunization with ethanolic extract of fruits of Piper longum and piperine produced a high titre antibody response against Russell's viper venom in mice. The antibodies against PLE and piperine could be useful in antivenom therapy of Russell's viper bites. PLE and piperine may also have a potential interest in view of the development of antivenom formulations used as antidote against snake bites. Copyright © 2013 Elsevier GmbH. All rights reserved.

Both epsilon-toxin and beta-toxin are important for the lethal properties of Clostridium perfringens type B isolates in the mouse intravenous injection model.

PubMed

Fernandez-Miyakawa, Mariano E; Fisher, Derek J; Poon, Rachael; Sayeed, Sameera; Adams, Vicki; Rood, Julian I; McClane, Bruce A; Uzal, Francisco A

2007-03-01

Clostridium perfringens is capable of producing up to 15 toxins, including alpha-toxin (CPA), beta-toxin (CPB), epsilon-toxin (ETX), enterotoxin, beta2-toxin (CPB2), and perfringolysin O. Type B isolates, which must produce CPA, CPB, and ETX, are associated with animal illnesses characterized by sudden death or acute neurological signs, with or without intestinal damage. Type B pathogenesis in ruminants is poorly understood, with some animals showing lesions and clinical signs similar to those caused by either type C or type D infections. It is unknown whether host or environmental conditions are dominant for determining the outcome of type B disease or if disease outcomes are determined by variable characteristics of type B isolates. To help clarify this issue, 19 type B isolates were evaluated for toxin production during late-log-phase growth via quantitative Western blotting and by biological activity assays. Most type B isolates produced CPB levels similar to those produced by type C isolates in vitro and have the potential to produce genotype C-like disease. The lethality of type B isolate supernatants administered intravenously to mice was evaluated with or without prior trypsin treatment, and monoclonal antibody neutralization studies also were performed. Correlation analyses comparing toxin levels in type B supernatants versus lethality and neutralization studies both found that the main contributor to lethality without pretreatment with trypsin was CPB, whereas neutralization studies indicated that CPB and ETX were both important after trypsin pretreatment. At least part of the CPB produced by type B isolates remained active after trypsin treatment. However, the overall lethalities of most supernatants were lower after trypsin pretreatment. Also, there was a significant association between ETX, CPB2, and CPA production in vitro among type B isolates. However, our results suggest that both CPB and ETX are likely the most important contributors to the pathogenesis of C. perfringens type B infections in domestic animals.

Pathology of carbon monoxide poisoning in two cats.

PubMed

Sobhakumari, Arya; Poppenga, Robert H; Pesavento, J Brad; Uzal, Francisco A

2018-03-05

Carbon monoxide (CO), a common cause of poisoning in human beings has also been implicated in the death of animals. Though there are multiple studies on CO poisoning and relevant lethal blood COHb concentrations in humans, there are no reliable reports of diagnostic lethal carboxyhemoglobin percentage of saturation (COHb%) in cats. Additionally, due to shared housing environments, exposures to companion animals can be a surrogate for lethal exposures in human beings and provide valuable information in concurrent forensic investigations. Two adult Singapura brown ticked cats were submitted to the California Animal Health and Food Safety Laboratory (CAHFS) for necropsy and diagnostic work-up. These animals were found dead along with their two deceased owners. Similar lesions were observed in both cats. At necropsy, gross lesions consisted of multifocal, large, irregular, bright red spots on the skin of the abdomen and the inner surface of ear pinnae, bright red muscles and blood. The carcasses, and tissues fixed in formalin retained the bright red discoloration for up to two weeks. Microscopic lesions included diffuse pulmonary congestion and edema, and multifocal intense basophilia of cardiomyocytes mostly affecting whole fibers or occasionally a portion of the fiber. Based on the clinical history,gross and microscopic changes, cyanide or carbon monoxide poisoning was suspected. Blood samples analyzed for carbon monoxide showed 57 and 41% carboxyhemoglobin COHb%. Muscle samples were negative for cyanide. There are no established reference values for lethal COHb concentration in cats. The COHb % values detected in this case which fell within the lethal range reported for other species, along with the gross lesions and unique histological findings in the heart suggest a helpful criteria for diagnosis of CO intoxication associated death in cats. This case demonstrates that since pets share the same environment as human beings and often are a part of their activities, they can be useful adjuncts in potential forensic investigations to help solve human cases.

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Myc requires RhoA/SRF to reprogram glutamine metabolism.

PubMed

Haikala, Heidi M; Marques, Elsa; Turunen, Mikko; Klefström, Juha

2018-05-04

RhoA regulates actin cytoskeleton but recent evidence suggest a role for this conserved Rho GTPase also in other cellular processes, including transcriptional control of cell proliferation and survival. Interestingy, loss of RhoA is synthetic lethal with oncogenic Myc, a master transcription factor that turns on anabolic metabolism to promote cell growth in many cancers. We show evidence indicating that the synthetic lethal interaction between RhoA loss and Myc arises from deficiency in glutamine utilization, resulting from impaired co-regulation of glutaminase expression and anaplerosis by Myc and RhoA - serum response factor (SRF) pathway. The results suggest metabolic coordination between Myc and RhoA/SRF in sustaining cancer cell viability and indicate RhoA/SRF as a potential vulnerability in cancer cells for therapeutic targeting.

Establishment of conditional vectors for hairpin siRNA knockdowns

PubMed Central

Matsukura, Shiro; Jones, Peter A.; Takai, Daiya

2003-01-01

Small interference RNA (siRNA) is an emerging methodology in reverse genetics. Here we report the development of a new tetracycline-inducible vector-based siRNA system, which uses a tetracycline-responsive derivative of the U6 promoter and the tetracycline repressor for conditional in vivo transcription of short hairpin RNA. This method prevents potential lethality immediately after transfection of a vector when the targeted gene is indispensable, or the phenotype of the knockdown is lethal or results in a growth abnormality. We show that the controlled knockdown of DNA methyltransferase 1 (DNMT1) in human cancer resulted in growth arrest. Removal of the inducer, doxycycline, from treated cells led to re-expression of the targeted gene. Thus the method allows for a highly controlled approach to gene knockdown. PMID:12888529

Evaluating the formulae for integrated lethality in ethylene oxide sterilization using six different endospore forming strains of bacteria, and comparisons of integrated lethality for ethylene oxide and steam systems.

PubMed

Mosley, Gregg A; Gillis, John R; Krushefski, Garrett

2005-01-01

Bacterial endospores from six different species of bacteria were exposed to a spectrum of ethylene oxide (EtO) sterilizing conditions. Temperature was varied from 40 to 60 degrees C and the ethylene oxide concentration was varied from 300 to 750 mg/L. Relative humidity was maintained at 60+/-10% RH. The fraction negative procedure was used to determine the D value for each of the test conditions. Bacterial species tested included Bacillus atrophaeus ATCC # 9372, Bacillus smithii ATCC # 51232, Bacillus subtilis "5230" ATCC # 35021, Bacillus subtilis, DSM # 4181, Bacillus pumilus ATCC # 27142, and Geobacillus stearothermophilus ATCC # 7953. All spore preparations were inoculated on filter paper strips packaged in blue, sterilizable glassine pouches. G. stearothermophilus was the least resistant organism tested. The most resistant organisms tested were B. atrophaeus and B. subtilis "5230". The B. subtilis "5230" strain was slightly more resistant than B. atrophaeus at conditions of 54C and EtO concentrations of 400, 600, and 750 mg/L, as well as at 60C/750mg/L EtO. The other species were between these extremes. This empirical data allowed the application of the recently published formula for converting D values from one set of conditions to another and evaluations of accuracy. The measured D values also allowed the determination of Z values based on temperature variations. These formulae, when applied to process temperatures independent of gas concentration, result in a Z value of approximately 32 degrees C that appears to be similar for all species tested. These data support the application of the previously published formulae 1-6 and allow the same approach to integrated lethality for ethylene oxide processes as is commonly applied to steam sterilization. A review of steam sterilization and related principles was conducted for comparison of integrated lethality for these two methods of sterilization. Errors associated with D values, Z values, extrapolation, and integrated lethality for both methods of sterilization are discussed.

Effects of sub-lethal neurite outgrowth inhibitory concentrations of chlorpyrifos oxon on cytoskeletal proteins and acetylcholinesterase in differentiating N2a cells

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

Flaskos, J., E-mail: flaskos@vet.auth.gr; Nikolaidis, E.; Harris, W.

2011-11-15

Previous work in our laboratory has shown that sub-lethal concentrations (1-10 {mu}M) of chlorpyrifos (CPF), diazinon (DZ) and diazinon oxon (DZO) inhibit the outgrowth of axon-like neurites in differentiating mouse N2a neuroblastoma cells concomitant with altered levels and/or phosphorylation state of axonal cytoskeleton and growth-associated proteins. The aim of the present work was to determine whether chlorpyrifos oxon (CPO) was capable of inhibiting N2a cell differentiation in a similar manner. Using experimental conditions similar to our previous work, sub-lethal concentrations (1-10 {mu}M) of CPO were found to inhibit N2a cell differentiation. However, unlike previous studies with DZ and DZO, theremore » was a high level of sustained inhibition of acetylcholinesterase (AChE) in CPO treated cells. Impairment of neurite outgrowth was also associated with reduced levels of growth associated protein-43 and neurofilament heavy chain (NFH), and the distribution of NFH in cells stained by indirect immunofluorescence was disrupted. However, in contrast to previous findings for DZO, the absolute level of phosphorylated NFH was unaffected by CPO exposure. Taken together, the findings suggest that sub-lethal concentrations of CPO inhibit axon outgrowth in differentiating N2a cells and that this effect involves reduced levels of two proteins that play key roles in axon outgrowth and maintenance. Although the inhibition of neurite outgrowth is unlikely to involve AChE inhibition directly, further work will help to determine whether the persistent inhibition of AChE by CPO can account for the different effects induced by CPO and DZO on the levels of total and phosphorylated NFH. -- Highlights: Black-Right-Pointing-Pointer Sub-lethal levels of chlorpyrifos oxon inhibit neurite outgrowth in N2a cells Black-Right-Pointing-Pointer Acetylcholinesterase exhibits sustained inhibition throughout exposure Black-Right-Pointing-Pointer The levels of neurofilament heavy chain and GAP-43 protein are reduced Black-Right-Pointing-Pointer Neurofilament heavy chain forms aggregates in cell bodies Black-Right-Pointing-Pointer Thus at least two axon-associated cytoskeletal proteins are disrupted by this agent.« less

Airpower’s Emasculation? -- Non-lethal Weapons in Joint Urban Operations

DTIC Science & Technology

2005-02-14

Lethal, Subdue the Enemy Without Killing,” 14, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 /Shadowlands/6583...37 “Non-Lethal, Subdue the Enemy Without Killing,” 10-11, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 ... Area51 /Shadowlands/6583/project035.html> [15 December 2004]. 42 “US Plans for Use of Gas in Iraq,” The Sunshine Project, 7 February 2003, <http

Heterochromatin position effects on circularized sex chromosomes cause filicidal embryonic lethality in Drosophila melanogaster.

PubMed

Ferree, Patrick M; Gomez, Karina; Rominger, Peter; Howard, Dagnie; Kornfeld, Hannah; Barbash, Daniel A

2014-04-01

Some circularized X-Y chromosomes in Drosophila melanogaster are mitotically unstable and induce early embryonic lethality, but the genetic basis is unknown. Our experiments suggest that a large region of X-linked satellite DNA causes anaphase bridges and lethality when placed into a new heterochromatic environment within certain circularized X-Y chromosomes. These results reveal that repetitive sequences can be incompatible with one another in cis. The lethal phenotype also bears a remarkable resemblance to a case of interspecific hybrid lethality.

Organophosphorus insecticides in honey, pollen and bees (Apis mellifera L.) and their potential hazard to bee colonies in Egypt.

PubMed

Al Naggar, Yahya; Codling, Garry; Vogt, Anja; Naiem, Elsaied; Mona, Mohamed; Seif, Amal; Giesy, John P

2015-04-01

There is no clear single factor to date that explains colony loss in bees, but one factor proposed is the wide-spread application of agrochemicals. Concentrations of 14 organophosphorous insecticides (OPs) in honey bees (Apis mellifera) and hive matrices (honey and pollen) were measured to assess their hazard to honey bees. Samples were collected during spring and summer of 2013, from 5 provinces in the middle delta of Egypt. LC/MS-MS was used to identify and quantify individual OPs by use of a modified Quick Easy Cheap Effective Rugged Safe (QuEChERS) method. Pesticides were detected more frequently in samples collected during summer. Pollen contained the greatest concentrations of OPs. Profenofos, chlorpyrifos, malation and diazinon were the most frequently detected OPs. In contrast, ethoprop, phorate, coumaphos and chlorpyrifos-oxon were not detected. A toxic units approach, with lethality as the endpoint was used in an additive model to assess the cumulative potential for adverse effects posed by OPs. Hazard quotients (HQs) in honey and pollen ranged from 0.01-0.05 during spring and from 0.02-0.08 during summer, respectively. HQs based on lethality due to direct exposure of adult worker bees to OPs during spring and summer ranged from 0.04 to 0.1 for best and worst case respectively. It is concluded that direct exposure and/or dietary exposure to OPs in honey and pollen pose little threat due to lethality of bees in Egypt. Copyright © 2014 Elsevier Inc. All rights reserved.

Uptake of hexanitrohexaazaisowurtzitane (CL-20) by the earthworm Eisenia fetida through dermal contact.

PubMed

Gong, Ping; Escalon, B Lynn; Hayes, Charolett A; Perkins, Edward J

2008-02-01

The explosive compound hexanitrohexaazaisowurtzitane (CL-20) has been shown to cause both lethal and sublethal (reproductive and neurotoxic) effects in exposed oligochaetes. However, whether worms take up CL-20 and how much CL-20 enters worm bodies leading to toxicity (e.g., lethality) remain to be determined. In the present study, we used high performance liquid chromatography (HPLC) and radiolabeled tracer methods to investigate the CL-20 uptake in the whole worm body after contact exposures. Worms (Eisenia fetida) were exposed to filter paper spiked with non-radioactive or [U-(14)C]-labeled CL-20 for 1-3 d. The radiolabeled tracer method allowed us to detect the parent compound and transformation products in worms exposed to as low as 0.04 microg CL-20 cm(-2) of filter paper. The HPLC method without radiolabeled tracer was far less sensitive with a detection limit of 2.17 microg CL-20 cm(-2). Using the radiolabeled tracer, we were able to demonstrate that the worm body concentration linearly correlated to the filter paper concentration < or =0.34 microg cm(-2) (r=0.94) if no breakdown products are assumed. At higher concentrations, the body concentration increased slowly and saturated at around 11 microg g(-1) dry mass resulting in an estimated lethal critical body burden of 10-15 microg CL-20 g(-1) dry mass. These findings demonstrate that CL-20 or potential transformation products are taken into the earthworm body through dermal contact. This information should prove valuable in assessing the bioaccumulation potential and ecological risks of CL-20.

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

PubMed

Paul, James M; Toosi, Behzad; Vizeacoumar, Frederick S; Bhanumathy, Kalpana Kalyanasundaram; Li, Yue; Gerger, Courtney; El Zawily, Amr; Freywald, Tanya; Anderson, Deborah H; Mousseau, Darrell; Kanthan, Rani; Zhang, Zhaolei; Vizeacoumar, Franco J; Freywald, Andrew

2016-08-02

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

Mapping evaporative water loss in desert passerines reveals an expanding threat of lethal dehydration.

PubMed

Albright, Thomas P; Mutiibwa, Denis; Gerson, Alexander R; Smith, Eric Krabbe; Talbot, William A; O'Neill, Jacqueline J; McKechnie, Andrew E; Wolf, Blair O

2017-02-28

Extreme high environmental temperatures produce a variety of consequences for wildlife, including mass die-offs. Heat waves are increasing in frequency, intensity, and extent, and are projected to increase further under climate change. However, the spatial and temporal dynamics of die-off risk are poorly understood. Here, we examine the effects of heat waves on evaporative water loss (EWL) and survival in five desert passerine birds across the southwestern United States using a combination of physiological data, mechanistically informed models, and hourly geospatial temperature data. We ask how rates of EWL vary with temperature across species; how frequently, over what areas, and how rapidly lethal dehydration occurs; how EWL and die-off risk vary with body mass; and how die-off risk is affected by climate warming. We find that smaller-bodied passerines are subject to higher rates of mass-specific EWL than larger-bodied counterparts and thus encounter potentially lethal conditions much more frequently, over shorter daily intervals, and over larger geographic areas. Warming by 4 °C greatly expands the extent, frequency, and intensity of dehydration risk, and introduces new threats for larger passerine birds, particularly those with limited geographic ranges. Our models reveal that increasing air temperatures and heat wave occurrence will potentially have important impacts on the water balance, daily activity, and geographic distribution of arid-zone birds. Impacts may be exacerbated by chronic effects and interactions with other environmental changes. This work underscores the importance of acute risks of high temperatures, particularly for small-bodied species, and suggests conservation of thermal refugia and water sources.

Mapping evaporative water loss in desert passerines reveals an expanding threat of lethal dehydration

PubMed Central

Mutiibwa, Denis; Gerson, Alexander. R.; Smith, Eric Krabbe; Talbot, William A.; O’Neill, Jacqueline J.; McKechnie, Andrew E.; Wolf, Blair O.

2017-01-01

Extreme high environmental temperatures produce a variety of consequences for wildlife, including mass die-offs. Heat waves are increasing in frequency, intensity, and extent, and are projected to increase further under climate change. However, the spatial and temporal dynamics of die-off risk are poorly understood. Here, we examine the effects of heat waves on evaporative water loss (EWL) and survival in five desert passerine birds across the southwestern United States using a combination of physiological data, mechanistically informed models, and hourly geospatial temperature data. We ask how rates of EWL vary with temperature across species; how frequently, over what areas, and how rapidly lethal dehydration occurs; how EWL and die-off risk vary with body mass; and how die-off risk is affected by climate warming. We find that smaller-bodied passerines are subject to higher rates of mass-specific EWL than larger-bodied counterparts and thus encounter potentially lethal conditions much more frequently, over shorter daily intervals, and over larger geographic areas. Warming by 4 °C greatly expands the extent, frequency, and intensity of dehydration risk, and introduces new threats for larger passerine birds, particularly those with limited geographic ranges. Our models reveal that increasing air temperatures and heat wave occurrence will potentially have important impacts on the water balance, daily activity, and geographic distribution of arid-zone birds. Impacts may be exacerbated by chronic effects and interactions with other environmental changes. This work underscores the importance of acute risks of high temperatures, particularly for small-bodied species, and suggests conservation of thermal refugia and water sources. PMID:28193891

The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent

PubMed Central

Farese, AM; Brown, CR; Smith, CP; Gibbs, AM; Katz, B P; Johnson, CS; Prado, K; MacVittie, TJ

2013-01-01

The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 hours following total body irradiation in a nonhuman primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gray, (target lethal dose 50/60) delivered at 0.80 Gray minute-1, using linear accelerator-derived 6 Megavolt photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg day-1) or the control (5% dextrose in water) was administered subcutaneously, daily through effect (absolute neutrophil count ≥ 1,000 cells μL-1 for 3 consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 hours post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 hours after irradiation, did not improve survival (2.5% increase, P = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure. PMID:24276548

Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

PubMed

Kumar, Anoop

2016-01-01

Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice.

PubMed

Marzi, Andrea; Emanuel, Jackson; Callison, Julie; McNally, Kristin L; Arndt, Nicolette; Chadinha, Spencer; Martellaro, Cynthia; Rosenke, Rebecca; Scott, Dana P; Safronetz, David; Whitehead, Stephen S; Best, Sonja M; Feldmann, Heinz

2018-01-01

The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR -/- ) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR -/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR -/- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

Large epidemics of hemorrhagic fevers in Mexico 1545-1815.

PubMed

Acuna-Soto, R; Romero, L C; Maguire, J H

2000-06-01

In 1545, twenty-four years after the Spanish conquest of the Aztec empire, an epidemic of a malignant form of a hemorrhagic fever appeared in the highlands of Mexico. The illness was characterized by high fever, headache, and bleeding from the nose, ears, and mouth, accompanied by jaundice, severe abdominal and thoracic pain as well as acute neurological manifestations. The disease was highly lethal and lasted three to four days. It attacked primarily the native population, leaving the Spaniards almost unaffected. The hemorrhagic fevers remained in the area for three centuries and the etiologic agent is still unknown. In this report we describe, and now that more information is available, analyze four epidemics that occurred in Mexico during the colonial period with a focus on the epidemic of 1576 which killed 45% of the entire population of Mexico. It is important to retrieve such diseases and the epidemics they caused from their purely historical context and consider the reality that if they were to reemerge, they are potentially dangerous.

HIV-risk behaviours of American spring break vacationers: a case of situational disinhibition?

PubMed

Apostolopoulos, Y; Sönmez, S; Yu, C H

2002-11-01

Young adults are at high risk for acquiring STDs/HIV due primarily to multiple sex partners, unprotected sex, and substance use combined with sexual activity. Contranormative settings--such as the annual spring break vacation--provide ideal conditions for the potentially lethal interaction between alcohol, drugs, and sexual risk-taking. As a steadily growing form of youth travel and characterized by binge drinking, illicit drug use, and unsafe sexual practices, spring break has become a North American institution involving large numbers of travellers. In this study, the theory of interpersonal behaviour was used to explain college students' health-risk behaviours in the context of spring break and pre- and post-spring break surveys were used to examine casual sex and condom use behaviours. Multivariate analyses revealed peer influences, prior experiences with casual sex, alcohol consumption prior to sex, and impulsivity to be significant predictors of casual sex, while impulsivity and condom availability were significant predictors of students' use of condoms during casual sex.

Plague in Kazakhstan at the present time.

PubMed

Aikimbajev, Alim; Meka-Mechenko, Tatyana; Temiralieva, Gulnara; Bekenov, Jumabek; Sagiyev, Zaurbek; Kaljan, Kani; Mukhambetova, A K

2003-01-01

Since 1990 to 2002, 19 human plague cases and 2 bacteria-carriers cases were registered in natural plague foci on the territory of the republic. For last 12 years plague in forms of bubonic and bubonic-septic was diagnosed in Kazakhstan. Out of 19 patients (14 men--73.6% and 5 women--26.3%), 13 persons recovered (8.4%), 6 persons died (31.6%). Employment of the treatment in the new scheme sharply lowered lethality from plague. Live attenuated Y. pestis EV vaccine available for human and camel use is applied as a basic preventive measure in plague natural foci. Epidemiological importance of ill camels remains high. At the analyzed period, in 5 cases infection was a result of forced camel slaughter. 11 people (57.8%) were infected through flea bites. Central Asian desert plague focus is still the most active and its potential to start epidemic increases in connection with rising of anthropogenic influence. All these changes occur on the background of epidemiological survey decreasing in natural plague foci.

Cardiac arrhythmia and thyroid dysfunction: a novel genetic link

PubMed Central

Purtell, Kerry; Roepke, Torsten K.; Abbott, Geoffrey W.

2010-01-01

Inherited Long QT Syndrome, a cardiac arrhythmia that predisposes to the often lethal ventricular fibrillation, is commonly linked to mutations in KCNQ1. The KCNQ1 voltage-gated K+ channel α subunit passes ventricular myocyte K+ current that helps bring a timely end to each heart-beat. KCNQ1, like many K+ channel α subunits, is regulated by KCNE β subunits, inherited mutations in which also associate with Long QT Syndrome. KCNQ1 and KCNE mutations are also associated with atrial fibrillation. It has long been known that thyroid status strongly influences cardiac function, and that thyroid dysfunction causes abnormal cardiac structure and rhythm. We recently discovered that KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated K+ channel in the thyroid that is required for normal thyroid hormone biosynthesis. Here, we review this novel genetic link between cardiac and thyroid physiology and pathology, and its potential influence upon future therapeutic strategies in cardiac and thyroid disease. PMID:20688187

Should we consider IgG hypogammaglobulinemia a risk factor for severe complications of Ludwig angina?

PubMed Central

Baez-Pravia, Orville V.; Díaz-Cámara, Miriam; De La Sen, Oscar; Pey, Carlos; Ontañón Martín, Mercedes; Jimenez Hiscock, Luis; Morató Bellido, Begoña; Córdoba Sánchez, Ángel Luis

2017-01-01

Abstract Rationale: Cervical necrotizing fasciitis (CNF) and descending necrotizing mediastinitis (DNM) are rare forms of complication of Ludwig angina. These potentially lethal infections are difficult to recognize in early stages and are often associated with predisposing factors like diabetes and immunocompromised states. Moreover, IgG hypogammaglobulinemia (hypo-IgG) is considered to be a risk factor of mortality in patients with septic shock; however, it is not routinely quantified in patients with extremely serious infections, particularly in cases with no history or evidence of immunocompromising disorders. Patient concerns: We present a case of a 58-year-old woman who survived Ludwig angina, complicated by CNF and DNM. Despite a rapid diagnosis, aggressive surgical debridement and broad-spectrum antibiotics, the infection and necrosis advanced, requiring multiple surgical interventions and long intensive care unit (ICU) support. Conclusion: We hypothesize that detecting a low level of endogenous IgG and treating with adjuvant passive immunotherapy was key in determining a favorable outcome. PMID:29381958

Calculating Hematopoietic-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident

PubMed Central

Scott, Bobby R.

2009-01-01

This paper provides theoretical health-risk-assessment tools that are designed to facilitate planning for and managing radiological terrorism incidents that involve ingestion exposure to bone-seeking radionuclides (e.g., radiostrontium nuclides). The focus is on evaluating lethality risk avoidance (RAV; i.e., the decrease in risk) that is associated with radionuclide decorporation countermeasures employed to remove ingested bone-seeking beta and/or gamma-emitting radionuclides from the body. To illustrate the application of tools presented, hypothetical radiostrontium decorporation scenarios were considered that involved evaluating the hematopoietic-mode-lethality RAV. For evaluating the efficacy of specific decorporation countermeasures, the lethality risk avoidance proportion (RAP; which is the RAV divided by the total lethality risk in the absence of protective countermeasures) is introduced. The lethality RAP is expected to be a useful tool for designing optimal radionuclide decorporation schemes and for identifying green, yellow and red dose-rate zones. For the green zone, essentially all of the lethality risk is expected to be avoided (RAP = 1) as a consequence of the radionuclide decorporation scheme used. For the yellow zone, some but not all of the lethality risk is expected to be avoided. For the red zone, none of the lethality risk (which equals 1) is expected to be avoided. PMID:20011652

Chaperonins: The hunt for the Group II mechanism.

PubMed

Bigotti, Maria Giulia; Clarke, Anthony R

2008-06-15

Chaperonins are multi-subunit complexes that enhance the efficiency of protein-folding reactions by capturing protein substrates in their central cavities. They occur in all prokaryotic and eukaryotic cell types and, alone amongst molecular chaperones, chaperonin knockouts are always lethal. Chaperonins come in two forms; the Group I are found in bacteria, mitochondria and plastids [W.A. Fenton, A.L. Horwich, Q. Rev. Biophys. 36 (2003) 229-256, [1

Comparison of Hemostatic Efficacy of ChitoGauze and Combat Gauze in a Lethal Femoral Arterial Injury in Swine Model

DTIC Science & Technology

2010-04-01

range of gram positive and gram negative organisms, including methicillin resistant Staphylococcus aureus ATCC33591 (MRSA), Enterococcus faecalis...range of gram positive and gram negative organisms, including methicillin resistant Staphylococcus aureus ATCC33591 (MRSA), Enterococcus faecalis...control with less blood loss than Combat Gauze in this model. Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for

Uncovering the Role of BMP Signaling in Melanocyte Development and Melanoma Tumorigenesis

DTIC Science & Technology

2015-06-01

Undergrad. student 2013 (W. New England University) Dissertation committees: Shawna Guillemette, UMass Medical School, Cancer Biology Program Tomoko...SUPPLEMENTARY NOTES 14. ABSTRACT Melanoma is the most aggressive and lethal form of skin cancer . In 2013 over 75,000 Americans were diagnosed with...skin cancer , and every year it kills nearly 10,000 Americans and roughly 60,000 people worldwide. A greater understanding of the genetic basis for

Lethal and sub-lethal responses of the biogenic reef forming polychaete Sabellaria alveolata to aqueous chlorine and temperature.

PubMed

Last, K S; Hendrick, V J; Beveridge, C M; Roberts, D A; Wilding, T A

2016-06-01

Sabellaria alveolata, a reef-forming marine polychaete, was exposed to aqueous chlorine which is routinely used as an anti-fouling agent in power station cooling water. Worms were treated to a range of chlorination levels (0, 0.02, 0.1 and 0.5 mg l(-1) Total Residual Oxidant referred to as control, low, intermediate and high TRO) at mean and maximum summer temperatures (18 and 23 °C respectively). Overall mortality was relatively low, however a combination of high temperature and intermediate and high TRO resulted in a significant increase in mortality compared to the control and low TRO treatments. In contrast the extension of dwelling tubes was reduced at high TRO, but increased at low and intermediate TRO levels relative to the controls independent of temperature. Finally, tube strength was found to decrease with increasing TRO, again independent of temperature. On the basis of these findings, S. alveolata can be considered tolerant of one month exposures to low TRO at water temperatures up to and including the summer maxima for southern UK waters. However, at higher TRO levels and during warm weather, high mortality would be predicted. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A most dangerous game: death and injury to birds from porcupine quills

Treesearch

Todd Katzner; Tricia A. Miller; Jane Rodrigue; Steven Shaffer

2015-01-01

Predation is dangerous, not only for the prey but sometimes also for the predator. Because these dangers to predators are not well understood, we document evidence of predation or scavenging by a Golden Eagle (Aquila chrysaetos) on a North American porcupine (Erethizon dorsatum) in Pennsylvania, USA, with potentially lethal...

ASSESSING THE INFLUENCE OF PLANT GROWTH REGULATOR HERBICIDE VAPOR DRIFT ON ARTHROPOD COMMUNITIES IN FIELD CROP AGRO-ECOSYSTEMS

EPA Science Inventory

Sub-lethal herbicide damage is likely to have negative consequences for plant health. This in turn could lead to positive or negative effects on insects. Plants that are not healthy may not provide the best floral resources for pollinators, potentially further stressing hon...

Enhancing the stability and ecological safety of mass-reared transgenic strains for field release by redundant conditional lethality systems

USDA-ARS?s Scientific Manuscript database

Advances in the genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notably SIT, in fruit pests throughout the world. Potentially, these condit...

Effects of high pressure processing on the composition, functional and rheological properties of fresh Queso Fresco

USDA-ARS?s Scientific Manuscript database

Although Queso Fresco (QF), a popular high moisture Hispanic-style cheese sold in the U.S., is made from pasteurized milk it is subject to post pasteurization bacterial contamination. High pressure processing (HPP) of cheese is being considered because of its lethality to bacteria and potential to ...

Dietary silver nanoparticles reduce fitness in a beneficial, but not, pest insect species

USDA-ARS?s Scientific Manuscript database

Silver nanoparticles (AgNPs) have antimicrobial and insecticidal properties and they have been considered for their potential use as insecticides. While they do, indeed, kill some insects, two broader issues have not been considered in a critical way. First, reports of insect-lethal AgNPs are often ...

Radioprotection by polysaccharides alone and in combination with aminothiols

NASA Astrophysics Data System (ADS)

Patchen, Myra L.; Macvittie, Thomas J.; Solberg, Brian D.; D'Alesandro, Michele M.; Brook, Itzhak

We demonstrated that glucan, a beta-1,3 polysaccharide immunomodulator, enhances survival of mice when administered before radiation exposure. Glucan's prophylactic survival-enhancing effects are mediated by several mechanisms including (1) increasing macrophage-mediated resistance to potentially lethal postirradiation opportunistic infections, (2) increasing the Do of hematopoietic progenitor cells, and (3) accelerating hematopoietic reconstitution. In addition, even when administered shortly after some otherwise lethal doses of radiation, glucan increases survival. Glucan's therapeutic survival-enhancing effects are also mediated through its ability to enhance macrophage function and to accelerate hematopoietic reconstitution; glucan's therapeutic potential, however, is ultimately dependent on the survival of a critical number of hematopoietic stem cells capable of responding to glucan's stimulatory effects. Preirradiation administration of the traditional aminothiol radioprotectants WR-2721 and WR-3689 has been previously demonstrated to be an extremely effective means to increase hematopoietic stem cell survival. Therapeutic glucan treatment administered in combination with preirradiation WR-2721 or WR-3689 treatment synergistically increases both hematopoietic reconstitution and survival. Such combined modality treatments offer new promise in treating acute radiation injury.

An Ultrasensitive Gold Nanoparticle-based Lateral Flow Test for the Detection of Active Botulinum Neurotoxin Type A

NASA Astrophysics Data System (ADS)

Liu, Jing; Gao, Shan; Kang, Lin; Ji, Bin; Xin, Wenwen; Kang, Jingjing; Li, Ping; Gao, Jie; Wang, Hanbin; Wang, Jinglin; Yang, Hao

2017-03-01

Botulism is a severe and potentially lethal paralytic disease caused by several botulinum neurotoxin-producing Clostridia spp. In China, the majority of the cases caused by botulism were from less-developed rural areas. Here, we designed specific substrate peptides and reconfigured gold nanoparticle-based lateral flow test strip (LFTS) to develop an endopeptidase-based lateral flow assay for the diagnosis of botulism. We performed this lateral flow assay on botulinum neurotoxin-spiked human serum samples. The as-prepared LFTS had excellent performance in the detection of botulinum neurotoxin using only 1 μL of simulated serum, and its sensitivity and specificity were comparable to that of mouse lethality assay. Moreover, the assay takes only half a day and does not require highly trained laboratory staff, specialized facility, or equipment. Finally, our LFTS can be potentially extended to other serotypes of BoNTs by designing specific substrate peptides against the different types of BoNTs. Overall, we demonstrate a strategy by which LFTS and endopeptidase activity assays can be integrated to achieve facile and economic diagnosis of botulism in resource-limited settings.

Weapon Involvement in the Victimization of Children.

PubMed

Mitchell, Kimberly J; Hamby, Sherry L; Turner, Heather A; Shattuck, Anne; Jones, Lisa M

2015-07-01

To report the prevalence of weapons involved in the victimization of youth with particular emphasis on weapons with a "high lethality risk" and how such exposure fits into the broader victimization and life experiences of children and adolescents. Data were collected as part of the Second National Survey of Children's Exposure to Violence, a nationally representative telephone survey of youth ages 2 to 17 years and caregivers (N = 4114) conducted in 2011. Estimates from the Second National Survey of Children's Exposure to Violence indicate that almost 14 million youth, ages 2–17, in the United States have been exposed to violence involving a weapon in their lifetimes as witnesses or victims,or .1 in 5 children in this age group [corrected]. More than 2 million youth in the United States (1 in 33) have been directly assaulted in incidents where the high lethality risk weapons of guns and knives were used. Differences were noted between victimizations involving higher and lower lethality risk weapons as well as between any weapon involvement versus none. Poly-victims, youth with 7 or more victimization types, were particularly likely to experience victimization with any weapon, as well as victimization with a highly lethal weapon compared with nonpoly-victims. Findings add to the field's broadening conceptualization of youth victimization highlighting the potentially highly consequential risk factor of weapon exposure as a component of victimization experiences on the mental health of youth. Further work on improving gun safety practices and taking steps to reduce children's exposure to weapon-involved violence is warranted to reduce this problem. Copyright © 2015 by the American Academy of Pediatrics.

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

Herkovits, J.; Herkovits, F.D.; Perez-Coll

As a result of their aquatic embryonic and larval development, many species of amphibians are potentially affected by adverse environmental conditions. In this study the possibility of reducing the lethal effect of aluminum (ALC13, Mallinckrodt) in Bufo arenarum embryos by means of simultaneous zinc (ZnSO4) treatment is reported. The aluminum hazard was evaluated in a 7 day renewal toxicity testing study conducted with batches of 10 individuals (by quadruplicate) in six concentrations of aluminum plus the control at 20 C. The pH of the experimental solutions were measured. The LC100 expressed as Al(3 +) mg/L at 24 and up tillmore » 168 hours of treatment were 0.9 (the pH of the solution was 6.2 while in control Holtfreter solution the pH was 6.8). Therefore, aluminum exert a lethal effect on amphibian embryos in concentrations which reduce only slightly the pH of the maintaining solution. The lethal effect of aluminum could be reduced 100% by means of simultaneous treatment with 2 mg Zn(2 +)/L. The results point out the high sensibility of the amphibian embryos to aluminum (LC100/24hs:0.9mg Al(3 +)/L) and therefore, episodic increases in dissolved aluminum, usually concomitant with surface water pH decreases, could produce very harmful effects during embryonic stages of amphibians. The noteworthy beneficial effect of zinc against the lethal effect of aluminum could be of practical value in reducing the harmful effects exerted by aluminum. The conspicuous Al-Zn antagonism points out the need of biological test systems for recording the integrated effects of substances released to the environment.« less

Reanalysis of parabiosis of obesity mutants in the age of leptin.

PubMed

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M

2015-07-21

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.

A hepatic metabolomics-based diagnostic approach to assess lethal toxicity of dithiocarbamate fungicide polycarbamate in three marine fish species.

PubMed

Hano, Takeshi; Ohkubo, Nobuyuki; Mochida, Kazuhiko

2017-04-01

The present study was performed to evaluate the toxic effect of the dithiocarbamate fungicide polycarbamate (PC) on the hepatic metabolic profiles of three marine fish species, red sea bream (Pagrus major), spotted halibut (Verasper variegatus), and marbled flounder (Pleuronectes yokohamae). First, juvenile fish were exposed to graded concentrations of PC for 96h; the 96-h LC 50 values obtained were 22-29, 239-553, and 301-364µgL -1 for red sea bream, spotted halibut, and marbled flounder, respectively, indicating that red sea bream possessed higher sensitivity to PC than the two benthic species. Second, the fish were exposed to lethal-equivalent concentration (H group) or sub-lethal (one-tenth of the H group concentrations; L group) for 24 and 96h and gas-chromatography based metabolomics approach was employed to explore the crucial biomarker metabolite associated with lethal toxicity. Of the 53 metabolites identified, only reduced glutathione (GSH) was consistently elevated in the H group for the three fish species at 96h. The calculated cut-off value of GSH (mM) based on receiver operating curve analysis between H group and the other treatment groups (control, solvent control, and L group) was obtained at 0.56mM, which allowed to distinguish between the groups with high confidence for the three fish species. These results are the first to demonstrate the potential of using GSH as a possible biomarker metabolite and its usefulness of threshold cut-off value for diagnosing life-threatening health conditions of fish. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection.

PubMed

Percopo, Caroline M; Rice, Tyler A; Brenner, Todd A; Dyer, Kimberly D; Luo, Janice L; Kanakabandi, Kishore; Sturdevant, Daniel E; Porcella, Stephen F; Domachowske, Joseph B; Keicher, Jesse D; Rosenberg, Helene F

2015-09-01

We reported previously that priming of the respiratory tract with immunobiotic Lactobacillus prior to virus challenge protects mice against subsequent lethal infection with pneumonia virus of mice (PVM). We present here the results of gene microarray which document differential expression of proinflammatory mediators in response to PVM infection alone and those suppressed in response to Lactobacillus plantarum. We also demonstrate for the first time that intranasal inoculation with live or heat-inactivated L. plantarum or Lactobacillus reuteri promotes full survival from PVM infection when administered within 24h after virus challenge. Survival in response to L. plantarum administered after virus challenge is associated with suppression of proinflammatory cytokines, limited virus recovery, and diminished neutrophil recruitment to lung tissue and airways. Utilizing this post-virus challenge protocol, we found that protective responses elicited by L. plantarum at the respiratory tract were distinct from those at the gastrointestinal mucosa, as mice devoid of the anti-inflammatory cytokine, interleukin (IL)-10, exhibit survival and inflammatory responses that are indistinguishable from those of their wild-type counterparts. Finally, although L. plantarum interacts specifically with pattern recognition receptors TLR2 and NOD2, the respective gene-deleted mice were fully protected against lethal PVM infection by L. plantarum, as are mice devoid of type I interferon receptors. Taken together, L. plantarum is a versatile and flexible agent that is capable of averting the lethal sequelae of severe respiratory infection both prior to and post-virus challenge via complex and potentially redundant mechanisms. Published by Elsevier B.V.

Sudden cardiac death: the pro-arrhythmic interaction of an acute loading with an underlying substrate.

PubMed

Sutherland, George R

2017-10-21

Sudden cardiac death (SCD) is a complex phenomenon, occurring either in apparently normal individuals or in those where there is a recognized underlying cardiac abnormality. In both groups, the lethal arrhythmia has frequently been related to the physiologic trigger of either exercise or stress. Prior research into SCD has focused mainly on a combination of identifying either vulnerable myocardial substrates; pharmacological approaches to altering electrical activation/repolarisation in substrates; or the suppression of induced lethal arrhythmias with implantable defibrillators. However, it has been suggested that in a significant number of cases, the interaction of a transient induced trigger with a pre-existing electrical or mechanical substrate is the basis for the induction of the sustained lethal arrhythmia. In this manuscript we will discuss the precise mechanisms whereby one of such potential physiologic trigger: an acute change in systolic blood pressure, can induce a sequence of alterations in global and local cardiac mechanics which in turn result in regional left ventricular post-systolic deformation which, mediated (through stretch-induced changes in local mechano-electrical coupling) provokes local electrical after-depolarisations which can spill over into complex runs of premature ventricular beats. These local acute pressure/stretch induced runs of ventricular ectopy originate in either basal or apical normal myocardium and, in combination with a co-existing distal pro-arrhymic substrate, can interact to induce a lethal arrhythmia. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Thermal tolerance of the invasive Belonesox belizanus, pike killifish, throughout ontogeny.

PubMed

Kerfoot, James Roy

2012-06-01

The goal of this study was to characterize the variability of thermal tolerances between life-history stages of the invasive Belonesox belizanus and attempt to describe the most likely stage of dispersal across south Florida. In the laboratory, individuals were acclimated to three temperatures (20, 25, or 30°C). Upper and lower lethal thermal limits and temperatures at which feeding ceased were measured for neonates, juveniles, and adults. Thermal tolerance polygons were developed to represent the thermal tolerance range of each life-history stage. Results indicated that across acclimation temperatures upper lethal thermal limits were similar for all three stages (38°C). However, minimum lethal thermal limits were significantly different at the 30°C acclimation temperature, where juveniles (9°C) had an approximately 2.0°C and 4.0°C lower minimum lethal thermal limit compared with adults and neonates, respectively. According to thermal tolerance polygons, juveniles had an average tolerance polygonal area almost 20°C(2) larger than adults, indicating the greatest thermal tolerance of the three life-history stages. Variation in cessation of feeding temperatures indicated no significant difference between juveniles and adults. Overall, results of this study imply that juvenile B. belizanus may be equipped with the physiological flexibility to exercise habitat choice and reduce potential intraspecific competition with adults for limited food resources. Given its continued dispersal, the minimum thermal limit of juveniles may aid in continued dispersal of this species, especially during average winter temperatures throughout Florida where juveniles could act to preserve remnant populations until seasonal temperatures increase. © 2012 WILEY PERIODICALS, INC.

Reanalysis of parabiosis of obesity mutants in the age of leptin

PubMed Central

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M.

2015-01-01

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin−/− double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure. PMID:26150485

Resistance to genetic insect control: Modelling the effects of space.

PubMed

Watkinson-Powell, Benjamin; Alphey, Nina

2017-01-21

Genetic insect control, such as self-limiting RIDL 2 (Release of Insects Carrying a Dominant Lethal) technology, is a development of the sterile insect technique which is proposed to suppress wild populations of a number of major agricultural and public health insect pests. This is achieved by mass rearing and releasing male insects that are homozygous for a repressible dominant lethal genetic construct, which causes death in progeny when inherited. The released genetically engineered ('GE') insects compete for mates with wild individuals, resulting in population suppression. A previous study modelled the evolution of a hypothetical resistance to the lethal construct using a frequency-dependent population genetic and population dynamic approach. This found that proliferation of resistance is possible but can be diluted by the introgression of susceptible alleles from the released homozygous-susceptible GE males. We develop this approach within a spatial context by modelling the spread of a lethal construct and resistance trait, and the effect on population control, in a two deme metapopulation, with GE release in one deme. Results show that spatial effects can drive an increased or decreased evolution of resistance in both the target and non-target demes, depending on the effectiveness and associated costs of the resistant trait, and on the rate of dispersal. A recurrent theme is the potential for the non-target deme to act as a source of resistant or susceptible alleles for the target deme through dispersal. This can in turn have a major impact on the effectiveness of insect population control. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

From tails to toes: developing nonlethal tissue indicators of mercury exposure in five amphibian species.

PubMed

Pfleeger, Adam Z; Eagles-Smith, Collin A; Kowalski, Brandon M; Herring, Garth; Willacker, James J; Jackson, Allyson K; Pierce, John R

2016-04-01

Exposure to environmental contaminants has been implicated as a factor in global amphibian decline. Mercury (Hg) is a particularly widespread contaminant that biomagnifies in amphibians and can cause a suite of deleterious effects. However, monitoring contaminant exposure in amphibian tissues may conflict with conservation goals if lethal take is required. Thus, there is a need to develop non-lethal tissue sampling techniques to quantify contaminant exposure in amphibians. Some minimally invasive sampling techniques, such as toe-clipping, are common in population-genetic research, but it is unclear if these methods can adequately characterize contaminant exposure. We examined the relationships between mercury (Hg) concentrations in non-lethally sampled tissues and paired whole-bodies in five amphibian species. Specifically, we examined the utility of three different tail-clip sections from four salamander species and toe-clips from one anuran species. Both tail and toe-clips accurately predicted whole-body THg concentrations, but the relationships differed among species and the specific tail-clip section or toe that was used. Tail-clips comprised of the distal 0-2 cm segment performed the best across all salamander species, explaining between 82 and 92% of the variation in paired whole-body THg concentrations. Toe-clips were less effective predictors of frog THg concentrations, but THg concentrations in outer rear toes accounted for up to 79% of the variability in frog whole-body THg concentrations. These findings suggest non-lethal sampling of tails and toes has potential applications for monitoring contaminant exposure and risk in amphibians, but care must be taken to ensure consistent collection and interpretation of samples.

Pest management through Bacillus thuringiensis (Bt) in a tea-silkworm ecosystem: status and potential prospects.

PubMed

Dashora, Kavya; Roy, Somnath; Nagpal, Akanksha; Roy, Sudipta Mukhopadhyay; Flood, Julie; Prasad, Anjali Km; Khetarpal, Ravinder; Neave, Suzanne; Muraleedharan, N

2017-03-01

Bacillus thuringiensis (Bt) is a soil bacterium that forms spores containing crystals comprising one or more Cry or Cyt proteins having potential and specific insecticidal activity. Different strains of Bt produce different types of toxins, affecting a narrow taxonomic group of insects. Therefore, it is used in non-chemical pest management, including inherent pest resistance through GM crops. The specificity of action of Bt toxins reduces the concern of adverse effects on non-target species, a concern which remains with chemical insecticides as well. To make use of Bt more sustainable, new strains expressing novel toxins are actively being sought globally. Since Bt is successfully used against many pests including the lepidopteran pests in different crop groups, the insecticidal activity against Samia cynthia (Drury) (Eri silkworm) and Antheraea assamensis Helfer (Muga silkworm) becomes a concern in the state of Assam in India which is a predominantly tea- and silk-producing zone. Though Bt can be used as an effective non-chemical approach for pest management for tea pests in the same geographical region, yet, it may potentially affect the silk industry which depends on silkworm. There is a need to identify the potentially lethal impact (through evaluating their mortality potential) of local Bt strains on key silkworm species in North Eastern India. This will allow the use of existing Bt for which the silkworms have natural resistance. Through this review, the authors aim to highlight recent progress in the use of Bt and its insecticidal toxins in tea pest control and the potential sensitivity for tea- and silk-producing zone of Assam in India.

Full recovery from a potentially lethal dose of mercuric chloride.

PubMed

Beasley, D Michael G; Schep, Leo J; Slaughter, Robin J; Temple, Wayne A; Michel, Jonathan M

2014-03-01

Mercuric chloride poisoning is rare yet potentially life-threatening. We report a case of poisoning with a potentially significant amount of mercuric chloride which responded to aggressive management. A 19-year-old female presented to the Emergency Department with nausea, abdominal discomfort, vomiting of blood-stained fluid, and diarrhea following suicidal ingestion of 2-4 g of mercuric chloride powder. An abdominal radiograph showed radio-opaque material within the gastric antrum and the patient's initial blood mercury concentration was 17.9 μmol/L (or 3.58 mg/L) at 3 h post-ingestion. Given the potential toxicity of inorganic mercury, the patient was admitted to the intensive care unit and chelation with dimercaprol was undertaken. Further clinical effects included mild hemodynamic instability, acidosis, hypokalemia, leukocytosis, and fever. The patient's symptoms began to improve 48 h after admission and resolved fully within a week. Mercuric chloride has an estimated human fatal dose of between 1 and 4 g. Despite a reported ingestion of a potentially lethal dose and a high blood concentration, this patient experienced mild to moderate poisoning only and she responded to early and appropriate intervention. Mercuric chloride can produce a range of toxic effects including corrosive injury, severe gastrointestinal disturbances, acute renal failure, circulatory collapse, and eventual death. Treatment includes close observation and aggressive supportive care along with chelation, preferably with 2,3-dimercapto-1-propane sulfonate or 2,3-meso-dimercaptosuccinic acid.

Lethal and sublethal effects of cypermethrin to Hypsiboas pulchellus tadpoles.

PubMed

Agostini, M Gabriela; Natale, Guillermo S; Ronco, Alicia E

2010-11-01

The study of the effects of the insecticide cypermethrin (CY) technical grade and its Sherpa® commercial formulation on Hypsiboas pulchellus tadpoles assessing lethality, behavior, growth, and abnormalities under standardized laboratory conditions is reported. Observed behaviors were identified and categorized by means of a ranking system according to the loss of mobility. Results of acute lethal effects indicate higher potency for Sherpa® at this level of assessment. All effects on behavior showed an increasing degree of injury as insecticide concentration increased. Organisms exposed to technical grade CY showed lower body length with respect to controls from 3.44 µg CY/L to higher concentrations, whereas those exposed to Sherpa® exhibited lower growth from 0.83 µg CY/L. Both forms of the tested insecticide caused abnormalities between 0.34 and 4.18 µg CY/L, but 100% of malformed individuals was detected from 34.4 µg CY/L for those exposed to the technical grade CY, and from 8.36 µg CY/L for those exposed to Sherpa®. This study proposes the use of easily identifiable and distinguishable sublethal end-points. The high input loads of CY in natural environments, the detected concentrations in the field, in addition to the low levels of this insecticide required to induce sublethal effects (which could eventually lead to death), allow for the conclusion that the insecticide is a risk factor for amphibians inhabiting agroecosystems.

Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress.

PubMed

Feng, Wenyi; Bachant, Jeff; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

2009-12-01

Yeast replication checkpoint mutants lose viability following transient exposure to hydroxyurea, a replication-impeding drug. In an effort to understand the basis for this lethality, we discovered that different events are responsible for inviability in checkpoint-deficient cells harboring mutations in the mec1 and rad53 genes. By monitoring genomewide replication dynamics of cells exposed to hydroxyurea, we show that cells with a checkpoint deficient allele of RAD53, rad53K227A, fail to duplicate centromeres. Following removal of the drug, however, rad53K227A cells recover substantial DNA replication, including replication through centromeres. Despite this recovery, the rad53K227A mutant fails to achieve biorientation of sister centromeres during recovery from hydroxyurea, leading to secondary activation of the spindle assembly checkpoint (SAC), aneuploidy, and lethal chromosome segregation errors. We demonstrate that cell lethality from this segregation defect could be partially remedied by reinforcing bipolar attachment. In contrast, cells with the mec1-1 sml1-1 mutations suffer from severely impaired replication resumption upon removal of hydroxyurea. mec1-1 sml1-1 cells can, however, duplicate at least some of their centromeres and achieve bipolar attachment, leading to abortive segregation and fragmentation of incompletely replicated chromosomes. Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression.

Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48.

PubMed

Esaki, Masatoshi; Islam, Md Tanvir; Tani, Naoki; Ogura, Teru

2017-07-14

Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pivotal roles of Cdc48 remain unknown. Almost all AAA proteins form a ring-shaped structure with a conserved aromatic amino acid residue that is essential for proper function. The threading mechanism hypothesis suggests that this residue guides the intrusion of substrate proteins into a narrow pore of the AAA ring, thereby becoming unfolded. By contrast, the aromatic residue in one of the two AAA rings of Cdc48 has been eliminated through evolution. Here, we show that artificial retrieval of this aromatic residue in Cdc48 is lethal, and essential features to support the threading mechanism are required to exhibit the lethal phenotype. In particular, genetic and biochemical analyses of the Cdc48 lethal mutant strongly suggested that when in complex with the 20S proteasome, essential proteins are abnormally forced to thread through the Cdc48 pore to become degraded, which was not detected in wild-type Cdc48. Thus, the widely applicable threading model is less effective for wild-type Cdc48; rather, Cdc48 might function predominantly through an as-yet-undetermined mechanism.

Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome.

PubMed Central

Merrer, M L; Briard, M L; Girard, S; Mulliez, N; Moraine, C; Imbert, M C

1988-01-01

We report eight cases of a lethal association of failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung's disease, cardiac and renal malformation). This syndrome is likely to be autosomal recessive and resembles Smith-Lemli-Opitz (SLO) syndrome. However, the lethality, the common occurrence of polydactyly, and the sexual ambiguity distinguishes this condition from SLO syndrome. A review of published reports supports the separate classification of this syndrome for which we propose the name lethal acrodysgenital dwarfism. Images PMID:2831368

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.

A VLP-based vaccine targeting domain III of the West Nile virus E protein protects from lethal infection in mice.

PubMed

Spohn, Gunther; Jennings, Gary T; Martina, Byron Ee; Keller, Iris; Beck, Markus; Pumpens, Paul; Osterhaus, Albert Dme; Bachmann, Martin F

2010-07-06

Since its first appearance in the USA in 1999, West Nile virus (WNV) has spread in the Western hemisphere and continues to represent an important public health concern. In the absence of effective treatment, there is a medical need for the development of a safe and efficient vaccine. Live attenuated WNV vaccines have shown promise in preclinical and clinical studies but might carry inherent risks due to the possibility of reversion to more virulent forms. Subunit vaccines based on the large envelope (E) glycoprotein of WNV have therefore been explored as an alternative approach. Although these vaccines were shown to protect from disease in animal models, multiple injections and/or strong adjuvants were required to reach efficacy, underscoring the need for more immunogenic, yet safe DIII-based vaccines. We produced a conjugate vaccine against WNV consisting of recombinantly expressed domain III (DIII) of the E glycoprotein chemically cross-linked to virus-like particles derived from the recently discovered bacteriophage AP205. In contrast to isolated DIII protein, which required three administrations to induce detectable antibody titers in mice, high titers of DIII-specific antibodies were induced after a single injection of the conjugate vaccine. These antibodies were able to neutralize the virus in vitro and provided partial protection from a challenge with a lethal dose of WNV. Three injections of the vaccine induced high titers of virus-neutralizing antibodies, and completely protected mice from WNV infection. The immunogenicity of DIII can be strongly enhanced by conjugation to virus-like particles of the bacteriophage AP205. The superior immunogenicity of the conjugate vaccine with respect to other DIII-based subunit vaccines, its anticipated favourable safety profile and low production costs highlight its potential as an efficacious and cost-effective prophylaxis against WNV.

Recombinant raccoon pox vaccine protects mice against lethal plague

USGS Publications Warehouse

Osorio, J.E.; Powell, T.D.; Frank, R.S.; Moss, K.; Haanes, E.J.; Smith, S.R.; Rocke, T.E.; Stinchcomb, D.T.

2003-01-01

Using a raccoon poxvirus (RCN) expression system, we have developed new recombinant vaccines that can protect mice against lethal plague infection. We tested the effects of a translation enhancer (EMCV-IRES) in combination with a secretory (tPA) signal or secretory (tPA) and membrane anchoring (CHV-gG) signals on in vitro antigen expression of F1 antigen in tissue culture and the induction of antibody responses and protection against Yersinia pestis challenge in mice. The RCN vector successfully expressed the F1 protein of Y. pestis in vitro. In addition, the level of expression was increased by the insertion of the EMCV-IRES and combinations of this and the secretory signal or secretory and anchoring signals. These recombinant viruses generated protective immune responses that resulted in survival of 80% of vaccinated mice upon challenge with Y. pestis. Of the RCN-based vaccines we tested, the RCN-IRES-tPA-YpF1 recombinant construct was the most efficacious. Mice vaccinated with this construct withstood challenge with as many as 1.5 million colony forming units of Y. pestis (7.7×104 LD50). Interestingly, vaccination with F1 fused to the anchoring signal (RCN-IRES-tPA-YpF1-gG) elicited significant anti-F1 antibody titers, but failed to protect mice from plague challenge. Our studies demonstrate, in vitro and in vivo, the potential importance of the EMCV-IRES and secretory signals in vaccine design. These molecular tools provide a new approach for improving the efficacy of vaccines. In addition, these novel recombinant vaccines could have human, veterinary, and wildlife applications in the prevention of plague.

Structure and function of human α-lactalbumin made lethal to tumor cells (HAMLET)-type complexes.

PubMed

Mossberg, Ann-Kristin; Hun Mok, Kenneth; Morozova-Roche, Ludmilla A; Svanborg, Catharina

2010-11-01

Human α-lactalbumin made lethal to tumor cells (HAMLET) and equine lysozyme with oleic acid (ELOA) are complexes consisting of protein and fatty acid that exhibit cytotoxic activities, drastically differing from the activity of their respective proteinaceous compounds. Since the discovery of HAMLET in the 1990s, a wealth of information has been accumulated, illuminating the structural, functional and therapeutic properties of protein complexes with oleic acid, which is summarized in this review. In vitro, both HAMLET and ELOA are produced by using ion-exchange columns preconditioned with oleic acid. However, the complex of human α-lactalbumin with oleic acid with the antitumor activity of HAMLET was found to be naturally present in the acidic fraction of human milk, where it was discovered by serendipity. Structural studies have shown that α-lactalbumin in HAMLET and lysozyme in ELOA are partially unfolded, 'molten-globule'-like, thereby rendering the complexes dynamic and in conformational exchange. HAMLET exists in the monomeric form, whereas ELOA mostly exists as oligomers and the fatty acid stoichiometry varies, with HAMLET holding an average of approximately five oleic acid molecules, whereas ELOA contains a considerably larger number (11- 48). Potent tumoricidal activity is found in both HAMLET and ELOA, and HAMLET has also shown strong potential as an antitumor drug in different in vivo animal models and clinical studies. The gain of new, beneficial function upon partial protein unfolding and fatty acid binding is a remarkable phenomenon, and may reflect a significant generic route of functional diversification of proteins via varying their conformational states and associated ligands. © 2010 The Authors Journal compilation © 2010 FEBS.

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

PubMed Central

Sobarzo, Ariel; Perelman, Eddie; Groseth, Allison; Dolnik, Olga; Becker, Stephan; Lutwama, Julius Julian; Dye, John M.; Yavelsky, Victoria; Marks, Robert S.

2012-01-01

Ebolavirus, a member of the family Filoviridae, causes high lethality in humans and nonhuman primates. Research focused on protection and therapy for Ebola virus infection has investigated the potential role of antibodies. Recent evidence suggests that antibodies can be effective in protection from lethal challenge with Ebola virus in nonhuman primates. However, despite these encouraging results, studies have not yet determined the optimal antibodies and composition of an antibody cocktail, if required, which might serve as a highly effective and efficient prophylactic. To better understand optimal antibodies and their targets, which might be important for protection from Ebola virus infection, we sought to determine the profile of viral protein-specific antibodies generated during a natural cycle of infection in humans. To this end, we characterized the profile of antibodies against individual viral proteins of Sudan Ebola virus (Gulu) in human survivors and nonsurvivors of the outbreak in Gulu, Uganda, in 2000-2001. We developed a unique chemiluminescence enzyme-linked immunosorbent assay (ELISA) for this purpose based on the full-length recombinant viral proteins NP, VP30, and VP40 and two recombinant forms of the viral glycoprotein (GP1-294 and GP1-649) of Sudan Ebola virus (Gulu). Screening results revealed that the greatest immunoreactivity was directed to the viral proteins NP and GP1-649, followed by VP40. Comparison of positive immunoreactivity between the viral proteins NP, GP1-649, and VP40 demonstrated a high correlation of immunoreactivity between these viral proteins, which is also linked with survival. Overall, our studies of the profile of immunorecognition of antibodies against four viral proteins of Sudan Ebola virus in human survivors may facilitate development of effective monoclonal antibody cocktails in the future. PMID:22993411

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

PubMed Central

Bilen, Mehmet Asim; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago L.; Yeung, Sai‐ching J.; Lin, Sue‐Hwa; Logothetis, Christopher J.; Pisters, Louis L.

2016-01-01

BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID:27018785

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

PubMed

Tu, Shi-Ming; Bilen, Mehmet Asim; Hess, Kenneth R; Broaddus, Russell R; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C; Karam, Jose A; Ward, John F; Wood, Christopher G; Rao, Priya; Tu, Zachary H; General, Rosale; Chen, Adrienne H; Nieto, Yago L; Yeung, Sai-Ching J; Lin, Sue-Hwa; Logothetis, Christopher J; Pisters, Louis L

2016-06-15

Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2016 American Cancer Society.

Young coconut water ameliorates depression via modulation of neurotransmitters: possible mechanism of action.

PubMed

Rao, Sadia Saleem; Najam, Rahila

2016-10-01

In the current era, plants are frequently tested for its antidepressant potential. Therefore young coconut water, a commonly used plant based beverage, was selected to explore its antidepressant potential. Rodents were selected for this study and forced swim test was conducted to explore antidepressant activity. Analysis of brain biogenic amines using high performance liquid chromatography coupled with electrochemical detection and potentiation of noradrenaline toxicity model were also incorporated in this study to demonstrate probable antidepressant mechanism of action. Coconut water was administered orally at the dose of 4 ml/100 g. Young coconut water showed highly significant increase in struggling time (p < 0.001) in forced swim test. This suggests antidepressant effect of young coconut water. In noradrenaline toxicity model, it was observed that young coconut water is not a good adrenergic component as its lethality percentage in this test was observed 0 % unlike imipramine which showed lethality of 100 %. High performance liquid chromatography-electrochemical detection of rodent's brain revealed decline in 5-hydroxytryptamine, noradrenaline and dopamine, with concomitant decline in metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanillic acid and increase in 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio. Findings from the exploration of monoamines suggest antidepressant effect of young coconut water via homeostasis of monoamines synthesis.

Suicide Lethality: A Concept Analysis.

PubMed

DeBastiani, Summer; De Santis, Joseph P

2018-02-01

Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

Lethal trap trees and semiochemical repellents as area host protection strategies for spruce beetle (Coleoptera: Curculionidae, Scolytinae) in Utah

Treesearch

Matt Hansen; A. Steven Munson; Darren C. Blackford; David Wakarchuk; Scott Baggett

2016-01-01

We tested lethal trap trees and repellent semiochemicals as area treatments to protect host trees from spruce beetle (Dendroctonus rufipennis Kirby) attacks. Lethal trap tree treatments ("spray treatment") combined a spruce beetle bait with carbaryl treatment of the baited spruce. Repellent treatments ("spray-repellent”) combined a baited lethal...

[Prognostic value of the lethal triad among patients with multiple trauma].

PubMed

González Balverde, María; Ramírez Lizardo, Ernesto J; Cardona Muñoz, Ernesto G; Totsuka Sutto, Sylvia E; García Benavides, Leonel

2013-11-01

Patients who have suffered multiple traumatic injuries, have a serious risk for death. Hypothermia, acidosis and coagulopathy are three complications in these patients, whose presence is known as lethal triad and indicates bad prognosis. To determine if the lethal triad in multiple trauma patients is associated with higher mortality and Injury Score Severity (ISS). One hundred multiple trauma patients aged 26 to 56 years (90 males), admitted to an emergency room, were studied. Body temperature, prothrombin time, partial thromboplastin time, platelet count and blood gases were determined on admission. Twenty six patients had the lethal triad and 15% died in the emergency room within the first 6 hours. No death was recorded among the 74 patients without the lethal triad. The mean ISS among patients with and without the lethal triad was 31.7 and 25.6, respectively (p < 0.05). The presence of the lethal triad among patients with multiple trauma is associated with a higher mortality and ISS.

Effect of lethality on the extinction and on the error threshold of quasispecies.

PubMed

Tejero, Hector; Marín, Arturo; Montero, Francisco

2010-02-21

In this paper the effect of lethality on error threshold and extinction has been studied in a population of error-prone self-replicating molecules. For given lethality and a simple fitness landscape, three dynamic regimes can be obtained: quasispecies, error catastrophe, and extinction. Using a simple model in which molecules are classified as master, lethal and non-lethal mutants, it is possible to obtain the mutation rates of the transitions between the three regimes analytically. The numerical resolution of the extended model, in which molecules are classified depending on their Hamming distance to the master sequence, confirms the results obtained in the simple model and shows how an error catastrophe regime changes when lethality is taken in account. (c) 2009 Elsevier Ltd. All rights reserved.

Radiation tolerance in water bears.

NASA Astrophysics Data System (ADS)

Horikawa, D. D.; Sakashita, T.; Katagiri, C.; Watanabe, M.; Nakahara, Y.; Okuda, T.; Hamada, N.; Wada, S.; Funayama, T.; Kobayashi, Y.

Tardigrades water bears are tiny invertebrates forming a phylum and inhabit various environments on the earth Terrestrial tardigrades enter a form called as anhydrobiosis when the surrounding water disappears Anhyydrobiosis is defined as an ametabolic dry state and followed by recovering their activity when rehydrated Anhydrobiotic tardigrades show incredible tolerance to a variety of extreme environmental conditions such as temperatures -273 r C to 151 r C vacuum high pressure 600 MPa and chemicals that include alcohols and methyl bromide In these views there have been some discussions about their potential for surviving outer space In the present study we demonstrated the survival limit not merely against gamma-rays but against heavy ions in the tardigrade Milnesium tardigradum in order to evaluate the effects of radiations on them The animals were exposure to 500 to 7000 Gy of gamma-rays or 500 to 8000 Gy of heavy ions 4 He in their hydrated or anhydrobiotic state The results showed that both of hydrated and anhydrobiotic animals have high radio-tolerance median lethal dose LD50 48 h of gamma-rays or heavy ions in M tardigradum was more than 4000 Gy indicating that this species is categorized into the most radio-tolerant animals We suggest that tardigrades will be suitable model animals for extremophilic multicellular organisms and may provide a survival strategy in extraterrestrial environments

Inhibitory effects of Zanthoxylum rhoifolium Lam. (Rutaceae) against the infection and infectivity of macrophages by Leishmania amazonensis.

PubMed

Melo, Bernardo; Leitão, Joseana M S R; Oliveira, Luciano G C; Santos, Sérgio E M; Carneiro, Sabrina M P; Rodrigues, Klinger A F; Chaves, Mariana H; Arcanjo, Daniel D R; Carvalho, Fernando A A

2016-01-01

Zanthoxylum rhoifolium Lam. (Rutaceae) has been traditionally used in the treatment of microbial infections and parasitic diseases. In the present study, the antileishmanial effect induced by the ethanol extract of stem barks from Z. rhoifolium (ZR-EEtOH) and its n-hexane fraction (ZR-FHEX) on infection and infectivity of murine macrophages by promastigote forms of Leishmania amazonensis were investigated. In different set of experiments, macrophages or promastigotes were pretreated with ZR-EEtOH or ZR-FHEX at non-lethal concentrations for 24 hours, and then macrophages were submitted to infection by promastigotes. Moreover, their effects on activation of macrophages, as well as on the DNA content, size and number of promastigotes by flow cytometry were also evaluated. The infection rate and the number of internalized amastigote forms were markedly decreased after pretreatment of macrophages or promastigotes when compared with non-treated cells. The increase in phagocytic capability and nitrite content was also observed. Furthermore, the decrease of DNA content, size and number of promastigotes was also observed. In conclusion, ZR-EEtOH and ZR-FHEX promoted a markedly significant antileishmanial effect and reduction of infection of macrophages, probably underlying defense mechanisms activation in macrophages. These findings reinforce the potential application of Z. rhoifolium in the treatment of leishmaniasis.

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever.

PubMed

Oestereich, Lisa; Rieger, Toni; Lüdtke, Anja; Ruibal, Paula; Wurr, Stephanie; Pallasch, Elisa; Bockholt, Sabrina; Krasemann, Susanne; Muñoz-Fontela, César; Günther, Stephan

2016-03-15

We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits▿

PubMed Central

Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-01-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy. PMID:19279088

Myxoma virus expressing interleukin-15 fails to cause lethal myxomatosis in European rabbits.

PubMed

Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-06-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy.

The type IV pilin of Burkholderia mallei is highly immunogenic but fails to protect against lethal aerosol challenge in a murine model.

PubMed

Fernandes, Paula J; Guo, Qin; Waag, David M; Donnenberg, Michael S

2007-06-01

Burkholderia mallei is the cause of glanders and a proven biological weapon. We identified and purified the type IV pilin protein of this organism to study its potential as a subunit vaccine. We found that purified pilin was highly immunogenic. Furthermore, mice infected via sublethal aerosol challenge developed significant increases in titers of antibody against the pilin, suggesting that it is expressed in vivo. Nevertheless, we found no evidence that high-titer antipilin antisera provided passive protection against a sublethal or lethal aerosol challenge and no evidence of protection afforded by active immunization with purified pilin. These results contrast with the utility of type IV pilin subunit vaccines against other infectious diseases and highlight the need for further efforts to identify protective responses against this pathogen.

DefenseLink.mil - Special Report - Soldiers Train with Non-lethal Weapons

Science.gov Websites

Training 10th Mountain Division soldiers feel the effects of a Taser during non-lethal weapons training Nov soldiers feel the effects of a Taser during non-lethal weapons training Nov. 19, 2008, at Fort Drum, N.Y situation can be resolved without lethal measures, Army Staff Sgt. Eric Johnson said during training and

Anthrax toxin: the long and winding road that leads to the kill.

PubMed

Abrami, Laurence; Reig, Nuria; van der Goot, F Gisou

2005-02-01

The past five years have led to a tremendous increase in our molecular understanding of the mode of action of the anthrax toxin, one of the two main virulence factors produced by Bacillus anthracis. The structures of each of the three components of the toxin--lethal factor (LF), edema factor (EF) and protective antigen (PA)--have been solved not only in their monomeric forms but, depending on the subunit, in a heptameric form, bound to their substrate, co-factor or receptor. The endocytic route followed by the toxin has also been unraveled and the enzymatic mechanisms of EF and LF elucidated.

[The serotonin syndrome. Fatal course of intoxication with citalopram and moclobemide].

PubMed

Cassens, S; Nickel, E A; Quintel, M; Neumann, P

2006-11-01

The serotonin syndrome is caused by a drug-induced increase of the intrasynaptic serotonin concentration. Milder forms of the syndrome may be difficult to diagnose because of the variability of symptoms. Severe forms often rapidly turn into a life-threatening situation, therefore the serotonin syndrome may be a challenge for physicians. We describe the pathophysiology and therapeutic options of the serotonin syndrome and report about a 42-year-old female patient who ingested large amounts of moclobemide, a monoamine oxidase inhibitor, and citalopram, a selective serotonin reuptake inhibitor, for attempted suicide. Within a few hours the patient developed a lethal serotonin syndrome although ICU therapy was initiated immediately.

Novel Targeted Therapies for Inflammatory Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

Assessing Contract Management Maturity: U.S. Army Joint Munitions and Lethality Contracting Center, Army Contracting Command, Picatinny Arsenal

DTIC Science & Technology

2009-09-01

demonstrate competence” ( Jones , 2006). Most organizations conduct performance management for their employees with actions such as, setting goals...take the 14 form of comprehensive questionnaires, SWOT analyses or diagnostic models and include a comparison of results to various best practices...procnet.pica.army.mil/ Jones , R. (2006). CIDA Organizational Assessment Guide. Retrieved on March 1, 2009 from: http://www.acdi-cida.gc.ca/CIDAWEB

Detergent-Resistant Membrane Microdomains Facilitate Ib Oligomer Formation and Biological Activity of Clostridium perfringens Iota-Toxin

DTIC Science & Technology

2004-04-01

spore-forming bacilli such as Clostridium spiroforme (iota-like toxin), Clostridium botulinum (C2 toxin), Bacillus anthracis (lethal and edema toxins...ously (28). Goat C. spiroforme and C. perfringens type C antisera were purchased from TechLab, Inc. (Blacksburg, Va.). Mouse monoclonal antibodies...membrane preparations was specific. Previous studies showed that the binary C. spiroforme toxin shares common epitopes with iota-toxin, and antisera

Stimulating Central Carbon Metabolism to Re-sensitize Pseudomonas aeruginosa to Aminoglycosides.

PubMed

Martins, Dorival; Nguyen, Dao

2017-02-16

In this issue of Cell Chemical Biology, Meylan et al. (2017) examine how stimulation of central carbon metabolism of Pseudomonas aeruginosa modulates aminoglycoside lethality in tolerant bacteria. They identify fumarate as a tobramycin potentiator that stimulates proton motive force-dependent drug uptake and increases respiration-dependent killing. Copyright © 2017. Published by Elsevier Ltd.

A case of massive rhabdomyolysis following molindone administration.

PubMed

Johnson, S B; Alvarez, W A; Freinhar, J P

1986-12-01

Rhabdomyolysis is a potentially lethal syndrome that psychiatric patients seem predisposed to develop. The clinical signs and symptoms, typical laboratory features, and complications of rhabdomyolysis are presented. The case of a schizophrenic patient is reported to illustrate massive rhabdomyolysis and subsequent acute renal failure following molindone administration. Physicians who prescribe molindone should be aware of this reaction.

Overstory removal and residue treatments affect soil surface, air, and soil temperature: implications for seedling survival

Treesearch

Roger D. Hungerford; Ronald E. Babbitt

1987-01-01

Potentially lethal ground surface temperatures were measured at three locations in the Northern Rocky Mountains but occurred more frequently under treatments with greater overstory removal. Observed maximum and minimum temperatures of exposed surfaces are directly related to the thermal properties of the surface materials. Survival of planted seedlings was consistent...

Predicting the Significance of Injuries Potentially Caused by Non-Lethal Weapons: Tympanic Membrane Rupture (TMR), Permanent Threshold Shift (PTS), and Photothermal Retinal Lesions

DTIC Science & Technology

2016-06-21

during cooking . Retinal Lesions: medical care 29 of 37 • Suprathreshold lesions can lead to complications like hemorrhage, macular holes and...Effects Review Board (HERB). Members of the multi-service HERB include health care professionals and safety officers. The purpose of IDA’s analyses

Sickle cell hepatopathy.

PubMed

Bandyopadhyay, Ranjana; Bandyopadhyay, Sanjay K; Dutta, Anita

2008-01-01

Sickle cell hepatopathy is a well-documented entity that ranges from the self-limiting hepatic right upper quadrant syndrome to the potentially lethal intrahepatic cholestasis and acute hepatic sequestration syndromes. We describe a 26-year-male with homozygous sickle cell disease who had this unique hepatic presentation and was documented to have characteristic findings of cholestasis, portal inflammation and sinusoidal dilatation on histopathology.

High pressure processing of Queso Fresco: effects on textural and rheological properties over 12 weeks of storage

USDA-ARS?s Scientific Manuscript database

High pressure processing (HPP) is a non-thermal post-packaging process with the potential to improve cheese safety and shelf life because of its lethality to bacteria (spoilage and pathogens) and ability to inactivate many enzymes. Queso Fresco (QF), a high moisture Hispanic-style cheese popular in ...

The Decade Dance

PubMed Central

Neher, Jon O.

2005-01-01

This essay portrays the moment an adult survivor of childhood sexual abuse tells his physician about his traumatic past. Because of denial by both parties, the diagnosis had remained buried for years, and opportunities for appropriate intervention were repeatedly missed. When the patient is finally able to face his past, it unleashes a torrent of potentially lethal anger that challenges everyone involved. PMID:16189064

Effects of invertebrate iridescent virus 6 in Phyllophaga vandinei and its potential as a biocontrol delivery system

USDA-ARS?s Scientific Manuscript database

Invertebrate iridescent virus 6 (IIV6) was determined to cause infection in Phyllophaga vandinei Smyth, through a range of modes of transmissions. This is the first evidence of IIV6 infection in P. vandinei, which caused both patent and sub-lethal covert infections in larvae and adults. Mortality r...

White pine blister rust resistance in limber pine: Evidence for a major gene

Treesearch

A. W. Schoettle; R. A. Sniezko; A. Kegley; K. S. Burns

2014-01-01

Limber pine (Pinus flexilis) is being threatened by the lethal disease white pine blister rust caused by the non-native pathogen Cronartium ribicola. The types and frequencies of genetic resistance to the rust will likely determine the potential success of restoration or proactive measures. These first extensive inoculation trials using individual tree seed collections...

Evolution of a zoonotic pathogen: investigating prophage diversity in enterohaemorrhagic E. coli O157 by long-read sequencing

USDA-ARS?s Scientific Manuscript database

Enterohaemorrhagic Escherichia Coli (EHEC) is a zoonotic pathogen known to be potentially lethal in humans. Its main animal reservoir is ruminants, specifically cattle, and yearly outbreaks occur worldwide with the most prevalent serotype being EHEC O157:H7. Most virulence factors of EHEC O157, incl...

Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish.

PubMed

Yin, Jian; Wang, Ai-Ping; Li, Wan-Fang; Shi, Rui; Jin, Hong-Tao; Wei, Jin-Feng

2018-01-01

The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration-dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75μg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non-lethal concentrations. TNF-α and IL-1β gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-γ gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-γ gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-γ gene were more responsive to heavy metals, which may become early sensitive and potential biomarkers for evaluating inflammatory response induced by heavy metals. This work reinforces the concept of the usefulness of gene expression assays in the evaluation of chemicals effects and helps to establish a background data as well as contributes to evaluate early environmental risk for chemicals, even predicting toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Choline intake and risk of lethal prostate cancer: incidence and survival123

PubMed Central

Richman, Erin L; Kenfield, Stacey A; Stampfer, Meir J; Giovannucci, Edward L; Zeisel, Steven H; Willett, Walter C; Chan, June M

2012-01-01

Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer. PMID:22952174

Non-lethal Clostridium sordellii bacteraemia in an immunocompromised patient with pleomorphic sarcoma.

PubMed

Bonnecaze, Alex K; Stephens, Sarah Ellen Elza; Miller, Peter John

2016-08-03

Clostridium sordellii is a spore-forming anaerobic Gram-positive rod that has rarely been reported to cause disease in humans. Resultant mortality from infection is estimated at nearly 70% and is most often correlated with gynaecological procedures, intravenous drug abuse or trauma. C. sordellii infection often presents similarly to toxic shock syndrome (TSS); notable features of infection include refractory hypotension, haemoconcentration and marked leucocytosis. Although clinically similar to TSS, a notable difference is C. sordellii infections rarely involve fever. The organism's major toxins include haemorrhagic (TcsH) and lethal factor (TcsL), which function to disrupt cytoskeletal integrity. Current literature suggests treating C. sordelli infection with a broad-spectrum penicillin, metronidazole and clindamycin. We present a case of C. sordellii bacteraemia and septic shock in an immunocompromised patient who was recently diagnosed with pleomorphic gluteal sarcoma. Despite presenting in critical condition, the patient improved after aggressive hemodynamic resuscitation, source control and intravenous antibiotic therapy. 2016 BMJ Publishing Group Ltd.

Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

PubMed

Mucker, Eric M; Chapman, Jennifer; Huzella, Louis M; Huggins, John W; Shamblin, Joshua; Robinson, Camenzind G; Hensley, Lisa E

2015-01-01

Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

Human cooperation by lethal group competition

PubMed Central

Egas, Martijn; Kats, Ralph; van der Sar, Xander; Reuben, Ernesto; Sabelis, Maurice W.

2013-01-01

Why humans are prone to cooperate puzzles biologists, psychologists and economists alike. Between-group conflict has been hypothesized to drive within-group cooperation. However, such conflicts did not have lasting effects in laboratory experiments, because they were about luxury goods, not needed for survival (“looting”). Here, we find within-group cooperation to last when between-group conflict is implemented as “all-out war” (eliminating the weakest groups). Human subjects invested in helping group members to avoid having the lowest collective pay-off, whereas they failed to cooperate in control treatments with random group elimination or with no subdivision in groups. When the game was repeated, experience was found to promote helping. Thus, not within-group interactions alone, not random group elimination, but pay-off-dependent group elimination was found to drive within-group cooperation in our experiment. We suggest that some forms of human cooperation are maintained by multi-level selection: reciprocity within groups and lethal competition among groups acting together. PMID:23459158

CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

PubMed Central

Xu, Hong; Di Antonio, Marco; McKinney, Steven; Mathew, Veena; Ho, Brandon; O'Neil, Nigel J.; Santos, Nancy Dos; Silvester, Jennifer; Wei, Vivien; Garcia, Jessica; Kabeer, Farhia; Lai, Daniel; Soriano, Priscilla; Banáth, Judit; Chiu, Derek S.; Yap, Damian; Le, Daniel D.; Ye, Frank B.; Zhang, Anni; Thu, Kelsie; Soong, John; Lin, Shu-chuan; Tsai, Angela Hsin Chin; Osako, Tomo; Algara, Teresa; Saunders, Darren N.; Wong, Jason; Xian, Jian; Bally, Marcel B.; Brenton, James D.; Brown, Grant W.; Shah, Sohrab P.; Cescon, David; Mak, Tak W.; Caldas, Carlos; Stirling, Peter C.; Hieter, Phil; Balasubramanian, Shankar; Aparicio, Samuel

2017-01-01

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016). PMID:28211448