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Sample records for repair potentially lethal

  1. Potentially lethal damage repair by total and quiescent tumor cells following various DNA-damaging treatments

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    Masunaga, Shin-ichiro; Ono, Koji; Suzuki, Minoru; Kinashi, Yuko; Takagaki, Masao [Kyoto Univ., Kumatori, Osaka (Japan). Research Reactor Inst; Hori, Hitoshi; Kasai, Soko; Nagasawa, Hideko; Uto, Yoshihiro

    1999-08-01

    After continuous labeling of proliferating (P) cells with 5-bromo-2'-deoxyuridine (BrdU) for 5 days, SCC VII tumor-bearing mice received various kinds of DNA-damaging treatments: gamma-ray irradiation, tirapazamine (TPZ, hypoxia-specific cytotoxin) administration, or cisplatin injection. From 0.5 to 72 hr after treatment, tumors were excised, minced, and trypsinized. Single tumor cell suspensions were incubated for 48 hr with a cytokinesis-blocker, cytochalasin-B. Then, the micronucleus (MN) frequency for BrdU-unlabeled cells, quiescent (Q) cells at treatment, was determined using immunofluorescence staining for BrdU. The MN frequency for total (P+Q) cells was obtained from tumors that were not pretreated with BrdU labeling. The sensitivity to each DNA-damaging treatment was evaluated in terms of the frequency of induced micronuclei in binuclear tumor cells (MN frequency). Treatment with gamma-rays or cisplatin resulted in a larger MN frequency in total cells than in Q cells. In contrast, TPZ treatment produced a smaller MN frequency in total cells than in Q cells. Regardless of the treatment used, Q cells showed greater repair capacities than total cells. However, TPZ caused much smaller repair capacity in both total and Q cells, compared with gamma-rays or cisplatin. Gamma-rays and cisplatin produced similar repair patterns. Differences in sensitivity between total and Q cells and repair patterns of the two cell populations were thought to depend on differences between the two cell populations in the toxicity of the DNA-damaging treatment and distribution pattern of the anticancer agent. (author)

  2. Participation of gap junction communication in potentially lethal damage repair and DNA damage in human fibroblasts exposed to low- or high-LET radiation

    Science.gov (United States)

    Autsavapromporn, Narongchai; Suzuki, Masao; Plante, Ianik; Liu, Cuihua; Uchihori, Yukio; Hei, Tom K.; Azzam, Edouard I.; Murakami, Takeshi

    2014-01-01

    Existing research has not fully explained how different types of ionizing radiation (IR) modulate the responses of cell populations or tissues. In our previous work, we showed that gap junction intercellular communication (GJIC) mediates the propagation of stressful effects among irradiated cells exposed to high linear energy transfer (LET) radiations, in which almost every cells is traversed by an IR track. In the present study, we conducted an in-depth study of the role of GJIC in modulating the repair of potentially lethal damage (PLDR) and micronuclei formation in cells exposed to low- or high-LET IR. Confluent human fibroblasts were exposed in the presence or absence of a gap junction inhibitor to 200 kV X rays (LET ∼ 1.7 keV/µm), carbon ions (LET ∼ 76 keV/µm), silicon ions (LET ∼ 113 keV/µm) or iron ions (LET ∼ 400 keV/µm) that resulted in isosurvival levels. The fibroblasts were incubated for various times at 37 °C. As expected, high-LET IR were more effective than were low-LET X rays at killing cells and damaging DNA shortly after irradiation. However, when cells were held in a confluent state for several hours, PLDR associated with a reduction in DNA damage, occurred only in cells exposed to X rays. Interestingly, inhibition of GJIC eliminated the enhancement of toxic effects, which resulted in an increase of cell survival and reduction in the level of micronucleus formation in cells exposed to high, but not in those exposed to low-LET IR. The experiment shows that gap-junction communication plays an important role in the propagation of stressful effects among irradiated cells exposed to high-LET IR while GJIC has only a minimal effect on PLDR and DNA damage following low-LET irradiation. Together, our results show that PLDR and induction of DNA damage clearly depend on gap-junction communication and radiation quality. PMID:23867854

  3. Deficient recovery from potentially lethal damage in some gamma-irradiated human fibroblast cell strains

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    Arlett, C.F.; Priestley, A. (Medical Research Council, Brighton (UK). Cell Mutation Unit)

    1984-01-01

    The repair of potentially lethal damage following treatment with gamma radiation was investigated in human fibroblasts held in a non-cycling state by maintenance in a medium containing 0.5% foetal calf serum. Normal cells were found to be competent in the repair of PLD. Ataxia-telangiectasia cells were deficient as was a heterozygote suggesting that a failure to repair PLD may make it possible to detect such heterozygotes. Fibroblasts from Huntington's disease patients were either slightly or no more sensitive than cells from normal individuals. Cultures from two individuals in the former class showed limited capacity to repair PLD but cells from the latter class were as competent as normals. Thus assays of radiosensitivity where conditions allow for the repair of PLD may maximise small differences in sensitivity. Cells taken from three patients suffering from Basal Cell Naevus Syndrome were also shown to be defective in the repair of PLD. The existence of such a defect may be related to the increased frequency of basal cell cancer observed in exposed fields following irradiation of such individuals.

  4. Extra lethal damage due to residual incompletely repaired sublethal damage in hyperfractionated and continuous radiation treatment

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    Chen, J.; van de Geijn, J.; Goffman, T. (ROB, DCT, NCI, NIH, Bethesda, Maryland 20892 (US))

    1991-05-01

    In the conventional linear--quadratic model of single-dose response, the {alpha} and {beta} terms reflect lethal damage created {ital during} the delivery of a dose, from two different presumed molecular processes, one linear with dose, the other quadratic. With the conventional one-fraction-per-day (or less) regimens, the sublethal damage (SLD), presumably repairing exponentially over time, is essentially completely fixed by the time of the next dose of radiation. If this assumption is true, the effects of subsequent fractions of radiation should be independent, that is, there should be little, if any, reversible damage left from previous fractions, at the time of the next dose. For multiple daily fractions, or for the limiting case, continuous radiation, this simplification may overlook damaged cells that have had insufficient time for repair. A generalized method is presented for accounting for extra lethal damage (ELD) arising from such residual SLD for hyperfractionation and continuous irradiation schemes. It may help to predict differences in toxicity and tumor control, if any, obtained with unconventional'' treatment regimens. A key element in the present model is the finite size and the dynamic character of the pool of sublethal damage. Besides creating the usual linear and quadratic components of lethal damage, each new fraction converts a certain fraction of the existing SLD into ELD, and creates some new SLD.

  5. Bipyridine (2,2′-dipyridyl) potentiates Escherichia coli lethality induced by nitrogen mustard mechlorethamine

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    De Alencar, T.A.M.; Wilmart-Gonçalves, T.C.; Vidal, L.S.; Fortunato, R.S.; Leitão, A.C. [Laboratório de Radiobiologia Molecular (Brazil); Lage, C., E-mail: claudia_lage_dna@yahoo.com.br [Laboratório de Radiações em Biologia (Brazil)

    2014-07-15

    Highlights: • Reduction of Fe{sup 2+} ensues a respiratory burst to reduce the oxidized iron pool. • Through Harber–Weiss recycling, superoxide electrons can reduce oxidized iron. • Redox imbalance sensitized repair proficient Escherichia coli to mustard lethal crosslinks. • A stronger synergism impacted survival of a superoxide dismutase-deficient strain. • Anti-cancer cocktails added of an iron chelator may impact hypoxia and genotoxicity. - Abstract: Alkylating agents are used in anti-tumor chemotherapy because they bind covalently to DNA and generate adducts that may lead to cell death. Bifunctional (HN2) and monofunctional (HN1) nitrogen are two such agents, and HN2 was the first drug successfully employed in anti-leukemia chemotherapy. Currently, HN2 is used either alone or combined with other drugs to treat Hodgkin's disease. It is well known that several crosslinking agents require metabolic activation via reactive oxygen species (ROS) to exert their lethal effects. The objective of this work was therefore to determine whether the abovementioned mustards would also require metabolic activation to exert lethal action against Escherichia coli. For this purpose, we measured survival following exposure to HN2 in E. coli strains that were deficient in nucleotide excision repair (uvrA NER mutant), base excision repair (xthA nfo nth fpg BER mutant) or superoxide dismutase (sodAB mutant) activity. We also performed the same experiments in cells pretreated with an iron chelator (2,2′-dipyridyl, DIP). The NER and BER mutants were only sensitive to HN2 treatment (survival rates similar to those of the wild-type were achieved with 5-fold lower HN2 doses). However, wild-type and sodAB strains were not sensitive to treatment with HN2. In all tested strains, survival dropped by 2.5-fold following pretreatment with DIP compared to treatment with HN2 alone. Furthermore, DIP treatment increased ROS generation in both wild type and sodAB-deficient strains

  6. Synthetic lethal targeting of DNA double strand break repair deficient cells by human apurinic/apyrimidinic endonuclease (APE1) inhibitors

    OpenAIRE

    Sultana, Rebeka; McNeill, Daniel R.; Abbotts, Rachel; Mohammed, Mohammed Z.; Zdzienicka, Małgorzata Z.; Qutob, Haitham; Seedhouse, Claire; Charles A. Laughton; Fischer, Peter M.; Patel, Poulam M.; Wilson, David M.; Madhusudan, Srinivasan

    2012-01-01

    An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In the current study we have investigated the ability of APE1 inhibitors to induce synthetic lethality in a panel of DNA double strand break (DSB) repair deficient and proficient cells; a) Chine...

  7. Synthetic lethal targeting of DNA double strand break repair deficient cells by human apurinic/apyrimidinic endonuclease (APE1) inhibitors

    Science.gov (United States)

    Sultana, Rebeka; McNeill, Daniel R.; Abbotts, Rachel; Mohammed, Mohammed Z.; Zdzienicka, Małgorzata Z.; Qutob, Haitham; Seedhouse, Claire; Laughton, Charles A.; Fischer, Peter M.; Patel, Poulam M.; Wilson, David M.; Madhusudan, Srinivasan

    2013-01-01

    An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In the current study we have investigated the ability of APE1 inhibitors to induce synthetic lethality in a panel of DNA double strand break (DSB) repair deficient and proficient cells; a) Chinese hamster (CH) cells: BRCA2 deficient (V-C8), ATM deficient (V-E5), wild type (V79) and BRCA2 revertant (V-C8(Rev1)). b) Human cancer cells: BRCA1 deficient (MDA-MB-436), BRCA1 proficient (MCF-7), BRCA2 deficient (CAPAN-1 and HeLa SilenciX cells), BRCA2 proficient (PANC1 and control SilenciX cells). We also tested synthetic lethality (SL) in CH ovary cells expressing a dominant–negative form of APE1 (E8 cells) using ATM inhibitors and DNA-PKcs inhibitors (DSB inhibitors). APE1 inhibitors are synthetically lethal in BRCA and ATM deficient cells. APE1 inhibition resulted in accumulation of DNA DSBs and G2/M cell cycle arrest. Synthetic lethality was also demonstrated in CH cells expressing a dominant–negative form of APE1 treated with ATM or DNA-PKcs inhibitors. We conclude that APE1 is a promising synthetic lethality target in cancer. PMID:22377908

  8. Recurrent late cardiac tamponade following cardiac surgery : a deceiving and potentially lethal complication

    NARCIS (Netherlands)

    Harskamp, Ralf E.; Meuzelaar, Jacobus J.

    2010-01-01

    Background - Cardiac tamponade, characterized by inflow obstruction of the heart chambers by extracardiac compression, is a potentially lethal complication following cardiac surgery. Case report - We present a case of recurrent cardiac tamponade following valve surgery. At first presentation, diagno

  9. Recurrent late cardiac tamponade following cardiac surgery : a deceiving and potentially lethal complication

    NARCIS (Netherlands)

    Harskamp, Ralf E.; Meuzelaar, Jacobus J.

    2010-01-01

    Background - Cardiac tamponade, characterized by inflow obstruction of the heart chambers by extracardiac compression, is a potentially lethal complication following cardiac surgery. Case report - We present a case of recurrent cardiac tamponade following valve surgery. At first presentation,

  10. Recurrent late cardiac tamponade following cardiac surgery : a deceiving and potentially lethal complication

    NARCIS (Netherlands)

    Harskamp, Ralf E.; Meuzelaar, Jacobus J.

    2010-01-01

    Background - Cardiac tamponade, characterized by inflow obstruction of the heart chambers by extracardiac compression, is a potentially lethal complication following cardiac surgery. Case report - We present a case of recurrent cardiac tamponade following valve surgery. At first presentation, diagno

  11. Venous anomalies as potentially lethal risk factors during ordinary catheterization

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    Savino Occhionorelli

    2015-06-01

    Full Text Available Venous malformations are rare but possible findings too, constituting a further risk factor for central venous catheter procedures. Herein we describe a case of death because of an innominate vein perforation by a catheter that incidentally was tucked into a sacciform malformation. Even if the technology advancement is constantly offering us new investigation tools, up to now diagnostic options are limited in the detection of those malformations that could potentially lead to dramatic complications as the described one. The present work raises the awareness about rare venous anomalies and their potential clinical implications. A proper literature review and diagnostic implementation proposal are reported.

  12. A rare but potentially lethal complication of dengue

    Institute of Scientific and Technical Information of China (English)

    Yingjuan Mok; Jessica Quah; Chuin Siau

    2013-01-01

    Severe rhabdomyolysis is an uncommon but potentially fatal complication of dengue fever that is not well characterised and may be underreported. With the resurgence and continued rise of dengue cases worldwide, physicians must be aware of the less common but serious complications of dengue. Here, we report a patient who presented with severe rhabdomyolysis secondary to dengue fever with a serum creatine kinase of 742 900 U/L.

  13. Complications of otitis media - a potentially lethal problem still present

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    Norma de Oliveira Penido

    Full Text Available ABSTRACT INTRODUCTION: It is an erroneous but commonly held belief that intracranial complications (ICCs of chronic and acute otitis media (COM and AOM are past diseases or from developing countries. These problems remain, despite improvements in antibiotic care. OBJECTIVE: This paper analyzes the occurrence and clinical characteristics and course of the main ICCs of otitis media (OM. METHODS: Retrospective cohort study of 51 patients with ICCs from OM, drawn from all patients presenting with OM to the emergency room of a large inner-city tertiary care hospital over a 22-year period. RESULTS: 80% of cases were secondary to COM of which the incidence of ICC was 0.8%; 20% were due to AOM. The death occurrence was 7.8%, hearing loss in 90%, and permanent neurological sequelae in 29%. Patients were 61% male. In the majority, onset of ear disease had occurred during childhood. Delay of diagnosis of both the initial infection as well as the secondary ICC was significant. ICCs included brain abscess and meningitis in 78%, and lateral sinus thrombosis, empyema and otitic hydrocephalus in 13%, 8% and 1% of cases, respectively. Twenty-seven neurosurgical procedures and 43 otologic surgery procedures were performed. Two patients were too ill for surgical intervention. CONCLUSION: ICCs of OM, although uncommon, still occur. These cases require expensive, complex and long-term inpatient treatment and frequently result in hearing loss, neurological sequelae and mortality. It is important to be aware of this potentiality in children with COM, especially, and maintain a high index of suspicion in order to refer for otologic specialty care before such complications occur.

  14. Complications of otitis media - a potentially lethal problem still present.

    Science.gov (United States)

    Penido, Norma de Oliveira; Chandrasekhar, Sujana Sreedevi; Borin, Andrei; Maranhão, André Souza de Albuquerque; Gurgel Testa, José Ricardo

    2016-01-01

    It is an erroneous but commonly held belief that intracranial complications (ICCs) of chronic and acute otitis media (COM and AOM) are past diseases or from developing countries. These problems remain, despite improvements in antibiotic care. This paper analyzes the occurrence and clinical characteristics and course of the main ICCs of otitis media (OM). Retrospective cohort study of 51 patients with ICCs from OM, drawn from all patients presenting with OM to the emergency room of a large inner-city tertiary care hospital over a 22-year period. 80% of cases were secondary to COM of which the incidence of ICC was 0.8%; 20% were due to AOM. The death occurrence was 7.8%, hearing loss in 90%, and permanent neurological sequelae in 29%. Patients were 61% male. In the majority, onset of ear disease had occurred during childhood. Delay of diagnosis of both the initial infection as well as the secondary ICC was significant. ICCs included brain abscess and meningitis in 78%, and lateral sinus thrombosis, empyema and otitic hydrocephalus in 13%, 8% and 1% of cases, respectively. Twenty-seven neurosurgical procedures and 43 otologic surgery procedures were performed. Two patients were too ill for surgical intervention. ICCs of OM, although uncommon, still occur. These cases require expensive, complex and long-term inpatient treatment and frequently result in hearing loss, neurological sequelae and mortality. It is important to be aware of this potentiality in children with COM, especially, and maintain a high index of suspicion in order to refer for otologic specialty care before such complications occur. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  15. Lethal ovitrap deployment for Aedes aegypti control: potential implications for non-target organisms.

    Science.gov (United States)

    Long, Sharron A; Jacups, Susan P; Ritchie, Scott A

    2015-06-01

    In Australia, dengue control combines source reduction with lethal ovitraps to reduce Aedes aegypti populations during outbreaks. Lethal ovitraps are considered a sustainable and environmentally friendly method of controlling container-inhabiting mosquitoes, however, to-date, this claim has not been quantified. This study assesses the potential impact of lethal ovitraps on non-target organisms when used to control Ae. aegypti in tropical Australia. For retention of specimens, we substituted standard sticky ovitraps for lethal ovitraps. We collected 988 Ae. aegypti and 44,132 non-target specimens over 13 months from 16 sites. Although Ae. aegypti comprised only 2.2% of the total collection, they were were the eighth most dominant taxa collected, on the 93(rd) percentile. Of the non-target organisms, Collembola were the dominant taxa, 44.2%, with 36.8% and 10.5% Diptera and Hymenoptera, respectively. Of the Dipterans, 61% were family Phoridae. Lethal ovitraps were visited by 90 insect or invertebrate families in total. Ovitraps are attractive to Collembola, Phoridae, Sciaridae, Formicidae, and Culicidae, with minimal attraction by Apidae and other commonly monitored non-target organisms. For container-inhabiting mosquitoes, LOs are cost effective operationally, requiring minimal staff resources for placement and retrieval.

  16. Review on Potential of Geopolymer for Concrete Repair and Rehabilitation

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    Warid Wazien A.Z.

    2016-01-01

    Full Text Available Cracking, spalling, surface deterioration, seepage and other concrete damage of the existing infrastructure have raised concern among residents, local authorities and developers. Dealing with concrete infrastructure rehabilitation is an important issue due to most of infrastructures today are concrete based. To simply patch up the spalling concrete as temporary solution and sooner or later, the cracks will return to haunt. This paper reviewed the current research and studies on concrete repair materials, highlighting the properties of geopolymer. It covers geopolymer repair materials which addressed in the field of concrete infrastructure rehabilitation. Geopolymer had good repair characteristics and displays the potential as an excellent repair material.

  17. The effect of DN (dominant-negative) Ku70 and reoxygenation on hypoxia cell-kill: evidence of hypoxia-induced potentially lethal damage.

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    Urano, Muneyasu; Li, Gloria C; He, Fuqiu; Minami, Akiko; Burgman, Paul; Ling, C Clifton

    2012-07-01

    To study the effect of DN (dominant-negative) Ku70 and reoxygenation on the hypoxia-induced cell-kill. Cell lines were human colorectal carcinoma HCT8 and HT29 cells and their respective derivatives, v-HCT8 and v-HT29 infected with DNKu70-containing adenovirus. Cells were plated in glass tubes and made hypoxic by flushing N(2) gas containing 0, 0.1 or 0.5% O(2). Cell survival was determined by colony formation assay immediately after 0-96 h hypoxia. To reoxygenate medium were replaced fresh following 48 or 72 h in hypoxia and cells were incubated in aerobic environment for 2-24 h before survival assay. When incubated in hypoxia, cells lost reproductive capability ∼ exponentially as a function of time in hypoxia, and depending on the O(2) concentration. DNKu70 rendered cells more prone to hypoxia-induced cell-kill. Following reoxygenation cell survival increased rapidly but without detectable cell proliferation during first 24 hours. This evinced hypoxia-induced potentially lethal damage (PLD) that was repairable upon reoxygenation. DNKu70 did not significantly inhibit this repair. Hypoxia-induced cell lethality was facilitated by DNKu70, but substantially repaired upon reoxygenation. This may have negative impact on the effect of reoxygenation in cancer therapy.

  18. Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

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    Kim, Yoo-Shin; Lee, Tae Hoon; O' Neill, Brian E., E-mail: BEOneill@houstonmethodist.org

    2015-08-14

    Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

  19. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats.

    Science.gov (United States)

    Sawant, Sharmilee P; Dnyanmote, Ankur V; Shankar, Kartik; Limaye, Pallavi B; Latendresse, John R; Mehendale, Harihara M

    2004-02-01

    There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl(4) (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl(4) bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl(4) hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0-96 h) of CCl(4) (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and (14)CCl(4) covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl(4) administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl(4) hepatotoxicity is potentiated due to inhibited tissue repair.

  20. The Potential Contributions of Lethal and Edema Toxins to the Pathogenesis of Anthrax Associated Shock

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    Peter Q. Eichacker

    2011-09-01

    Full Text Available Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock.

  1. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

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    Jian Li

    2016-02-01

    Full Text Available Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose polymerase (PARPs inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8 and amber score (−51.42. Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.

  2. Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

    Science.gov (United States)

    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 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.

  3. Ion channels in postnatal neurogenesis: potential targets for brain repair.

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    Swayne, Leigh Anne; Wicki-Stordeur, Leigh

    2012-01-01

    Neural stem and progenitor cells (NSC/NPCs) are unspecialized cells found in the adult peri-ventricular and sub-granular zones that are capable of self-renewal, migration, and differentiation into new neurons through the remarkable process of postnatal neurogenesis. We are now beginning to understand that the concerted action of ion channels, multi-pass transmembrane proteins that allow passage of ions across otherwise impermeable cellular membranes tightly regulate this process. Specific ion channels control proliferation, differentiation and survival. Furthermore, they have the potential to be highly selective drug targets due to their complex structures. As such, these proteins represent intriguing prospects for control and optimization of postnatal neurogenesis for neural regeneration following brain injury or disease. Here, we concentrate on ion channels identified in adult ventricular zone NSC/NPCs that have been found to influence the stages of neurogenesis. Finally, we outline the potential of these channels to elicit repair, and highlight the outstanding challenges.

  4. Subepicardial haematoma, a rare and potentially lethal complication of CTO-PCI: case of an exceptional recovery after conservative management.

    Science.gov (United States)

    de Vos, Annemiek M J; van der Schaaf, Rene J

    2014-10-09

    We present the case of an 82-year-old woman undergoing high-risk chronic total occlusion percutaneous coronary intervention (CTO-PCI) of the right coronary artery. Hours after the procedure, a subepicardial haematoma was diagnosed as a result of coronary perforation during the procedure. This rare and potentially lethal complication evolved exceptionally benignly after conservative management; our patient fully recovered. Increasingly complex procedures in high-risk patient categories warrant awareness of procedural complications, especially those that are subtle and appear relatively late, and are therefore most hazardous. Recognition of this rare complication and choosing the optimal strategy is of the utmost importance when dealing with patients who undergo PCI. We here describe the rare case of a potential lethal complication in high-risk CTO-PCI, which evolved relatively benignly. 2014 BMJ Publishing Group Ltd.

  5. Biological consequences of potential repair intermediates of clustered base damage site in Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Shikazono, Naoya, E-mail: shikazono.naoya@jaea.go.jp [Japan Atomic Energy Agency, Advanced Research Science Center, 2-4 Shirakata-Shirane, Tokai-mura, Naka-gun, Ibaraki 319-1195 (Japan); O' Neill, Peter [Gray Institute for Radiation Oncology and Biology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ (United Kingdom)

    2009-10-02

    Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Using a plasmid-based assay in Escherichia coli, we previously found significantly higher mutation frequencies for bistranded clusters containing 7,8-dihydro-8-oxoguanine (8-oxoG) and 5,6-dihydrothymine (DHT) than for either a single 8-oxoG or a single DHT in wild type and in glycosylase-deficient strains of E. coli. This indicates that the removal of an 8-oxoG from a clustered damage site is most likely retarded compared to the removal of a single 8-oxoG. To gain further insights into the processing of bistranded base lesions, several potential repair intermediates following 8-oxoG removal were assessed. Clusters, such as DHT + apurinic/apyrimidinic (AP) and DHT + GAP have relatively low mutation frequencies, whereas clusters, such as AP + AP or GAP + AP, significantly reduce the number of transformed colonies, most probably through formation of a lethal double strand break (DSB). Bistranded AP sites placed 3' to each other with various interlesion distances also blocked replication. These results suggest that bistranded base lesions, i.e., single base lesions on each strand, but not clusters containing only AP sites and strand breaks, are repaired in a coordinated manner so that the formation of DSBs is avoided. We propose that, when either base lesion is initially excised from a bistranded base damage site, the remaining base lesion will only rarely be converted into an AP site or a single strand break in vivo.

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

    Science.gov (United States)

    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

    2017-07-12

    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 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. © 2017 American Cancer Society. © 2017 American Cancer Society.

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

    Science.gov (United States)

    2003-08-01

    Fluorescent Invisible – UV light visible Paint ball guns NON-LETHAL CASINGS ENCAPSULANTS TAGGERS – ACTIVE Italicized text signifies existing...preliminary legal review include gastrointestinal convulsives , calmative agents, sticky foam, aqueous foam, adhesives, malodorous agents, Oleoresin... convulsives , if classified as riot control agents (and not used on combatants), can be acceptable within the context of the Biological Weapons

  8. The potential of neural transplantation for brain repair and regeneration following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    Dong Sun

    2016-01-01

    Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent de-velopment in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.

  9. Potentials of Endogenous Neural Stem cells in Cortical Repair

    Directory of Open Access Journals (Sweden)

    Bhaskar eSaha

    2012-04-01

    Full Text Available In the last few decades great thrust has been put in the area of regenerative neurobiology research to combat brain injuries and neurodegenerative diseases. The recent discovery of neurogenic niches in the adult brain has led researchers to study how to mobilize these cells to orchestrate an endogenous repair mechanism. The brain can minimize injury-induced damage by means of an immediate glial response and by initiating repair mechanisms that involve the generation and mobilization of new neurons to the site of injury where they can integrate into the existing circuit. This review highlights the current status of research in this field. Here, we discuss the changes that take place in the neurogenic milieu following injury. We will focus, in particular, on the cellular and molecular controls that lead to increased proliferation in the Sub ventricular Zone (SVZ as well as neurogenesis. We will also concentrate on how these cellular and molecular mechanisms influence the migration of new cells to the affected area and their differentiation into neuronal/glial lineage that initiate the repair mechanism. Next, we will discuss some of the different factors that limit/retard the repair process and highlight future lines of research that can help to overcome these limitations. A clear understanding of the underlying molecular mechanisms and physiological changes following brain damage and the subsequent endogenous repair should help us develop better strategies to repair damaged brains.

  10. Failure of rats to escape from a potentially lethal microwave field

    Energy Technology Data Exchange (ETDEWEB)

    Carroll, D.R.; Levinson, D.M.; Justesen, D.R.; Clarke, R.L.

    1980-01-01

    Ocularly pigmented rats, all mature females of the Long-Evans strain, were repeatedly presented an opportunity to escape from an intense 918-MHz field (whole-body dose rate . 60 mW/g) to a field of lower intensity (40, 30, 20, or 2 mW/g) by performing a simple locomotor response. Other rats could escape 800-microamperemeter faradic shock to the feet and tail by performing the same response in the same milieu, a multimode cavity. None of 20 irradiated rats learned to associate entry into a visually well-demarcated area of the cavity with immediate reduction of dose rate, in spite of field-induced elevations of body temperature to levels that exceeded 41 degrees C and would have been lethal but for a limit on durations of irradiation. In contrast, all of ten rats motivated by faradic shock rapidly learned to escape. The failure of escape learning by irradiated animals probably arose from deficiencies of motivation and, especially, sensory feedback. Whole-body hyperthermia induced by a multipath field may lack the painful or directional sensory properties that optimally promote the motive to escape. Moreover, a decline of body temperature after an escape-response-contingent reduction of field strength will be relatively slow because of the large thermal time constants of mammalian tissues. Without timely sensory feedback, which is an essential element of negative reinforcement, stimulus-response associability would be imparied, which could retard or preclude learning of an escape response.

  11. Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations

    Science.gov (United States)

    Aziz, Ramy K.; Monk, Jonathan M.; Lewis, Robert M.; In Loh, Suh; Mishra, Arti; Abhay Nagle, Amrita; Satyanarayana, Chitkala; Dhakshinamoorthy, Saravanakumar; Luche, Michele; Kitchen, Douglas B.; Andrews, Kathleen A.; Fong, Nicole L.; Li, Howard J.; Palsson, Bernhard O.; Charusanti, Pep

    2015-01-01

    Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could be found that inhibit the growth of Gram-negative bacteria. One set of molecules was identified that, depending on the concentrations, inhibits E. coli and S. enterica serovar Typhimurium in an additive or antagonistic manner. These findings pinpoint specific ways in which to improve the predictive ability of metabolic models, and highlight one potential application of systems biology to drug discovery and translational medicine. PMID:26531810

  12. Therapeutic Potential of Noble Nanoparticles for Wound Repair

    Directory of Open Access Journals (Sweden)

    Timur Saliyev

    2014-12-01

    Full Text Available Introduction. Nanoparticles made of noble metals, such as gold and silver, have a great potential to be effectively employed for wound management. The nano-size of such particles provides an opportunity to enlarge the contacting area, which results in more effective anti-bacterial action and faster wound repair. It must be noted that the shape of noble nanoparticles might play a crucial role in the manifestation of their anti-microbial properties. The modern state of technology allows fabrication of the nanoparticles with the desired shape and physical properties. In order to provide efficacy and close contact with the wound, the noble nanoparticles can be incorporated into a special matrix made of a cryogel (based on polymethyl methacrylate. This combination might serve as a foundation for developing completely new types of wound dressing.Materials and methods. We have developed a few methods for synthesizing gold and silver nanoparticles of different shapes and sizes. After fabrication of metallic nanoparticles, they were characterized by using Tunneling Electron Microscopy (TEM and Malvern Zetasizer system in order to determine the average population size and consistency. The silver nanoparticles was synthesized using sodium borohydride reduction of silver nitrate. The synthesis of gold nanoparticles was conducted by using the Turkevich method.Results. We have developed a synthetic cryogel based on polyacrylamide (by cryogelation reaction at several temperatures. At the second step, we developed a method for conjugating fabricated gold and silver nanoparticles to the surface (or pores of cryogel through covalent bonds so they can provide antibacterial action within the wound. By following the developed protocol, we were able to obtain an approximate cryogel layer (1 cm thickness with embedded gold and silver nanoparticles. This conjugate was analyzed and confirmed using Scanning Electron Microscopy (SEM and TEM.Discussion. The obtained

  13. A rare but potentially lethal case of tuberculous aortic aneurysm presenting with repeated attacks of abdominal pain.

    Science.gov (United States)

    Hung, Yao-Min; Chang, Yun-Te; Wang, Jyh-Seng; Wang, Paul Yung-Pou; Wann, Shue-Ren

    2015-01-01

    Tuberculous aortic aneurysm is an extremely rare disease with a high mortality rate. The clinical features of this condition are highly variable, ranging from asymptomatic with or without constitutional symptoms, abdominal pain to frank rupture, bleeding and shock. We herein report the case of a 56-year-old man with a large tuberculous mycotic aneurysm in the abdominal aorta with an initial presentation of repeated attacks of abdominal pain lasting for several months. Due to the vague nature of the initial symptoms, tuberculous aortic aneurysms may take several months to diagnose. This case highlights the importance of having a high index of suspicion and providing timely surgery for this rare but potentially lethal disease.

  14. Potential of bacteria-based repair solution as healing agent for porous network concrete

    NARCIS (Netherlands)

    Wiktor, V.A.C.; Sangadji, S.; Jonkers, H.M.; Schlangen, H.E.J.G.

    2013-01-01

    Bacterially induced calcium carbonate precipitation has received considerable attention for its potential application in enforcing or repairing construction material. The mechanism of bacterially mediated calcite precipitation in those studies is primarily based on the enzymatic hydrolysis of urea.

  15. Potential of bacteria-based repair solution as healing agent for porous network concrete

    NARCIS (Netherlands)

    Wiktor, V.A.C.; Sangadji, S.; Jonkers, H.M.; Schlangen, H.E.J.G.

    2013-01-01

    Bacterially induced calcium carbonate precipitation has received considerable attention for its potential application in enforcing or repairing construction material. The mechanism of bacterially mediated calcite precipitation in those studies is primarily based on the enzymatic hydrolysis of urea.

  16. Half-cell potential mapping to assess repair work on RC structures

    Energy Technology Data Exchange (ETDEWEB)

    Elsener, B. [Cagliari Univ., Dept. of Materials Science (Italy)

    2000-07-01

    Results on the successful use and on the limitations of half-cell potential mapping as an assessment technique after completion of repair work on a concrete structure are reviewed. Examples of repair discussed include traditional repair, electrochemical chloride removal, electrochemical realkalization and the application of surface applied corrosion inhibitors. Results indicate that half-cell potential measurements after traditional repair work or electrochemical chloride removal provide direct evidence of repassivation of the rebars when performed several weeks after the repair work (readings during the first few days after repair tend to show very negative potentials). Special attention must be given to the use of polymer-modified mortars when used in surface treatment of rebars; half-cell potential could remain permanently negative due to restricted oxygen access. Half-cell potential measurements are not considered effective in measuring the efficiency and durability of surface applied corrosion inhibitors due to pore solution pH and composition, and the mostly unknown mechanism of action of inhibitor blends. 18 refs., 8 figs.

  17. Liver Trauma During Combined Liposuction and Abdominoplasty: A Rare but Potentially Lethal Complication.

    Science.gov (United States)

    Gialamas, Eleftherios; Oldani, Graziano; Modarressi, Ali; Morel, Philippe; Toso, Christian

    2015-09-01

    Liposuction is a well-established procedure that is generally safe. However, rare complications can occur. The authors report on a 38-year-old woman who underwent combined abdominoplasty and liposuction at a private clinic. Four hours after the procedure, severe hypovolemic shock developed and required emergency transfer to a tertiary-care center. After primary fluid resuscitation, abdominal ultrasonography and computerized tomography revealed severe right-sided liver trauma, with active bleeding and free intra-abdominal fluid. Two attempts at right hepatic artery embolization failed to fully control the bleeding, and surgical hemostasis was required. After a 2-week hospitalization, the patient was discharged, and she returned to work 3 months later. Although it appears that this is the first reported case of liver trauma during liposuction, this potential complication should be kept in mind and identified early to permit efficient and effective management.

  18. An ongoing search for potential targets and therapies for lethal sepsis

    Institute of Scientific and Technical Information of China (English)

    Guo-Qiang Bao; Li He; David Lee; John DAngelo; Hai-Chao Wang

    2015-01-01

    Sepsis, which refers to a systemic inflammatory response syndrome resulting from a microbial infection, represents the leading cause of death in intensive care units. The pathogenesis of sepsis remains poorly understood although it is attributable to dysregulated immune responses orchestrated by innate immune cells that sequentially release early (e.g., tumor necrosis factor(TNF), interleukin-1(IL-1), and interferon-γ(IFN-γ) and late (e.g., high mobility group box 1(HMGB1)) pro-inflammatory mediators. As a ubiquitous nuclear protein, HMGB1 can be passively released from pathologically damaged cells, thereby converging infection and injury on commonly dysregulated inflammatory responses. We review evidence that supports extracellular HMGB1 as a late mediator of inflammatory diseases and discuss the potential of several Chinese herbal components as HMGB1-targeting therapies. We propose that it is important to develop strategies for specifically attenuating injury-elicited inflammatory responses without compromising the infection-mediated innate immunity for the clinical management of sepsis and other inflammatory diseases.

  19. Shot through the heart-firepower and potential lethality of air weapons.

    Science.gov (United States)

    Bakovic, Marija; Petrovecki, Vedrana; Strinovic, Davor; Mayer, Davor

    2014-11-01

    Although certain air weapons attain muzzle velocities comparable to some firearms, their successful use for committing suicide is rarely seen. Herein, we report a case of a young female died shortly after urgent admission to the hospital with penetrating gunshot wound to the chest. The autopsy revealed perforation of the pericardium and two perforative defects to the right heart ventricle. Injury was inflicted by a 0.177 caliber pellet, fired from an air rifle found near her body. Investigation ruled the death as suicide. The used air rifle fired the pellet with the energy density of 1.9 J/mm(2) , substantially above the threshold for inflicting injury. The pellet penetrated through two layers of cotton fabric and several layers of tissue to inflict fatal injury to the heart. In addition, we provide an insight into the wounding potential of air weapons, which illustrates the need for greater caution in handling those devices. © 2014 American Academy of Forensic Sciences.

  20. Therapeutic potential of HDL in cardioprotection and tissue repair.

    Science.gov (United States)

    Van Linthout, Sophie; Frias, Miguel; Singh, Neha; De Geest, Bart

    2015-01-01

    Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.

  1. [Surgical complications in drug body-packers: an uncommon but potentially lethal emergency].

    Science.gov (United States)

    Álvarez Llano, Laura; Rey Valcárcel, Cristina; Mohamed Al-Lal, Yusef; Sánchez Rodríguez, Teresa; García Marín, Andrés; Pérez Díaz, María Dolores; Turégano Fuentes, Fernando

    2012-11-01

    Drug trafficking by means of introducing packets of illegal substances in body cavities carries a risk of suffering from a gastrointestinal obstruction and/or severe poisoning in the person who transports them. Spain is considered as the port of entry to Europe for drugs, and some Spanish hospitals have experience in managing these types of patients. Two hospitals in Madrid, including the Gregorio Marañón University General Hospital (HGUGM), received these potential patients from the Madrid Barajas airport. To analyse the results of the conservative treatment and the need for surgery in "body-packers". A retrospective, observational study of patients diagnosed as a body-packer between January 2000 and December 2008. Those with gastrointestinal symptoms, signs of poisoning, or positive for drugs of abuse, were admitted to the Custodial Unit of our hospital. The conservative treatment consisted of digestive rest and imaging studies until expulsion from the body. Asymptomatic patients were discharged from the Emergency Department. A total of 549 patients, with a median age of 31 years, and of whom 81% were males, were hospitalised during this period. Less than half (40%) showed positive for drugs in the urine, with cocaine in 80% of the cases. Of the 549 patients with initial conservative treatment, 27 (4.9%) had serious complications (16, bowel obstruction, and 11 with signs of poisoning). Of these, 23 required surgery (the 16 obstructions and 7 of the poisonings); 2 were successfully treated in ICU, and 2 died before surgery (0.4%) of the cases. The most frequent surgical treatment was enterotomy and/or gastrostomy to extract the packets. Thirteen (56%) of those operated on had associated morbidity (11 abdominal infections and 2 nosocomial infections). Conservative treatment is safe in 95% of the patients. A small percentage required surgical treatment, basically for gastrointestinal obstruction or severe poisoning. Copyright © 2011 AEC. Published by Elsevier

  2. Investigation into the potential of sub-lethal photodynamic antimicrobial chemotherapy (PACT) to reduce susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) to antibiotics

    Science.gov (United States)

    Cassidy, C. M.; Donnelly, R. F.; Tunney, M. M.

    2009-06-01

    In PACT, a combination of a sensitising drug and visible light cause the selective destruction of microbial cells via singlet oxygen production. As singlet oxygen is a non-specific oxidizing agent and is only present during illumination, development of resistance to this treatment is thought to be unlikely. However, in response to oxidative stress, bacteria can up-regulate oxidative stress genes and associated antibiotic resistance genes. The up-regulation of these genes and potential transfer of genetic material may result in a resistant bacterial population. This study determined whether treatment of clinically isolated meticillin resistant Staphylococcus aureus (MRSA) strains with sub-lethal doses of methylene blue (MB) and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP)-PACT resulted in reduced susceptibility to antibiotics and previously lethal PACT. Exposure of strains to sub-lethal doses of photosensitizer in combination with light had no effect on susceptibility to previously lethal photosensitization. Furthermore, exposure to sub-lethal concentrations of both photosensitizers caused no significant changes in the minimum inhibitory concentration (MIC) for each strain tested. Any differences in susceptibility were not significant as they did not cross breakpoints between resistant and susceptible for any organism or antibiotic tested. Therefore, PACT remains an attractive alternative option for treatment of MRSA infections.

  3. Therapeutic potential of stem cells in auditory hair cell repair

    Directory of Open Access Journals (Sweden)

    Ryuji Hata

    2009-01-01

    Full Text Available The prevalence of acquired hearing loss is very high. About 10% of the total population and more than one third of the population over 65 years suffer from debilitating hearing loss. The most common type of hearing loss in adults is idiopathic sudden sensorineural hearing loss (ISSHL. In the majority of cases, ISSHL is permanent and typically associated with loss of sensory hair cells in the organ of Corti. Following the loss of sensory hair cells, the auditory neurons undergo secondary degeneration. Sensory hair cells and auditory neurons do not regenerate throughout life, and loss of these cells is irreversible and cumulative. However, recent advances in stem cell biology have gained hope that stem cell therapy comes closer to regenerating sensory hair cells in humans. A major advance in the prospects for the use of stem cells to restore normal hearing comes with the recent discovery that hair cells can be generated ex vivo from embryonic stem (ES cells, adult inner ear stem cells and neural stem cells. Furthermore, there is increasing evidence that stem cells can promote damaged cell repair in part by secreting diffusible molecules such as growth factors. These results suggest that stem-cell-based treatment regimens can be applicable to the damaged inner ear as future clinical applications.Previously we have established an animal model of cochlear ischemia in gerbils and showed progressive hair cell loss up to 4 days after ischemia. Auditory brain stem response (ABR recordings have demonstrated that this gerbil model displays severe deafness just after cochlear ischemia and gradually recovers thereafter. These pathological findings and clinical manifestations are reminiscent of ISSHL in humans. In this study, we have shown the effectiveness of stem cell therapy by using this animal model of ISSHL.

  4. Antimalarial potential of China 30 and Chelidonium 30 in combination therapy against lethal rodent malaria parasite: Plasmodium berghei.

    Science.gov (United States)

    Rajan, Aswathy; Bagai, Upma

    2013-05-07

    Homeopathy is a therapeutic method based on the application of similia principle, utilizing ultra-low doses of medicinal substances made from natural products. The present study has been designed to evaluate the efficacy of Cinchona officinalis (Chin.) 30C and Chelidonium majus (Chel.) 30C in combination therapy against lethal murine malaria. Five groups having twelve BALB/c mice each were administered orally with 0.2 ml/mouse/day of different drugs, and their antimalarial potential was evaluated by Peter's 4-day test. The combination of Chin. 30 and Chel. 30 exhibited complete parasite clearance by the 28th day post-inoculation which was similar to the positive control [artesunate (4 mg/kg)+sulphadoxine-primethamine (1.2 mg/kg)] group. Both the groups exhibited enhanced mean survival time (MST) 28±0 days,whereas, the mice of infected control group survived up to 7.6±0.4 days only. The preventive and curative activities of the combination in comparison to the positive controls [pyrimethamine (1.2 mg/Kg) and chloroquine (20 mg/Kg), respectively] were also evaluated. The combination had a significant preventive activity (p<0.0005), with 89.2% chemosuppression which was higher than the standard drug, pyrimethamine (83.8%). It also showed a moderate curative activity with complete clearance of parasite in 50% of surviving mice, and enhancing the MST of mice up to 26.8±2.8 days. These findings point to the significant antiplasmodial efficacy of the combination of these homeopathic drugs against Plasmodium berghei.

  5. Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential.

    Science.gov (United States)

    Khandia, Rekha; Pattnaik, Bramhadev; Rajukumar, Katherukamem; Pateriya, Atul; Bhatia, Sandeep; Murugkar, Harshad; Prakash, Anil; Pradhan, Hare Krishna; Dhama, Kuldeep; Munjal, Ashok; Joshi, Sunil K

    2017-05-30

    Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = -773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.

  6. Skin appendage-derived stem cells: cell biology and potential for wound repair.

    Science.gov (United States)

    Xie, Jiangfan; Yao, Bin; Han, Yutong; Huang, Sha; Fu, Xiaobing

    2016-01-01

    Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration. These stem cells also participate in the repair of the epidermis after injuries, inducing restoration of tissue integrity and function of damaged tissue. Unlike epidermis-derived stem cells, comprehensive knowledge about skin appendage-derived stem cells remains limited. In this review, we summarize the current knowledge of skin appendage-derived stem cells, including their fundamental characteristics, their preferentially expressed biomarkers, and their potential contribution involved in wound repair. Finally, we will also discuss current strategies, future applications, and limitations of these stem cells, attempting to provide some perspectives on optimizing the available therapy in cutaneous repair and regeneration.

  7. Potential of Carbon Nanotube Reinforced Cement Composites as Concrete Repair Material

    Directory of Open Access Journals (Sweden)

    Tanvir Manzur

    2016-01-01

    Full Text Available Carbon nanotubes (CNTs are a virtually ideal reinforcing agent due to extremely high aspect ratios and ultra high strengths. It is evident from contemporary research that utilization of CNT in producing new cement-based composite materials has a great potential. Consequently, possible practical application of CNT reinforced cementitious composites has immense prospect in the field of applied nanotechnology within construction industry. Several repair, retrofit, and strengthening techniques are currently available to enhance the integrity and durability of concrete structures with cracks and spalling, but applicability and/or reliability is/are often limited. Therefore, there is always a need for innovative high performing concrete repair materials with good mechanical, rheological, and durability properties. Considering the mechanical properties of carbon nanotubes (CNTs and the test results of CNT reinforced cement composites, it is apparent that such composites could be used conveniently as concrete repair material. With this end in view, the applicability of multiwalled carbon nanotube (MWNT reinforced cement composites as concrete repair material has been evaluated in this study in terms of setting time, bleeding, and bonding strength (slant shear tests. It has been found that MWNT reinforced cement mortar has good prospective as concrete repair material since such composites exhibited desirable behavior in setting time, bleeding, and slant shear.

  8. Geopolymers as potential repair material in tiles conservation

    Science.gov (United States)

    Geraldes, Catarina F. M.; Lima, Augusta M.; Delgado-Rodrigues, José; Mimoso, João Manuel; Pereira, Sílvia R. M.

    2016-03-01

    The restoration materials currently used to fill gaps in historical architectural tiles (e.g. lime or organic resin pastes) usually show serious drawbacks in terms of compatibility, effectiveness or durability. The existing solutions do not fully protect Portuguese faïence tiles ( azulejos) in outdoor conditions and frequently result in further deterioration. Geopolymers can be a potential solution for tile lacunae infill, given the chemical-mineralogical similitude to the ceramic body, and also the durability and versatile range of physical properties that can be obtained through the manipulation of their formulation and curing conditions. This work presents and discusses the viability of the use of geopolymeric pastes to fill lacunae in tiles or to act as "cold" cast ceramic tile surrogates reproducing missing tile fragments. The formulation of geopolymers, namely the type of activators, the alumino-silicate source, the quantity of water required for adequate workability and curing conditions, was studied. The need for post-curing desalination was also considered envisaging their application in the restoration of outdoor historical architectural tiles frequently exposed to adverse environmental conditions. The possible advantages and disadvantages of the use of geopolymers in the conservation of tiles are also discussed. The results obtained reveal that geopolymers pastes are a promising material for the restoration of tiles, when compared to other solutions currently in use.

  9. Impact of potentially lethal ventricular arrhythmias on long-term outcome in patients with chronic heart failure

    Institute of Scientific and Technical Information of China (English)

    LIU Ye-hong; SHEN Wei-feng; SU Jing-ying; WANG Lin-jie; LI Jin-ping; ZHOU Qing-fen; GAN Qian; CHAI Xi-chen; DAI Li-ying; ZHANG Feng-ru

    2012-01-01

    Background Potentially lethal ventricular arrhythmias (PLVAs) occur frequently in survivors after acute myocardial infarction and are increasingly recognized in other forms of structural heart diseases.This study investigated the prevalence and prognostic significance of PLVAs in patients with chronic heart failure (CHF).Methods Data concerning demographics,etiology of heart failure,NYHA functional class,biochemical variables,electrocardiographic and echocardiographic findings,and medical treatments were collected by reviewing hospital medical records from 1080 patients with NYHA Ⅱ-Ⅳ and a left ventricular (LV) ejection fraction ≤45%.PLVAs were defined as multi-focal ventricular ectopy (>30 beats/h on Holter monitoring),bursts of ventricular premature beats,and nonsustained ventricular tachycardia.All-cause mortality,sudden death,and rehospitalization due to worsening heart failure,or cardiac transplantation during 5-year follow-up after discharge were recorded.Results The occurrence rate of PLVAs in CHF was 30.2%,and increased with age; 23.4% in patients <45 years old,27.8% in those between 45-65 years old,and 33.5% in patients >65 years old (P=0.033).Patients with PLVAs had larger LV size and lower ejection fraction (both P <0.01) and higher all-cause mortality (P=0.014) during 5-year follow-up than those without PLVAs.Age (OR 1.041,95% Cl 1.004-1.079,P=0.03) and LV end-diastolic dimension (OR 1.068,95% Cl 1.013-1.126,P=0.015) independently predicted the occurrence of PLVAs.And PLVA was an independent factor for all-cause mortality (RR 1.702,95% Cl 1.017-2.848,P=0.031) and sudden death (RR 1.937,95% CI 1.068-3.516,P=0.030) in patients with CHF.Conclusion PLVAs are common and exert a negative impact on Iona-term clinical outcome in patients with CHF.

  10. Potentials of plasma NGAL and MIC-1 as biomarker(s in the diagnosis of lethal pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Sukhwinder Kaur

    Full Text Available Pancreatic cancer (PC is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1 are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples from patients with pre-treatment PC patients (n = 91 and compared it with those in healthy control (HC individuals (n = 24 and patients with chronic pancreatitis (CP, n = 23. The diagnostic performance of these two proteins was further compared with that of CA19-9, a tumor marker commonly used to follow PC progression. The levels of all three biomarkers were significantly higher in PC compared to HCs. The mean (± standard deviation, SD plasma NGAL, CA19-9 and MIC-1 levels in PC patients was 111.1 ng/mL (2.2, 219.2 U/mL (7.8 and 4.5 ng/mL (4.1, respectively. In comparing resectable PC to healthy patients, all three biomarkers were found to have comparable sensitivities (between 64%-81% but CA19-9 and NGAL had a higher specificity (92% and 88%, respectively. For distinguishing resectable PC from CP patients, CA19-9 and MIC-1 were most specific (74% and 78% respectively. CA19-9 at an optimal cut-off of 54.1 U/ml is highly specific in differentiating resectable (stage 1/2 pancreatic cancer patients from controls in comparison to its clinical cut-off (37.1 U/ml. Notably, the addition of MIC-1 to CA19-9 significantly improved the ability to distinguish resectable PC cases from CP (p = 0.029. Overall, MIC-1 in combination with CA19-9 improved the diagnostic

  11. Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations

    DEFF Research Database (Denmark)

    Aziz, Ramy K.; Monk, Jonathan M.; Lewis, R. M.

    2015-01-01

    Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype...... and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25......% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could...

  12. Immunization with a synthetic robustoxin derivative lacking disulphide bridges protects against a potentially lethal challenge with funnel-web spider (Atrax robustus) venom.

    Science.gov (United States)

    Comis, Alfio; Tyler, Margaret; Mylecharane, Ewan; Spence, Ian; Howden, Merlin

    2009-03-01

    The venom of male Atrax robustus spiders is potentially lethal to primates. These spiders have been responsible for a number of human deaths. Robustoxin is the lethal toxin in the venom. It is a highly cross-linked polypeptide that has 42 amino acid residues and four disulphide bridges. If these bridges are broken, the resulting polypeptide is non-toxic. Robustoxin was chemically synthesized with all of its eight cysteine residues protected with acetamidomethyl groups in order to avoid formation of disulphide bridges. The resulting derivative was co-polymerized with keyhole limpet haemocyanin. Two Macaca fascicularis monkeys were immunized with this conjugate. The monkeys were challenged,under anaesthesia,with a potentially lethal dose of male A.robustus crude venom. Both monkeys showed some minor symptoms of intoxication but recovered fully with no adverse after-effects. Immunization with the same immunogen, in the absence of keyhole limpet haemocyanin, did not protect a third monkey. The N-terminal 23 amino acid peptide derived from the sequence of robustoxin was synthesized and conjugated with ovalbumin. A fourth monkey was immunized with this conjugate. However,it was not protected against challenge.The implications of these results for the preparation of synthetic peptide vaccines are discussed.

  13. Immunization with a synthetic robustoxin derivative lacking disulphide bridges protects against a potentially lethal challenge with funnel-web spider (Atrax robustus) venom

    Indian Academy of Sciences (India)

    Alfio Comis; Margaret Tyler; Ewan Mylecharane; Ian Spence; Merlin Howden

    2009-03-01

    The venom of male Atrax robustus spiders is potentially lethal to primates. These spiders have been responsible for a number of human deaths. Robustoxin is the lethal toxin in the venom. It is a highly cross-linked polypeptide that has 42 amino acid residues and four disulphide bridges. If these bridges are broken, the resulting polypeptide is nontoxic. Robustoxin was chemically synthesized with all of its eight cysteine residues protected with acetamidomethyl groups in order to avoid formation of disulphide bridges. The resulting derivative was co-polymerized with keyhole limpet haemocyanin. Two Macaca fascicularis monkeys were immunized with this conjugate. The monkeys were challenged, under anaesthesia, with a potentially lethal dose of male A. robustus crude venom. Both monkeys showed some minor symptoms of intoxication but recovered fully with no adverse after-effects. Immunization with the same immunogen, in the absence of keyhole limpet haemocyanin, did not protect a third monkey. The N-terminal 23 amino acid peptide derived from the sequence of robustoxin was synthesized and conjugated with ovalbumin. A fourth monkey was immunized with this conjugate. However, it was not protected against challenge. The implications of these results for the preparation of synthetic peptide vaccines are discussed.

  14. Development of a Micronized Meniscus Extracellular Matrix Scaffold for Potential Augmentation of Meniscal Repair and Regeneration.

    Science.gov (United States)

    Monibi, Farrah A; Bozynski, Chantelle C; Kuroki, Keiichi; Stoker, Aaron M; Pfeiffer, Ferris M; Sherman, Seth L; Cook, James L

    2016-12-01

    Decellularized scaffolds composed of extracellular matrix (ECM) hold promise for repair and regeneration of the meniscus, given the potential for ECM-based biomaterials to aid in stem cell recruitment, infiltration, and differentiation. The objectives of this study were to decellularize canine menisci to fabricate a micronized, ECM-derived scaffold and to determine the cytocompatibility and repair potential of the scaffold ex vivo. Menisci were decellularized with a combination of physical agitation and chemical treatments. For scaffold fabrication, decellularized menisci were cryoground into a powder and the size and morphology of the ECM particles were evaluated using scanning electron microscopy. Histologic and biochemical analyses of the scaffold confirmed effective decellularization with loss of proteoglycan from the tissue but no significant reduction in collagen content. When washed effectively, the decellularized scaffold was cytocompatible to meniscal fibrochondrocytes, synoviocytes, and whole meniscal tissue based on the resazurin reduction assay and histologic evaluation. In an ex vivo model for meniscal repair, radial tears were augmented with the scaffold delivered with platelet-rich plasma as a carrier, and compared to nonaugmented (standard-of-care) suture techniques. Histologically, there was no evidence of cellular migration or proliferation noted in any of the untreated or standard-of-care treatment groups after 40 days of culture. Conversely, cellular infiltration and proliferation were noted in scaffold-augmented repairs. These data suggest the potential for the scaffold to promote cellular survival, migration, and proliferation ex vivo. Further investigations are necessary to examine the potential for the scaffold to induce cellular differentiation and functional meniscal fibrochondrogenesis.

  15. Potential use of mesenchymal stem cells in human meniscal repair: current insights

    Science.gov (United States)

    Pak, Jaewoo; Lee, Jung Hun; Park, Kwang Seung; Jeon, Jeong Ho; Lee, Sang Hee

    2017-01-01

    The menisci of the human knee play an important role in maintaining normal functions to provide stability and nutrition to the articular cartilage, and to absorb shock. Once injured, these important structures have very limited natural healing potential. Unfortunately, the traditional arthroscopic meniscectomy performed on these damaged menisci may predispose the joint toward early development of osteoarthritis. Although a very limited number of studies are available, mesenchymal stem cells (MSCs) have been investigated as an alternative therapeutic modality to repair human knee meniscal tears. This review summarizes the results of published applications of MSCs in human patients, which showed that the patients who received MSCs (autologous adipose tissue-derived stem cells or culture-expanded bone marrow-derived stem cells) presented symptomatic improvements, along with magnetic resonance imaging evidences of the meniscal repair. PMID:28356779

  16. Arsenite release on enzymic transformation of arsonomethyl substrate analogues: a potentially lethal synthesis by glycerol-3-phosphate dehydrogenase.

    Science.gov (United States)

    Mutenda, E K; Sparkes, M J; Dixon, H B

    1995-09-15

    The isosteric arsenical analogue of glycerol 3-phosphate, 3,4-dihydroxybutylarsonic acid, is a good substrate for rabbit muscle glycerol-3-phosphate dehydrogenase. Its oxidation is accompanied by release of arsenite. This release seems to be due to a spontaneous elimination of arsenite by 3-oxoalkylarsonic acids, as it is also observed in (1) the oxidation of 3-hydroxypropylarsonic acid by yeast alcohol dehydrogenase, (2) treatment of 3,4-dihydroxybutylarsonic acid with periodate and (3) nonenzymic transamination of the glutamate analogue 2-amino-4-arsonobutyric acid. Enzymic formation of 3-oxoalkylarsonic acids in cells can therefore be lethal, as arsenite is poisonous to most organisms because of its high affinity for dithiols such as dihydrolipoyl groups.

  17. DNA Mismatch Repair and Oxidative DNA Damage: Implications for Cancer Biology and Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Bridge, Gemma; Rashid, Sukaina; Martin, Sarah A., E-mail: sarah.martin@qmul.ac.uk [Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ (United Kingdom)

    2014-08-05

    Many components of the cell, including lipids, proteins and both nuclear and mitochondrial DNA, are vulnerable to deleterious modifications caused by reactive oxygen species. If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer. Base excision repair and nucleotide excision repair are the two DNA repair pathways believed to orchestrate the removal of oxidative lesions. However, recent findings suggest that the mismatch repair pathway may also be important for the response to oxidative DNA damage. This is particularly relevant in cancer where mismatch repair genes are frequently mutated or epigenetically silenced. In this review we explore how the regulation of oxidative DNA damage by mismatch repair proteins may impact on carcinogenesis. We discuss recent studies that identify potential new treatments for mismatch repair deficient tumours, which exploit this non-canonical role of mismatch repair using synthetic lethal targeting.

  18. Stem/progenitor cells: a potential source of retina-specific cells for retinal repair.

    Science.gov (United States)

    Bi, Yong-Yan; Feng, Dong-Fu; Pan, Dong-Chao

    2009-11-01

    Retinal injury generally results in permanent visual disturbance or even blindness. Any effort to restore vision in such condition would require replacement of the highly specialized retinal cells. Stem/progenitor cells have been proposed as a potential source of new retina-specific cells to replace those lost due to retina injury. Evidence to date suggests that continued development of stem cell therapies may ultimately lead to viable treatment options for retina injury. A wide range of stem/progenitor cells from various sources is currently being investigated for the treatment of retinal injury. This article reviews the recent achievements about stem/progenitor cell source for retinal repair.

  19. Non-lethal control of the cariogenic potential of an agent-based model for dental plaque.

    Science.gov (United States)

    Head, David A; Marsh, Phil D; Devine, Deirdre A

    2014-01-01

    Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments.

  20. Non-lethal control of the cariogenic potential of an agent-based model for dental plaque.

    Directory of Open Access Journals (Sweden)

    David A Head

    Full Text Available Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments.

  1. Potential of cardiac stem/progenitor cells and induced pluripotent stem cells for cardiac repair in ischaemic heart disease

    OpenAIRE

    Wang, Wei Eric; Chen, Xiongwen; Houser, Steven R.; Zeng, Chunyu

    2013-01-01

    Stem cell therapy has emerged as a promising strategy for cardiac and vascular repair. The ultimate goal is to rebuild functional myocardium by transplanting exogenous stem cells or by activating native stem cells to induce endogenous repair. CS/PCs (cardiac stem/progenitor cells) are one type of adult stem cell with the potential to differentiate into cardiac lineages (cardiomyocytes, smooth muscle cells and endothelial cells). iPSCs (induced pluripotent stem cells) also ha...

  2. Dental pulp stem cells and their potential roles in central nervous system regeneration and repair.

    Science.gov (United States)

    Young, Fraser; Sloan, Alastair; Song, Bing

    2013-11-01

    Functional recovery from injuries to the brain or spinal cord represents a major clinical challenge. The transplantation of stem cells, traditionally isolated from embryonic tissue, may help to reduce damage following such events and promote regeneration and repair through both direct cell replacement and neurotrophic mechanisms. However, the therapeutic potential of using embryonic stem/progenitor cells is significantly restricted by the availability of embryonic tissues and associated ethical issues. Populations of stem cells reside within the dental pulp, representing an alternative source of cells that can be isolated with minimal invasiveness, and thus should illicit fewer moral objections, as a replacement for embryonic/fetal-derived stem cells. Here we discuss the similarities between dental pulp stem cells (DPSCs) and the endogenous stem cells of the central nervous system (CNS) and their ability to differentiate into neuronal cell types. We also consider in vitro and in vivo studies demonstrating the ability of DPSCs to help protect against and repair neuronal damage, suggesting that dental pulp may provide a viable alternative source of stem cells for replacement therapy following CNS damage.

  3. Potential of human dental stem cells in repairing the complete transection of rat spinal cord

    Science.gov (United States)

    Yang, Chao; Li, Xinghan; Sun, Liang; Guo, Weihua; Tian, Weidong

    2017-04-01

    Objective. The adult spinal cord of mammals contains a certain amount of neural precursor cells, but these endogenous cells have a limited capacity for replacement of lost cells after spinal cord injury. The exogenous stem cells transplantation has become a therapeutic strategy for spinal cord repairing because of their immunomodulatory and differentiation capacity. In addition, dental stem cells originating from the cranial neural crest might be candidate cell sources for neural engineering. Approach. Human dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAPs) and dental pulp stem cells (DPSCs) were isolated and identified in vitro, then green GFP-labeled stem cells with pellets were transplanted into completely transected spinal cord. The functional recovery of rats and multiple neuro-regenerative mechanisms were explored. Main results. The dental stem cells, especially DFSCs, demonstrated the potential in repairing the completely transected spinal cord and promote functional recovery after injury. The major involved mechanisms were speculated below: First, dental stem cells inhibited the expression of interleukin-1β to reduce the inflammatory response; second, they inhibited the expression of ras homolog gene family member A (RhoA) to promote neurite regeneration; third, they inhibited the sulfonylurea receptor1 (SUR-1) expression to reduce progressive hemorrhagic necrosis; lastly, parts of the transplanted cells survived and differentiated into mature neurons and oligodendrocytes but not astrocyte, which is beneficial for promoting axons growth. Significance. Dental stem cells presented remarkable tissue regenerative capability after spinal cord injury through immunomodulatory, differentiation and protection capacity.

  4. Quaternary ammonium silane-functionalized, methacrylate resin composition with antimicrobial activities and self-repair potential

    Science.gov (United States)

    Gong, Shi-qiang; Niu, Li-na; Kemp, Lisa K.; Yiu, Cynthia K.Y.; Ryou, Heonjune; Qi, Yi-pin; Blizzard, John D.; Nikonov, Sergey; Brackett, Martha G.; Messer, Regina L.W.; Wu, Christine D.; Mao, Jing; Brister, L. Bryan; Rueggeberg, Frederick A.; Arola, Dwayne D.; Pashley, David H.; Tay, Franklin R.

    2012-01-01

    Design of antimicrobial polymers for enhancing healthcare issues and minimizing environmental problems is an important endeavor with both fundamental and practical implications. Quaternary ammonium silane-functionalized methacrylate (QAMS) represents an example of antimicrobial macromonomers synthesized by a sol-gel chemical route; these compounds possess flexible Si-O-Si bonds. In present work, a partially-hydrolyzed QAMS copolymerized with bis-GMA is introduced. This methacrylate resin was shown to possess desirable mechanical properties with both a high degree of conversion and minimal polymerization shrinkage. Kill-on-contact microbiocidal activities of this resin were demonstrated using single-species biofilms of Streptococcus mutans (ATCC 36558), Actinomyces naeslundii (ATCC 12104) and Candida albicans (ATCC 90028). Improved mechanical properties after hydration provided the proof-of-concept that QAMS-incorporated resin exhibits self-repair potential via water-induced condensation of organic modified silicate (ormosil) phases within the polymerized resin matrix. PMID:22659173

  5. Allogeneic compact bone-derived mesenchymal stem cell transplantation increases survival of mice exposed to lethal total body irradiation: a potential immunological mechanism

    Institute of Scientific and Technical Information of China (English)

    Qiao Shukai; Ren Hanyun; Shi Yongjin; Liu Wei

    2014-01-01

    Background Radiation-induced injury after accidental or therapeutic total body exposure to ionizing radiation has serious pathophysiological consequences,and currently no effective therapy exists.This study was designed to investigate whether transplantation of allogeneic murine compact bone derived-mesenchymal stem cells (CB-MSCs) could improve the survival of mice exposed to lethal dosage total body irradiation (TBI),and to explore the potential immunoprotective role of MSCs.Methods BALB/c mice were treated with 8 Gy TBI,and then some were administered CB-MSCs isolated from C57BL/6 mice.Survival rates and body weight were analyzed for 14 days post-irradiation.At three days post-irradiation,we evaluated IFN-Y and IL-4 concentrations; CD4+CD25+Foxp3+ regulatory T cell (Treg) percentage; CXCR3,CCR5,and CCR7 expressions on CD3+T cells; and splenocyte T-bet and GATA-3 mRNA levels.CB-MSC effects on bone marrow hemopoiesis were assessed via colony-forming unit granulocyte/macrophage (CFU-GM) assay.Results After lethal TBI,compared to non-transplanted mice,CB-MSC-transplanted mice exhibited significantly increased survival,body weight,and CFU-GM counts of bone marrow cells (P<0.05),as well as higher Treg percentages,reduced IFN-Y,CXCR3 and CCR5 down-regulation,and CCR7 up-regulation.CB-MSC transplantation suppressed Th1 immunity.Irradiated splenocytes directly suppressed CFU-GM formation from bone marrow cells,and CB-MSC co-culture reversed this inhibition.Conclusion Allogeneic CB-MSC transplantation attenuated radiation-induced hematopoietic toxicity,and provided immunoprotection by alleviating lymphocyte-mediated CFU-GM inhibition,expanding Tregs,regulating T cell chemokine receptor expressions,and skewing the Th1/Th2 balance toward anti-inflammatory Th2 polarization.

  6. The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injur y

    Institute of Scientific and Technical Information of China (English)

    Dong Sun

    2014-01-01

    Traumatic brain injury (TBI) is the leading cause of death and disability of persons under 45 years old in the United States, affecting over 1.5 million individuals each year. It had been th ought that recovery from such injuries is severely limited due to the inability of the adult bra in to replace damaged neurons. However, recent studies indicate that the mature mammalian central nervous system (CNS) has the potential to replenish damaged neurons by proliferation and neuronal differentiation of adult neural stem/progenitor cells residing in the neurogenic regions in the brain. Furthermore, increasing evidence indicates that these endogenous stem/progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. In support of this notion, heightened levels of cell proliferation and neurogenesis have been ob-served in response to brain trauma or insults suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons. This review will discuss the potential functions of adult neurogenesis and recent development of strategies aiming at harnessing this neurogenic capacity in order to repopulate and repair the injured brain.

  7. Biocompatibility and neurotoxicity of magnesium alloys potentially used for neural repairs.

    Science.gov (United States)

    Fei, Jianjun; Wen, Xiaoxiao; Lin, Xiao; Saijilafu; Wang, Weihua; Ren, Olga; Chen, Xinjian; Tan, Lili; Yang, Ke; Yang, Huilin; Yang, Lei

    2017-09-01

    Nerve injury, especially the large-size nerve damage, is a serious problem affecting millions of people. Entubulation of two ends of the injured nerve by using an implantable device, e.g., nerve guidance conduit (NGC), to guide the regeneration of nerve tissue is a promising approach for treating the large-size nerve defect. Magnesium (Mg) and its alloys are biodegradable, conductive, and own good mechanical properties. Mg(2+) ion, one of the main degradation products of Mg and its alloys, was reported to promote the proliferation of neural stem cells and their neurite production. Thus, Mg and its alloys are potential materials for fabricating the nerve repair implants, such as NGC or scaffold. However, the compatibility of Mg alloys to cells, especially neurons is not clear. In this work, NZ20 (Mg-2Nd-Zn), ZN20 (Mg-2Zn-Nd) and Mg-10Li magnesium alloys were selected for study, due to the improved mechanical properties of NZ20 and ZN20 alloys and bio-function of Li(+) ions from Mg-10Li to nervous system, respectively. The degradation behavior and biocompatibility were studied by in vitro degradation test and cell adhesion assay, respectively. Specifically, the cytocompatibility to dorsal root ganglion (DRG) neurons, RF/6A choroid-retina endothelial cells, and osteoblasts in the cell culture media containing Mg alloy extracts were investigated. The results showed that Mg alloys degraded at different rates in cell culture media and artificial cerebrospinal fluid. The three alloy extracts showed negligible toxic effects on the endothelial cells and osteoblasts at short term (1 day), while NZ20 extract inhibited the proliferation of these two types of cells. The effect of Mg alloy extracts on cell proliferation was also concentration-dependent. For DRG neurons, ZN20 and Mg-10Li alloy extracts showed no neural toxicity compared with control group. The results of the present work show a potential and feasibility of Mg-10Li and ZN20 for nerve repair applications. Copyright

  8. Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells.

    Science.gov (United States)

    Arora, Sanjeevani; Heyza, Joshua; Zhang, Hao; Kalman-Maltese, Vivian; Tillison, Kristin; Floyd, Ashley M; Chalfin, Elaine M; Bepler, Gerold; Patrick, Steve M

    2016-11-15

    ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range. These compounds were validated in secondary screens against two other non-related endonucleases to ensure specificity. Results from these screens were validated using an in vitro gel-based nuclease assay. Electrophoretic mobility shift assays (EMSAs) further show that these compounds do not inhibit the binding of purified ERCC1-XPF to DNA. Next, in lung cancer cells these compounds potentiated cisplatin cytotoxicity and inhibited DNA repair. Structure activity relationship (SAR) studies identified related compounds for one of the original Hits, which also potentiated cisplatin cytotoxicity in cancer cells. Excitingly, dosing with NSC16168 compound potentiated cisplatin antitumor activity in a lung cancer xenograft model. Further development of ERCC1-XPF DNA repair inhibitors is expected to sensitize cancer cells to DNA damage-based chemotherapy.

  9. DNA Single-Strand Break Repair and Spinocerebellar Ataxia with Axonal Neuropathy-1

    OpenAIRE

    Caldecott, K. W.

    2007-01-01

    DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiester...

  10. DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1

    OpenAIRE

    El-Khamisy, S.F.; Caldecott, K. W.

    2007-01-01

    DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiester...

  11. Repairable-conditionally repairable damage model based on dual Poisson processes.

    Science.gov (United States)

    Lind, B K; Persson, L M; Edgren, M R; Hedlöf, I; Brahme, A

    2003-09-01

    The advent of intensity-modulated radiation therapy makes it increasingly important to model the response accurately when large volumes of normal tissues are irradiated by controlled graded dose distributions aimed at maximizing tumor cure and minimizing normal tissue toxicity. The cell survival model proposed here is very useful and flexible for accurate description of the response of healthy tissues as well as tumors in classical and truly radiobiologically optimized radiation therapy. The repairable-conditionally repairable (RCR) model distinguishes between two different types of damage, namely the potentially repairable, which may also be lethal, i.e. if unrepaired or misrepaired, and the conditionally repairable, which may be repaired or may lead to apoptosis if it has not been repaired correctly. When potentially repairable damage is being repaired, for example by nonhomologous end joining, conditionally repairable damage may require in addition a high-fidelity correction by homologous repair. The induction of both types of damage is assumed to be described by Poisson statistics. The resultant cell survival expression has the unique ability to fit most experimental data well at low doses (the initial hypersensitive range), intermediate doses (on the shoulder of the survival curve), and high doses (on the quasi-exponential region of the survival curve). The complete Poisson expression can be approximated well by a simple bi-exponential cell survival expression, S(D) = e(-aD) + bDe(-cD), where the first term describes the survival of undamaged cells and the last term represents survival after complete repair of sublethal damage. The bi-exponential expression makes it easy to derive D(0), D(q), n and alpha, beta values to facilitate comparison with classical cell survival models.

  12. Effect of surface roughness and adhesive system on repair potential of silorane-based resin composite

    Directory of Open Access Journals (Sweden)

    Enas H. Mobarak

    2012-07-01

    Full Text Available This study was performed to evaluate the influence of surface roughness and adhesive system on the repair strength of silorane-based resin composite. Twenty-four substrate discs from silorane-based FiltekP90 were made and stored for 24 h. Half of the discs were roughened against 320 grit SiC paper while the other half was polished against 4000 grit SiC paper. All discs were etched with phosphoric acid. Repair resin composite, FiltekP90 or FiltekZ250, was bonded to the treated surfaces using their corresponding adhesive; P90 System Adhesive (SA or Adper Scotchbond Multipurpose (SBMP ending up with four repair groups. The groups were as follows: G1: Smooth + SA + FiltekP90; G2: Roughened + SA + FiltekP90; G3: Smooth + SBMP + FiltekZ250; G4: Roughened + SBMP + FiltekZ250. Additional six unrepaired discs from each resin composite (G5 and G6 were prepared to test the cohesive strength. After 24 h, discs (n = 6/group were serially sectioned to obtain sticks (n = 30/group for microtensile bond strength (μTBS testing. Scanning electron microscopic (SEM evaluation of substrates that received different treatments as well as representative substrate-repair sticks from each group were performed. Modes of failure were also determined. Two-way ANOVA with Repeated-Measures revealed that surface treatment and repair material had no significant effect on repair bond strength of silorane-based composite material. Paired t-test showed that all repair strength values were significantly lower than the cohesive strength of FiltekP90. Adhesive failure was the predominant mode of failure which was confirmed by SEM. Surface treated FiltekP90 composite showed different textures under SEM whereas phosphoric acid did not produce clear changes. An interaction layer between SBMP adhesive and FiltekZ250 repairing composite was detected. Repair of the silorane composite was successful irrespective of the surface roughness and chemistry of the repair

  13. Mining of lethal recessive genetic variation in Danish cattle

    DEFF Research Database (Denmark)

    Das, Ashutosh

    2015-01-01

    in fertility. The primary objective of this PhD projekt was to identify recessive lethal gentic variants in the main Danish dairy cattle breed. Holstein-Friesian utilzing next generation sequencing (NGS) data. This study shows a potential for the use of the NGS-based reverse genetic approach in identifying...... lethal or semi-lethal recessive gentic variation...

  14. Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines.

    Science.gov (United States)

    Yamamoto, Kimiyo N; Hirota, Kouji; Kono, Koichi; Takeda, Shunichi; Sakamuru, Srilatha; Xia, Menghang; Huang, Ruili; Austin, Christopher P; Witt, Kristine L; Tice, Raymond R

    2011-08-01

    Included among the quantitative high throughput screens (qHTS) conducted in support of the US Tox21 program are those being evaluated for the detection of genotoxic compounds. One such screen is based on the induction of increased cytotoxicity in seven isogenic chicken DT40 cell lines deficient in DNA repair pathways compared to the parental DNA repair-proficient cell line. To characterize the utility of this approach for detecting genotoxic compounds and identifying the type(s) of DNA damage induced, we evaluated nine of 42 compounds identified as positive for differential cytotoxicity in qHTS (actinomycin D, adriamycin, alachlor, benzotrichloride, diglycidyl resorcinol ether, lovastatin, melphalan, trans-1,4-dichloro-2-butene, tris(2,3-epoxypropyl)isocyanurate) and one non-cytotoxic genotoxic compound (2-aminothiamine) for (1) clastogenicity in mutant and wild-type cells; (2) the comparative induction of γH2AX positive foci by melphalan; (3) the extent to which a 72-hr exposure duration increased assay sensitivity or specificity; (4) the use of 10 additional DT40 DNA repair-deficient cell lines to better analyze the type(s) of DNA damage induced; and (5) the involvement of reactive oxygen species in the induction of DNA damage. All compounds but lovastatin and 2-aminothiamine were more clastogenic in at least one DNA repair-deficient cell line than the wild-type cells. The differential responses across the various DNA repair-deficient cell lines provided information on the type(s) of DNA damage induced. The results demonstrate the utility of this DT40 screen for detecting genotoxic compounds, for characterizing the nature of the DNA damage, and potentially for analyzing mechanisms of mutagenesis.

  15. Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells

    Science.gov (United States)

    Sultana, Rebeka; Abdel-Fatah, Tarek; Perry, Christina; Moseley, Paul; Albarakti, Nada; Mohan, Vivek; Seedhouse, Claire; Chan, Stephen; Madhusudan, Srinivasan

    2013-01-01

    Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. Methods In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. Results ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. Conclusions Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells. PMID:23451157

  16. Ataxia telangiectasia mutated and Rad3 related (ATR protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

    Directory of Open Access Journals (Sweden)

    Rebeka Sultana

    Full Text Available INTRODUCTION: Ataxia telangiectasia mutated and Rad3 Related (ATR protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. METHODS: In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO and human ovarian cancer cells using ATR inhibitors (NU6027. In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. RESULTS: ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. CONCLUSIONS: Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells.

  17. Molecular mechanisms of DNA repair inhibition by caffeine

    Energy Technology Data Exchange (ETDEWEB)

    Selby, C.P.; Sancar, A. (Univ. of North Carolina School of Medicine, Chapel Hill (USA))

    1990-05-01

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

  18. Controlled delivery of sonic hedgehog morphogen and its potential for cardiac repair.

    Directory of Open Access Journals (Sweden)

    Noah Ray Johnson

    Full Text Available The morphogen Sonic hedgehog (Shh holds great promise for repair or regeneration of tissues suffering ischemic injury, however clinical translation is limited by its short half-life in the body. Here, we describe a coacervate delivery system which incorporates Shh, protects it from degradation, and sustains its release for at least 3 weeks. Shh released from the coacervate stimulates cardiac fibroblasts to upregulate the expression of multiple trophic factors including VEGF, SDF-1α, IGF-1, and Shh itself, for at least 48 hours. Shh coacervate also demonstrates cytoprotective effects for cardiomyocytes in a hydrogen peroxide-induced oxidative stress environment. In each of these studies the bioactivity of the Shh coacervate is enhanced compared to free Shh. These results warrant further investigation of the in vivo efficacy of Shh coacervate for cardiac repair.

  19. Controlled delivery of sonic hedgehog morphogen and its potential for cardiac repair.

    Science.gov (United States)

    Johnson, Noah Ray; Wang, Yadong

    2013-01-01

    The morphogen Sonic hedgehog (Shh) holds great promise for repair or regeneration of tissues suffering ischemic injury, however clinical translation is limited by its short half-life in the body. Here, we describe a coacervate delivery system which incorporates Shh, protects it from degradation, and sustains its release for at least 3 weeks. Shh released from the coacervate stimulates cardiac fibroblasts to upregulate the expression of multiple trophic factors including VEGF, SDF-1α, IGF-1, and Shh itself, for at least 48 hours. Shh coacervate also demonstrates cytoprotective effects for cardiomyocytes in a hydrogen peroxide-induced oxidative stress environment. In each of these studies the bioactivity of the Shh coacervate is enhanced compared to free Shh. These results warrant further investigation of the in vivo efficacy of Shh coacervate for cardiac repair.

  20. Lethal Midline Granuloma

    Directory of Open Access Journals (Sweden)

    Ghosh S.N

    1995-01-01

    Full Text Available Midline granuloma is a term with several synonyms: Stewart’s granuloma, granuloma gangraenescens nasi, lethal granuloma, polymorphous reticulosis 2-4 The conditiin is characterized by localized inflammation, destruction and often mutilation of tissues of the upper respiratory tract and face and, unless treated, it ends fatally within 12 to 18 months of onset. The pathological changes are those of nonspecific chronic inflammation to necrotizing vasculitis and granulomatosis. A case of lethal midline granuloma is reported.

  1. Transcription inhibition by DRB potentiates recombinational repair of UV lesions in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Ivaylo Stoimenov

    Full Text Available Homologous recombination (HR is intricately associated with replication, transcription and DNA repair in all organisms studied. However, the interplay between all these processes occurring simultaneously on the same DNA molecule is still poorly understood. Here, we study the interplay between transcription and HR during ultraviolet light (UV-induced DNA damage in mammalian cells. Our results show that inhibition of transcription with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB increases the number of UV-induced DNA lesions (γH2AX, 53BP1 foci formation, which correlates with a decrease in the survival of wild type or nucleotide excision repair defective cells. Furthermore, we observe an increase in RAD51 foci formation, suggesting HR is triggered in response to an increase in UV-induced DSBs, while inhibiting transcription. Unexpectedly, we observe that DRB fails to sensitise HR defective cells to UV treatment. Thus, increased RAD51 foci formation correlates with increased cell death, suggesting the existence of a futile HR repair of UV-induced DSBs which is linked to transcription inhibition.

  2. Genipin-crosslinked fibrin hydrogels as a potential adhesive to augment intervertebral disc annulus repair.

    Science.gov (United States)

    Schek, R M; Michalek, A J; Iatridis, J C

    2011-04-18

    Treatment of damaged intervertebral discs is a significant clinical problem and, despite advances in the repair and replacement of the nucleus pulposus, there are few effective strategies to restore defects in the annulus fibrosus. An annular repair material should meet three specifications: have a modulus similar to the native annulus tissue, support the growth of disc cells, and maintain adhesion to tissue under physiological strain levels. We hypothesized that a genipin crosslinked fibrin gel could meet these requirements. Our mechanical results showed that genipin crosslinked fibrin gels could be created with a modulus in the range of native annular tissue. We also demonstrated that this material is compatible with the in vitro growth of human disc cells, when genipin:fibrin ratios were 0.25:1 or less, although cell proliferation was slower and cell morphology more rounded than for fibrin alone. Finally, lap tests were performed to evaluate adhesion between fibrin gels and pieces of annular tissue. Specimens created without genipin had poor handling properties and readily delaminated, while genipin crosslinked fibrin gels remained adhered to the tissue pieces at strains exceeding physiological levels and failed at 15-30%. This study demonstrated that genipin crosslinked fibrin gels show promise as a gap-filling adhesive biomaterial with tunable material properties, yet the slow cell proliferation suggests this biomaterial may be best suited as a sealant for small annulus fibrosus defects or as an adhesive to augment large annulus repairs. Future studies will evaluate degradation rate, fatigue behaviors, and long-term biocompatibility.

  3. Potential of cardiac stem/progenitor cells and induced pluripotent stem cells for cardiac repair in ischaemic heart disease.

    Science.gov (United States)

    Wang, Wei Eric; Chen, Xiongwen; Houser, Steven R; Zeng, Chunyu

    2013-10-01

    Stem cell therapy has emerged as a promising strategy for cardiac and vascular repair. The ultimate goal is to rebuild functional myocardium by transplanting exogenous stem cells or by activating native stem cells to induce endogenous repair. CS/PCs (cardiac stem/progenitor cells) are one type of adult stem cell with the potential to differentiate into cardiac lineages (cardiomyocytes, smooth muscle cells and endothelial cells). iPSCs (induced pluripotent stem cells) also have the capacity to differentiate into necessary cells to rebuild injured cardiac tissue. Both types of stem cells have brought promise for cardiac repair. The present review summarizes recent advances in cardiac cell therapy based on these two cell sources and discusses the advantages and limitations of each candidate. We conclude that, although both types of stem cells can be considered for autologous transplantation with promising outcomes in animal models, CS/PCs have advanced more in their clinical application because iPSCs and their derivatives possess inherent obstacles for clinical use. Further studies are needed to move cell therapy forward for the treatment of heart disease.

  4. Single molecule PCR reveals similar patterns of non-homologous DSB repair in tobacco and Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Andrew H Lloyd

    Full Text Available DNA double strand breaks (DSBs occur constantly in eukaryotes. These potentially lethal DNA lesions are repaired efficiently by two major DSB repair pathways: homologous recombination and non-homologous end joining (NHEJ. We investigated NHEJ in Arabidopsis thaliana and tobacco (Nicotiana tabacum by introducing DNA double-strand breaks through inducible expression of I-SceI, followed by amplification of individual repair junction sequences by single-molecule PCR. Using this process over 300 NHEJ repair junctions were analysed in each species. In contrast to previously published variation in DSB repair between Arabidopsis and tobacco, the two species displayed similar DSB repair profiles in our experiments. The majority of repair events resulted in no loss of sequence and small (1-20 bp deletions occurred at a minority (25-45% of repair junctions. Approximately ~1.5% of the observed repair events contained larger deletions (>20 bp and a similar percentage contained insertions. Strikingly, insertion events in tobacco were associated with large genomic deletions at the site of the DSB that resulted in increased micro-homology at the sequence junctions suggesting the involvement of a non-classical NHEJ repair pathway. The generation of DSBs through inducible expression of I-SceI, in combination with single molecule PCR, provides an effective and efficient method for analysis of individual repair junctions and will prove a useful tool in the analysis of NHEJ.

  5. Single molecule PCR reveals similar patterns of non-homologous DSB repair in tobacco and Arabidopsis.

    Science.gov (United States)

    Lloyd, Andrew H; Wang, Dong; Timmis, Jeremy N

    2012-01-01

    DNA double strand breaks (DSBs) occur constantly in eukaryotes. These potentially lethal DNA lesions are repaired efficiently by two major DSB repair pathways: homologous recombination and non-homologous end joining (NHEJ). We investigated NHEJ in Arabidopsis thaliana and tobacco (Nicotiana tabacum) by introducing DNA double-strand breaks through inducible expression of I-SceI, followed by amplification of individual repair junction sequences by single-molecule PCR. Using this process over 300 NHEJ repair junctions were analysed in each species. In contrast to previously published variation in DSB repair between Arabidopsis and tobacco, the two species displayed similar DSB repair profiles in our experiments. The majority of repair events resulted in no loss of sequence and small (1-20 bp) deletions occurred at a minority (25-45%) of repair junctions. Approximately ~1.5% of the observed repair events contained larger deletions (>20 bp) and a similar percentage contained insertions. Strikingly, insertion events in tobacco were associated with large genomic deletions at the site of the DSB that resulted in increased micro-homology at the sequence junctions suggesting the involvement of a non-classical NHEJ repair pathway. The generation of DSBs through inducible expression of I-SceI, in combination with single molecule PCR, provides an effective and efficient method for analysis of individual repair junctions and will prove a useful tool in the analysis of NHEJ.

  6. Genipin-crosslinked fibrin hydrogels as a potential adhesive to augment intervertebral disc annulus repair

    Directory of Open Access Journals (Sweden)

    RM Schek

    2011-04-01

    Full Text Available Treatment of damaged intervertebral discs is a significant clinical problem and, despite advances in the repair and replacement of the nucleus pulposus, there are few effective strategies to restore defects in the annulus fibrosus. An annular repair material should meet three specifications: have a modulus similar to the native annulus tissue, support the growth of disc cells, and maintain adhesion to tissue under physiological strain levels. We hypothesized that a genipin crosslinked fibrin gel could meet these requirements. Our mechanical results showed that genipin crosslinked fibrin gels could be created with a modulus in the range of native annular tissue. We also demonstrated that this material is compatible with the in vitro growth of human disc cells, when genipin:fibrin ratios were 0.25:1 or less, although cell proliferation was slower and cell morphology more rounded than for fibrin alone. Finally, lap tests were performed to evaluate adhesion between fibrin gels and pieces of annular tissue. Specimens created without genipin had poor handling properties and readily delaminated, while genipin crosslinked fibrin gels remained adhered to the tissue pieces at strains exceeding physiological levels and failed at 15-30%. This study demonstrated that genipin crosslinked fibrin gels show promise as a gap-filling adhesive biomaterial with tunable material properties, yet the slow cell proliferation suggests this biomaterial may be best suited as a sealant for small annulus fibrosus defects or as an adhesive to augment large annulus repairs. Future studies will evaluate degradation rate, fatigue behaviors, and long-term biocompatibility.

  7. Metatropic dysplasia lethal variants

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Christine M. [Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, WCIN 3JH, London (United Kingdom); Elcioglu, Nursel H. [Department of Pediatric Genetics, Marmara University Hospital, Istanbul (Turkey)

    2004-01-01

    Background: The metatropic dysplasia group includes fibrochondrogenesis, Schneckenbecken dysplasia and metatropic dysplasia (various forms). The overlapping features of this group with other dysplasias may cause diagnostic confusion, particularly in perinatal lethal cases. Objective: To attempt to classify the radiological findings of the presented eight sporadic cases based on a broad review of the perinatally lethal metatropic group of conditions and to discuss some overlapping features in the light of current knowledge. Results: The first four cases are of recognised conditions, namely lethal metatropic dysplasia (Type 2) or hyperchondrogenesis, lethal hyperplastic metatropic dysplasia (Type 1) and fibrochondrogenesis. The remaining four cases cannot be categorised accurately and are different from each other but with some features of the metatropic group of dysplasias. Conclusions: The dysplasias within the metatropic dysplasia group are phenotypically distinct from many forms of chondrodysplasia but the pathogenesis still remains poorly understood from the morphological and molecular perspectives. Chondro-osseous morphology might be helpful in all lethal cases especially in our last four cases. (orig.)

  8. The potential of nanoporous anodic aluminium oxide membranes to influence skin wound repair.

    Science.gov (United States)

    Parkinson, Leigh G; Giles, Natalie L; Adcroft, Katharine F; Fear, Mark W; Wood, Fiona M; Poinern, Gerard E

    2009-12-01

    Cells respond to changes in the environment by altering their phenotype. The ability to influence cell behavior by modifying their environment provides an opportunity for therapeutic application, for example, to promote faster wound healing in response to skin injury. Here, we have modified the preparation of an aluminium oxide template to generate large uniform membranes with differing nano-pore sizes. Epidermal cells (keratinocytes) and dermal cells (fibroblasts) readily adhere to these nanoporous membranes. The pore size appears to influence the rate of cell proliferation and migration, important aspects of cell behavior during wound healing. The suitability of the membrane to act as a dressing after a burn injury was assessed in vivo; application of the membrane demonstrated adherence and conformability to the skin surface of a pig, with no observed degradation or detrimental effect on the repair. Our results suggest that keratinocytes are sensitive to changes in topography at the nanoscale level and that this property may be exploited to improve wound repair after tissue injury.

  9. Exploring the potential interference of estuarine sediment contaminants with the DNA repair capacity of human hepatoma cells.

    Science.gov (United States)

    Pinto, Miguel Ferreira; Louro, Henriqueta; Costa, Pedro M; Caeiro, Sandra; Silva, Maria João

    2015-01-01

    Estuaries may be reservoirs of a wide variety of pollutants, including mutagenic and carcinogenic substances that may impact on the ecosystem and human health. A previous study showed that exposure of human hepatoma (HepG2) cells to extracts from sediment samples collected in two areas (urban/industrial and riverine/agricultural) of an impacted estuary (Sado, Portugal), produced differential cytotoxic and genotoxic effects. Those effects were found to be consistent with levels and nature of sediment contamination. The present study aimed at evaluating whether the mixtures of contaminants contained in those extracts were able to modulate DNA repair capacity of HepG2 cells. The residual level of DNA damage was measured by the comet assay in cells exposed for 24 or 48 h to different extracts, after a short preexposure to a challenging concentration range of ethyl methanesulfonate (EMS), as a model alkylating agent. The results suggested that the mixture of contaminants present in the tested samples, besides a potential direct effect on the DNA molecule, may also interfere with DNA repair mechanisms in HepG2 cells, thus impairing their ability to deal with genotoxic stress and, possibly, facilitating accumulation of mutations. Humans are environmentally/occupationally exposed to mixtures rather than to single chemicals. Thus, the observation that estuarine contaminants induce direct and indirect DNA strand breakage in human cells, the latter through the impairment of DNA repair, raises additional concerns regarding potential hazards from exposure and the need to further explore these endpoints in the context of environmental risk assessment.

  10. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    Directory of Open Access Journals (Sweden)

    Daruka Mahadevan

    Full Text Available Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL, while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932 mouse model showed tumor growth inhibition (TGI of ∼ 10-20% (p = 0.001 for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001. M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

  11. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.

    Directory of Open Access Journals (Sweden)

    Ella R Thompson

    2012-09-01

    Full Text Available Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.

  12. Moving stem cells to the clinic: potential and limitations for brain repair.

    Science.gov (United States)

    Steinbeck, Julius A; Studer, Lorenz

    2015-04-08

    Stem cell-based therapies hold considerable promise for many currently devastating neurological disorders. Substantial progress has been made in the derivation of disease-relevant human donor cell populations. Behavioral data in relevant animal models of disease have demonstrated therapeutic efficacy for several cell-based approaches. Consequently, cGMP grade cell products are currently being developed for first in human clinical trials in select disorders. Despite the therapeutic promise, the presumed mechanism of action of donor cell populations often remains insufficiently validated. It depends greatly on the properties of the transplanted cell type and the underlying host pathology. Several new technologies have become available to probe mechanisms of action in real time and to manipulate in vivo cell function and integration to enhance therapeutic efficacy. Results from such studies generate crucial insight into the nature of brain repair that can be achieved today and push the boundaries of what may be possible in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Respiratory displacement of the thoracic aorta: physiological phenomenon with potential implications for thoracic endovascular repair.

    Science.gov (United States)

    Weber, Tim Frederik; Tetzlaff, Ralf; Rengier, Fabian; Geisbüsch, Philipp; Kopp-Schneider, Annette; Böckler, Dittmar; Eichinger, Monika; Kauczor, Hans-Ulrich; von Tengg-Kobligk, Hendrik

    2009-07-01

    The purpose of this study was to assess the magnitude and direction of respiratory displacement of the ascending and descending thoracic aorta during breathing maneuvers. In 11 healthy nonsmokers, dynamic magnetic resonance imaging was performed in transverse orientation at the tracheal bifurcation during maximum expiration and inspiration as well as tidal breathing. The magnitude and direction of aortic displacement was determined relatively to resting respiratory position for the ascending (AA) and descending (DA) aorta. To estimate a respiratory threshold for occurrence of distinct respiratory aortic motion, the latter was related to the underlying change in anterior-posterior thorax diameter. Compound displacement between maximum expiration and inspiration was 24.3 +/- 6.0 mm for the AA in the left anterior direction and 18.2 +/- 5.5 mm for the DA in the right anterior direction. The mean respiratory thorax excursion during tidal breathing was 8.9 +/- 2.8 mm. The respiratory threshold, i.e., the increase in thorax diameter necessary to result in respiratory aortic displacement, was estimated to be 15.7 mm. The data suggest that after a threshold of respiratory thorax excursion is exceeded, respiration is accompanied by significant displacement of the thoracic aorta. Although this threshold may not be reached during tidal breathing in the majority of individuals, segmental differences during forced respiration impact on aortic geometry, may result in additional extrinsic forces on the aortic wall, and may be of significance for aortic prostheses designed for thoracic endovascular aortic repair.

  14. The Emerging Role of TRα1 in Cardiac Repair: Potential Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Constantinos Pantos

    2014-01-01

    Full Text Available Thyroid hormone (TH is critical for adapting living organisms to environmental stress. Plasma circulating tri-iodothyronine (T3 levels drop in most disease states and are associated with increased oxidative stress. In this context, T3 levels in plasma appear to be an independent determinant for the recovery of cardiac function after myocardial infarction in patients. Thyroid hormone receptor α1 (TRα1 seems to be crucial in this response; TRα1 accumulates to cell nucleus upon activation of stress induced growth kinase signaling. Furthermore, overexpression of nuclear TRα1 in cardiomyocytes can result in pathological or physiological growth (dual action in absence or presence of its ligand, respectively. Accordingly, inactivation of TRα1 receptor prevents reactive hypertrophy after myocardial infarction and results in heart failure with increased phospholamban (PLB expression and marked activation of p38MAPK. In line with this evidence, TH is shown to limit ischemia/reperfusion injury and convert pathologic to physiologic growth after myocardial infarction via TRα1 receptor. TRα1 receptor may prove to be a novel pharmacological target for cardiac repair/regeneration therapies.

  15. Retrograde ascending aortic dissection during or after thoracic aortic stent graft placement: insight from the European registry on endovascular aortic repair complications

    DEFF Research Database (Denmark)

    Eggebrecht, Holger; Thompson, Matt; Rousseau, Hervé

    2009-01-01

    BACKGROUND: Single-center reports have identified retrograde ascending aortic dissection (rAAD) as a potentially lethal complication of thoracic endovascular aortic repair (TEVAR). METHODS AND RESULTS: Between 1995 and 2008, 28 centers participating in the European Registry on Endovascular Aortic...

  16. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs.

    Science.gov (United States)

    Jackson, Rebecca A; Chen, Ee Sin

    2016-06-01

    The recent advances in pharmacogenomics have made personalized medicine no longer a pipedream but a precise and powerful way to tailor individualized cancer treatment strategies. Cancer is a devastating disease, and contemporary chemotherapeutic strategies now integrate several agents in the treatment of some types of cancer, with the intent to block more than one target simultaneously. This constitutes the premise of synthetic lethality, an attractive therapeutic strategy already demonstrating clinical success in patients with breast and ovarian cancers. Synthetic lethal combinations offer the potential to also target the hitherto "undruggable" mutations that have challenged the cancer field for decades. However, synthetic lethality in clinical cancer therapy is very much still in its infancy, and selecting the most appropriate combinations-or synthetic lethal pairs-is not always an intuitive process. Here, we review some of the recent progress in identifying synthetic lethal combinations and their potential for therapy and highlight some of the tools through which synthetic lethal pairs are identified.

  17. Wound repair and anti-inflammatory potential of Lonicera japonica in excision wound-induced rats

    Directory of Open Access Journals (Sweden)

    Chen Wei-Cheng

    2012-11-01

    Full Text Available Abstract Background Lonicera japonica Thunb. (Caprifoliaceae, a widely used traditional Chinese medicinal plant, is used to treat some infectious diseases and it may have uses as a healthy food and applications in cosmetics and as an ornamental groundcover. The ethanol extract of the flowering aerial parts of L. japonica (LJEE was investigated for its healing efficiency in a rat excision wound model. Methods Excision wounds were inflicted upon three groups of eight rats each. Healing was assessed by the rate of wound contraction in skin wound sites in rats treated with simple ointment base, 10% (w/w LJEE ointment, or the reference standard drug, 0.2% (w/w nitrofurazone ointment. The effects of LJEE on the contents of hydroxyproline and hexosamine during healing were estimated. The antimicrobial activity of LJEE against microorganisms was also assessed. The in vivo anti-inflammatory activity of LJEE was investigated to understand the mechanism of wound healing. Results LJEE exhibited significant antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans, and Candida tropicalis. The ointment formulation prepared with 10% (w/w LJEE exhibited potent wound healing capacity as evidenced by the wound contraction in the excision wound model. The contents of hydroxyproline and hexosamine also correlated with the observed healing pattern. These findings were supported by the histopathological characteristics of healed wound sections, as greater tissue regeneration, more fibroblasts, and angiogenesis were observed in the 10% (w/w LJEE ointment-treated group. The results also indicated that LJEE possesses potent anti-inflammatory activity, as it enhanced the production of anti-inflammatory cytokines that suppress proinflammatory cytokine production. Conclusions The results suggest that the antimicrobial and anti-inflammatory activities of LJEE act synergistically to accelerate wound repair.

  18. Potential Repair of Escherichia coli DNA following Exposure to UV Radiation from Both Medium- and Low-Pressure UV Sources Used in Drinking Water Treatment

    Science.gov (United States)

    Zimmer, J. L.; Slawson, R. M.

    2002-01-01

    The increased use of UV radiation as a drinking water treatment technology has instigated studies of the repair potential of microorganisms following treatment. This study challenged the repair potential of an optimally grown nonpathogenic laboratory strain of Escherichia coli after UV radiation from low- and medium-pressure lamps. Samples were irradiated with doses of 5, 8, and 10 mJ/cm2 from a low-pressure lamp and 3, 5, 8, and 10 mJ/cm2 from a medium-pressure UV lamp housed in a bench-scale collimated beam apparatus. Following irradiation, samples were incubated at 37°C under photoreactivating light or in the dark. Sample aliquots were analyzed for up to 4 h following incubation using a standard plate count. Results of this study showed that E. coli underwent photorepair following exposure to the low-pressure UV source, but no repair was detectable following exposure to the medium-pressure UV source at the initial doses examined. Minimal repair was eventually observed upon medium-pressure UV lamp exposure when doses were lowered to 3 mJ/cm2. This study clearly indicates differences in repair potential under laboratory conditions between irradiation from low-pressure and medium-pressure UV sources of the type used in water treatment. PMID:12089006

  19. Crash Lethality Model

    Science.gov (United States)

    2014-02-05

    26,800 400 Ethyl Benzene 0.121 40,900 4,900 Ethyl Ether 0.094 33,800 3,200 Gasoline 0.055 43,700 2,400 Hexane 0.074 44,700 3,300 Heptane 0.101...the product of projectile diameter and target weight. The animal lethality data were entered into MATLAB© and the function cftool() was used to...generate a logistic function. The x-axis represents a ratio of kinetic energy to the product of projectile diameter and target weight as defined by

  20. Synthetic lethality-based targets for discovery of new cancer therapeutics.

    Science.gov (United States)

    Weidle, Ulrich H; Maisel, Daniela; Eick, Dirk

    2011-01-01

    Synthetic lethality is based on the incompatibility of cell survival with the loss of function of two or more genes, not with loss of function of a single gene. If targets of synthetic lethality are deregulated or mutated in cancer cells, the strategy of synthetic lethality can result in significant increase of therapeutic efficacy and a favourable therapeutic window. In this review, we discuss synthetic lethality based on deficient DNA repair mechanisms, activating mutations of RAS, loss of function mutations of the tumor suppressor genes p53, Rb and von Hippel-Lindau, and disruption of interactive protein kinase networks in the context of development of new anticancer agents.

  1. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    Directory of Open Access Journals (Sweden)

    Jaan-Olle Andressoo

    2006-10-01

    Full Text Available Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

  2. Intraluminal pressure, transmucosal potential difference, and pH studies in the oesophagus of patients before and after Collis repair of a hiatal hernia

    Science.gov (United States)

    Habibulla, K. S.; Collis, J. Leigh

    1973-01-01

    Intraluminal pressure, transmucosal potential difference, and endo-oesophageal pH measurements were studied in patients with hiatal hernia—before and after a hiatal repair. The operation employed is the Collis (1968) repair for uncomplicated hiatal hernia and does not refer to gastroplasty as recommended for peptic stricture (Collis, 1961). Postoperative studies show that the repair approximates the inferior oesophageal sphincter to the hiatus with the production of a single band of raised pressure at the lower end of the oesophagus. This band is similar to that seen in normal subjects and its appearance was associated with cure of the symptoms, abolition of the gastro-oesophageal reflux, and improvement in the function of the inferior oesophageal sphincter and the musculature of the body of the oesophagus. Certain physiological implications of this study are discussed. Images PMID:4724501

  3. Meniscus repair and regeneration: review on current methods and research potential

    Directory of Open Access Journals (Sweden)

    C Scotti

    2013-01-01

    Full Text Available Meniscus regeneration is an unsolved clinical challenge. Despite the wide acceptance of the degenerative consequences of meniscectomy, no surgical procedure has succeeded to date in regenerating a functional and long-lasting meniscal fibrocartilage. Research proposed a number of experimental approaches encompassing all the typical strategies of regenerative medicine: cell-free scaffolds, gene therapy, intra-articular delivery of progenitor cells, biological glues for enhanced bonding of reparable tears, partial and total tissue engineered meniscus replacement. None of these approaches has been completely successful and can be considered suitable for all patients, as meniscal tears require specific and patient-related treatments depending on the size and type of lesion. Recent advances in cell biology, biomaterial science and bioengineering (e.g., bioreactors have now the potential to drive meniscus regeneration into a series of clinically relevant strategies. In this tutorial paper, the clinical need for meniscus regeneration strategies will be explained, and past and current experimental studies on meniscus regeneration will be reported.

  4. The therapeutic potential of microRNAs in nervous system damage, degeneration, and repair.

    Science.gov (United States)

    Hutchison, Emmette R; Okun, Eitan; Mattson, Mark P

    2009-01-01

    MicroRNAS (miRNAs) have been suggested to play important roles in the central nervous system during development as well as disease. miRNAs appear to be dysregulated in a number of neurodegenerative diseases, developmental disorders, and as a result of stroke. Each miRNA has the ability to regulate hundreds of messenger RNA transcripts, both by causing degradation of the mRNA and by inhibition of protein translation. Recent findings suggest that it may eventually be possible to treat some neurological disorders by restoring or inhibiting miRNAs altered by disease pathology. Both viral delivery and administration of modified oligonucleotides mimicking or inhibiting specific miRNAs have been effective in model systems. Artificial miRNAs have also been generated for the repression of specific transcripts. Alteration of miRNA expression by disease and insult also holds the potential for improved diagnostic tools. Finally, miRNAs have been shown to control cellular proliferation and specification, suggesting that manipulation of miRNAs in cultured cells could result in more convenient generation of pure cell populations for transplantation.

  5. Potential Benefit of the Charge-Stabilized Nanostructure Saline RNS60 for Myelin Maintenance and Repair.

    Science.gov (United States)

    Rao, Vijayaraghava T S; Khan, Damla; Jones, Russell G; Nakamura, Diane S; Kennedy, Timothy E; Cui, Qiao-Ling; Rone, Malena B; Healy, Luke M; Watson, Richard; Ghosh, Supurna; Antel, Jack P

    2016-07-25

    Myelin injury in multiple sclerosis (MS) has been attributed both to "outside-in" primary immune mediated and "inside-out" metabolic stress of oligodendrocyte (OL) related mechanisms. Subsequent remyelination is dependent on recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). RNS60 is a physically-modified saline containing charge-stabilized nanobubbles generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. Administration of RNS60 has been shown to reduce the severity of EAE by dampening the immune response and myelin loss. Additionally, RNS60 has been demonstrated to enhance mitochondrial ATP synthesis in neurons. Here, we used post-natal rat derived OLs and OPCs to assess the impact of RNS60 on the response of OLs to metabolic stress in vitro (glucose-nutrient deprivation, referred to as 'NG') and on OPC differentiation capacity. Under the NG condition, our findings indicate that RNS60 decreases caspases 3/7 activation. Respirometric analyses revealed that RNS60 increased spare glycolytic capacity (SGC) under normal culture conditions. However, RNS60 enhanced OL spare respiratory capacity (SRC) when a metabolic stress was present. Furthermore, we show that RNS60 promotes OPC differentiation under physiological conditions. Our findings provide evidence for the potential therapeutic efficacy of RNS60 through the promotion of OL survival and OPC differentiation.

  6. Mesenchymal stem cells: Potential role in corneal wound repair and transplantation

    Institute of Scientific and Technical Information of China (English)

    Fei; Li; Shao-Zhen; Zhao

    2014-01-01

    Corneal diseases are a major cause of blindness in the world. Although great progress has been achieved in the treatment of corneal diseases, wound healing after severe corneal damage and immunosuppressive therapy after corneal transplantation remain prob-lematic. Mesenchymal stem cells(MSCs) derived from bone marrow or other adult tissues can differentiate into various types of mesenchymal lineages, such as osteocytes, adipocytes, and chondrocytes, both in vivo and in vitro. These cells can further differentiate into specific cell types under specific conditions. MSCs migrate to injury sites and promote wound healing by secreting anti-inflammatory and growth factors. In ad-dition, MSCs interact with innate and acquired immune cells and modulate the immune response through their powerful paracrine function. Over the last decade, MSCs have drawn considerable attention because of their beneficial properties and promising therapeutic prospective. Furthermore, MSCs have been applied to various studies related to wound healing, autoim-mune diseases, and organ transplantation. This review discusses the potential functions of MSCs in protecting corneal tissue and their possible mechanisms in corneal wound healing and corneal transplantation.

  7. Shiga Toxin 1, as DNA Repair Inhibitor, Synergistically Potentiates the Activity of the Anticancer Drug, Mafosfamide, on Raji Cells

    Directory of Open Access Journals (Sweden)

    Piero Sestili

    2013-02-01

    Full Text Available Shiga toxin 1 (Stx1, produced by pathogenic Escherichia coli, targets a restricted subset of human cells, which possess the receptor globotriaosylceramide (Gb3Cer/CD77, causing hemolytic uremic syndrome. In spite of the high toxicity, Stx1 has been proposed in the treatment of Gb3Cer/CD77-expressing lymphoma. Here, we demonstrate in a Burkitt lymphoma cell model expressing this receptor, namely Raji cells, that Stx1, at quasi-non-toxic concentrations (0.05–0.1 pM, inhibits the repair of mafosfamide-induced DNA alkylating lesions, synergistically potentiating the cytotoxic activity of the anticancer drug. Conversely, human promyelocytic leukemia cells HL-60, which do not express Gb3Cer/CD77, were spared by the toxin as previously demonstrated for CD34+ human progenitor cells, and hence, in this cancer model, no additive nor synergistic effects were observed with the combined Stx1/mafosfamide treatment. Our findings suggest that Stx1 could be used to improve the mafosfamide-mediated purging of Gb3Cer/CD77+ tumor cells before autologous bone marrow transplantation.

  8. Derivation of Human Lethal Doses

    Science.gov (United States)

    2006-01-19

    Hardman, JG; Limbird, LE; Goodman Gilman , A, (editors). (2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw... Goodman and Gilman’s N/A No LDLo, MLD, or lethal dose for humans; no LD50 for rat or mouse NIOSH N/A No LDLo, MLD, or lethal dose for humans; no LD50...Basis of Therapeutics– Goodman and Gilman’s N/A No LDLo, MLD, or lethal dose for humans; no LD50 for rat or mouse NIOSH N/A No LDLo, MLD, or lethal

  9. Dominant-lethal mutations and heritable translocations in mice

    Energy Technology Data Exchange (ETDEWEB)

    Generoso, W.M.

    1983-01-01

    Chromosome aberrations are a major component of radiation or chemically induced genetic damage in mammalian germ cells. The types of aberration produced are dependent upon the mutagen used and the germ-cell stage treated. For example, in male meiotic and postmeiotic germ cells certain alkylating chemicals induce both dominant-lethal mutations and heritable translocations while others induce primarily dominant-lethal mutations. Production of these two endpoints appears to be determined by the stability of alkylation products with the chromosomes. If the reaction products are intact in the male chromosomes at the time of sperm entry, they may be repaired in fertilized eggs. If repair is not effected and the alkylation products persist to the time of pronuclear chromosome replication, they lead to chromatid-type aberrations and eventually to dominant-lethality. The production of heritable translocations, on the other hand, requires a transformation of unstable alkylation products into suitable intermediate lesions. The process by which these lesions are converted into chromosome exchange within the male genome takes place after sperm enters the egg but prior to the time of pronuclear chromosome replication (i.e., chromosome-type). Thus, dominant-lethal mutations result from both chromatid- and chromosome-type aberrations while heritable translocations result primarily from the latter type. DNA target sites associated with the production of these two endpoints are discussed.

  10. Evaluation of lethal and non-lethal sampling methods for the detection of white sturgeon iridovirus infection in white sturgeon, Acipenser transmontanus (Richardson).

    Science.gov (United States)

    Drennan, J D; Lapatra, S E; Samson, C A; Ireland, S; Eversman, K F; Cain, K D

    2007-06-01

    Pectoral fin tissue of white sturgeon was investigated as a potential non-lethal sample source for the detection of white sturgeon iridovirus (WSIV) infection. Histopathology and polymerase chain reaction (PCR) results using fin tissue were compared with the standard lethal histopathology sampling method that utilizes head tissue. Tissues for each of the three sampling methods were collected weekly for 8 weeks from individual sturgeon undergoing an experimental cohabitation challenge with fish infected with the Abernathy isolate of WSIV. Non-lethal fin histopathological evaluation did not reveal infection during the first 3 weeks of sampling, while non-lethal PCR and the lethal method were variable. However, all three sampling methods were equally capable of identifying infection from 4 to 8 weeks post-exposure. Of the survivors tested, all were negative by PCR and the lethal method, and only one fish was identified as being positive by non-lethal fin histopathology. In another experiment, all three sampling methods were applied to asymptomatic WSIV carriers in a case study conducted at the Kootenai Tribal Sturgeon Conservation Hatchery. Results showed that both lethal and non-lethal fin histopathology were equally effective in detecting infection, but PCR was unable to identify this strain of WSIV. Depending on the virus isolate, these results suggest that non-lethal sampling of fin tissue (histopathology or PCR) is comparable with the lethal sampling method at identifying WSIV infection once infection is established, and under certain circumstances may provide an alternative to lethal sampling.

  11. XRCC1 and XPD DNA repair gene polymorphisms: a potential risk factor for glaucoma in the Pakistani population

    NARCIS (Netherlands)

    Yousaf, S.; Khan, M.I.; Micheal, S.; Akhtar, F.; Ali, S.H.; Riaz, M.; Ali, M.; Lall, P.; Waheed, N.K.; Hollander, A.I. den; Ahmed, A.; Qamar, R.

    2011-01-01

    PURPOSE: The present study was designed to determine the association of polymorphisms of the DNA repair genes X-ray cross-complementing group 1 (XRCC1) (c.1316G>A [rs25487]) and xeroderma pigmentosum complementation group D (XPD) (c.2298A>C [rs13181]) with primary open-angle glaucoma (POAG) an

  12. Potential of human γD-crystallin for hair damage repair: insights into the mechanical properties and biocompatibility.

    Science.gov (United States)

    Ribeiro, A; Matamá, T; Cruz, C F; Gomes, A C; Cavaco-Paulo, A M

    2013-10-01

    The objective of this work was to develop a new strategy to physically 'repair' chemically damaged hair. Hence the human eye γD-crystallin, a protein from the superfamily characterized structurally by the Greek key motif, was studied. The human γD-crystallin was chosen based on the ability of proteins belonging to this superfamily to be involved in the coating of specific structures. Two crystallins were used on the study, the wild type (Protein Data Bank ID: 1HK0) and the mutant protein. The mutant form was intended to induce a strong and quick protein polymerization as well to have new possible points of anchorage to hair. The ability of both crystallins to bind to damaged hair and even penetrate into its cortex was checked by fluorescence microscopy, confocal microscopy and scanning electron microscopy. Furthermore the reinforcement of hair mechanical resistance, the potential cytotoxic/inflammatory effect of crystallins were studied in order to have a fully comprehension about the protein based formulation. Although the chemical over-bleaching treatment induced a decrease of 20% on the resistance of the hair, the crystallins which bind and penetrate the hair fibre were able to recover and even to improve its mechanical properties when compared to the virgin hair. Moreover none of the crystallins displayed a toxic effect in fibroblasts for all the range of tested concentrations upon 72 h of exposure. The active aggregation process of mutant crystallin induced an inflammatory response in fibroblasts in the first 24 h of contact, measured by the amount of released pro-inflammatory cytokine IL-6 to the medium. In contrast contact with wild type crystallin did not lead to significant inflammation. Outcome from protein formulation characterization supports the hypothesis that the γD-crystallin it is able to recover and improve the mechanical properties of chemical damaged hair. Therefore it can be considered as a very promising strengthening agent for the

  13. DNA repair: Dynamic defenders against cancer and aging

    Energy Technology Data Exchange (ETDEWEB)

    Fuss, Jill O.; Cooper, Priscilla K.

    2006-04-01

    (UV) component of sunlight. NER can be divided into two classes based on where the repair occurs. NER occurring in DNA that is not undergoing transcription (i.e., most of the genome) is called global genome repair (GGR or GGNER), while NER taking place in the transcribed strand of active genes is called transcription-coupled repair (TCR or TC-NER). We will explore NER in more detail below. Mismatch repair (MMR) is another type of excision repair that specifically removes mispaired bases resulting from replication errors. DNA damage can also result in breaks in the DNA backbone, in one or both strands. Single-strand breaks (SSBs) are efficiently repaired by a mechanism that shares common features with the later steps in BER. Double-strand breaks (DSBs) are especially devastating since by definition there is no intact complementary strand to serve as a template for repair, and even one unrepaired DSB can be lethal [3]. In cells that have replicated their DNA prior to cell division, the missing information can be supplied by the duplicate copy, or sister chromatid, and DSBs in these cells are faithfully repaired by homologous recombination involving the exchange of strands of DNA between the two copies. However, most cells in the body are non-dividing, and in these cells the major mechanism for repairing DSBs is by non-homologous end joining (NHEJ), which as the name implies involves joining two broken DNA ends together without a requirement for homologous sequence and which therefore has a high potential for loss of genetic information.

  14. Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine.

    Science.gov (United States)

    Murata, Stephen; Zhang, Catherine; Finch, Nathan; Zhang, Kevin; Campo, Loredana; Breuer, Eun-Kyoung

    2016-01-01

    Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers.

  15. Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

    Directory of Open Access Journals (Sweden)

    Stephen Murata

    2016-01-01

    Full Text Available Poly(ADP-ribose polymerase (PARP inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281 has gained both United States Food and Drug Administration (USFDA and the European Commission (EC approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers.

  16. A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina

    DEFF Research Database (Denmark)

    Soerensen, Mette; Gredilla, Ricardo; Müller-Ohldach, Mathis

    2009-01-01

    . anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage......The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA...... instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the P...

  17. Bundles of spider silk, braided into sutures, resist basic cyclic tests: potential use for flexor tendon repair.

    Directory of Open Access Journals (Sweden)

    Kathleen Hennecke

    Full Text Available Repair success for injuries to the flexor tendon in the hand is often limited by the in vivo behaviour of the suture used for repair. Common problems associated with the choice of suture material include increased risk of infection, foreign body reactions, and inappropriate mechanical responses, particularly decreases in mechanical properties over time. Improved suture materials are therefore needed. As high-performance materials with excellent tensile strength, spider silk fibres are an extremely promising candidate for use in surgical sutures. However, the mechanical behaviour of sutures comprised of individual silk fibres braided together has not been thoroughly investigated. In the present study, we characterise the maximum tensile strength, stress, strain, elastic modulus, and fatigue response of silk sutures produced using different braiding methods to investigate the influence of braiding on the tensile properties of the sutures. The mechanical properties of conventional surgical sutures are also characterised to assess whether silk offers any advantages over conventional suture materials. The results demonstrate that braiding single spider silk fibres together produces strong sutures with excellent fatigue behaviour; the braided silk sutures exhibited tensile strengths comparable to those of conventional sutures and no loss of strength over 1000 fatigue cycles. In addition, the braiding technique had a significant influence on the tensile properties of the braided silk sutures. These results suggest that braided spider silk could be suitable for use as sutures in flexor tendon repair, providing similar tensile behaviour and improved fatigue properties compared with conventional suture materials.

  18. Bundles of Spider Silk, Braided into Sutures, Resist Basic Cyclic Tests: Potential Use for Flexor Tendon Repair

    Science.gov (United States)

    Hennecke, Kathleen; Redeker, Joern; Kuhbier, Joern W.; Strauss, Sarah; Allmeling, Christina; Kasper, Cornelia; Reimers, Kerstin; Vogt, Peter M.

    2013-01-01

    Repair success for injuries to the flexor tendon in the hand is often limited by the in vivo behaviour of the suture used for repair. Common problems associated with the choice of suture material include increased risk of infection, foreign body reactions, and inappropriate mechanical responses, particularly decreases in mechanical properties over time. Improved suture materials are therefore needed. As high-performance materials with excellent tensile strength, spider silk fibres are an extremely promising candidate for use in surgical sutures. However, the mechanical behaviour of sutures comprised of individual silk fibres braided together has not been thoroughly investigated. In the present study, we characterise the maximum tensile strength, stress, strain, elastic modulus, and fatigue response of silk sutures produced using different braiding methods to investigate the influence of braiding on the tensile properties of the sutures. The mechanical properties of conventional surgical sutures are also characterised to assess whether silk offers any advantages over conventional suture materials. The results demonstrate that braiding single spider silk fibres together produces strong sutures with excellent fatigue behaviour; the braided silk sutures exhibited tensile strengths comparable to those of conventional sutures and no loss of strength over 1000 fatigue cycles. In addition, the braiding technique had a significant influence on the tensile properties of the braided silk sutures. These results suggest that braided spider silk could be suitable for use as sutures in flexor tendon repair, providing similar tensile behaviour and improved fatigue properties compared with conventional suture materials. PMID:23613793

  19. Tendon repair

    Science.gov (United States)

    Repair of tendon ... Tendon repair can be performed using: Local anesthesia (the immediate area of the surgery is pain-free) ... a cut on the skin over the injured tendon. The damaged or torn ends of the tendon ...

  20. Tendon Collagen Crosslinking Offers Potential to Improve Suture Pullout in Rotator Cuff Repair: An Ex Vivo Sheep Study.

    Science.gov (United States)

    Camenzind, Roland S; Wieser, Karl; Fessel, Gion; Meyer, Dominik C; Snedeker, Jess G

    2016-08-01

    The suture-tendon interface is often the weakest link in tendon to bone repair of massive rotator cuff tears. Genipin is a low-toxicity collagen crosslinker derived from the gardenia fruit that has been shown to augment collagen tissue strength and mechanically arrest tendon-tear progression. The purpose of the current study was to evaluate whether genipin crosslinking can sufficiently augment the suture-tendon interface to improve suture pullout strength using simple single-loop sutures and the modified Mason-Allen technique. The study also aimed to assess whether time of genipin treatment is a relevant factor in efficacy. In an ex vivo (cadaveric) sheep rotator cuff tendon model, a total of 142 suture pullout tests were performed on 32 infraspinatus tendons. Each tendon was prepared with three single-loop stitches. Two groups were pretreated by incubation in genipin solution for either 4 hours or 24 hours. Two corresponding control groups were incubated in phosphate buffered saline for the same periods. The same test protocol was applied to tendons using modified Mason-Allen technique stitch patterns. Each suture was loaded to failure on a universal materials testing machine. Suture pullout force, stiffness, and work to failure were calculated from force-displacement data, and then compared among the groups. Median single-loop pullout force on tendons incubated for 24 hours in genipin yielded an approximately 30% increase in maximum pullout force for single-loop stitches with a median of 73 N (range, 56-114 N) compared with 56 N (range, 40-69 N; difference of medians = 17 N; p = 0.028), with corresponding increases in the required work to failure but not stiffness. Genipin treatment for 4 hours showed no added benefit for suture-pullout behavior (46 N, [range, 35-95 N] versus 45 N, [range, 28-63 N]; difference of medians, 1 N; p = 1). No tested genipin crosslinking conditions indicated benefit for tendons grasped using the modified Mason-Allen technique after 4

  1. Cognitive Inhibition in Elderly High-Lethality Suicide Attempters

    Science.gov (United States)

    Richard-Devantoy, Stéphane; Szanto, Katalin; Butters, Meryl A.; Kalkus, Jan; Dombrovski, Alexandre Y.

    2014-01-01

    Background People who attempt suicide often display cognitive impairments, particularly poor cognitive control. Could poor cognitive control contribute to high suicide rates in old age? A component of cognitive control, cognitive inhibition – active suppression of task-irrelevant processing – is very sensitive to aging and has been linked to attempted suicide. We investigated cognitive inhibition in older high-lethality suicide attempters, closely resembling suicide victims, as well as low-lethality attempters, and control groups with and without depression and suicidal ideation. Methods 102 participants aged 60+ (17 psychiatrically healthy control subjects, 38 depressed control subjects, 16 suicide ideators, 14 low-lethality suicide attempters, and 17 high-lethality suicide attempters) underwent comprehensive clinical and cognitive assessments. They completed the Delis–Kaplan Executive Function System Color-Word Interference Test, a validated modification of the Stroop test. Results High-lethality suicide attempters demonstrated a distinct pattern of cognitive inhibition deficits. Compared to psychiatrically healthy control subjects and suicide ideators, high-lethality attempters took longer to complete inhibition trials, even after accounting for potential confounding factors (age, education, MMSE score, information processing speed, and accuracy). Compared to non-suicidal depressed and healthy control subjects, low-lethality suicide attempters committed more uncorrected errors; however, this difference was not specific to the inhibition condition. Conclusions Older suicide attempters are a cognitively heterogeneous group. Poor cognitive control in high-lethality attempters may undermine their ability to solve real-life problems, precipitating a catastrophic accumulation of stressors. Meanwhile, low-lethality attempters' poor performance may reflect a careless approach to the task or faulty monitoring. PMID:24816626

  2. INTERNAL REPAIR OF PIPELINES

    Energy Technology Data Exchange (ETDEWEB)

    Bill Bruce; Nancy Porter; George Ritter; Matt Boring; Mark Lozev; Ian Harris; Bill Mohr; Dennis Harwig; Robin Gordon; Chris Neary; Mike Sullivan

    2005-07-20

    The two broad categories of fiber-reinforced composite liner repair and deposited weld metal repair technologies were reviewed and evaluated for potential application for internal repair of gas transmission pipelines. Both are used to some extent for other applications and could be further developed for internal, local, structural repair of gas transmission pipelines. Principal conclusions from a survey of natural gas transmission industry pipeline operators can be summarized in terms of the following performance requirements for internal repair: (1) Use of internal repair is most attractive for river crossings, under other bodies of water, in difficult soil conditions, under highways, under congested intersections, and under railway crossings. (2) Internal pipe repair offers a strong potential advantage to the high cost of horizontal direct drilling when a new bore must be created to solve a leak or other problem. (3) Typical travel distances can be divided into three distinct groups: up to 305 m (1,000 ft.); between 305 m and 610 m (1,000 ft. and 2,000 ft.); and beyond 914 m (3,000 ft.). All three groups require pig-based systems. A despooled umbilical system would suffice for the first two groups which represents 81% of survey respondents. The third group would require an onboard self-contained power unit for propulsion and welding/liner repair energy needs. (4) The most common size range for 80% to 90% of operators surveyed is 508 mm (20 in.) to 762 mm (30 in.), with 95% using 558.8 mm (22 in.) pipe. Evaluation trials were conducted on pipe sections with simulated corrosion damage repaired with glass fiber-reinforced composite liners, carbon fiber-reinforced composite liners, and weld deposition. Additional un-repaired pipe sections were evaluated in the virgin condition and with simulated damage. Hydrostatic failure pressures for pipe sections repaired with glass fiber-reinforced composite liner were only marginally greater than that of pipe sections without

  3. INTERNAL REPAIR OF PIPELINES

    Energy Technology Data Exchange (ETDEWEB)

    Robin Gordon; Bill Bruce; Ian Harris; Dennis Harwig; George Ritter; Bill Mohr; Matt Boring; Nancy Porter; Mike Sullivan; Chris Neary

    2004-12-31

    The two broad categories of fiber-reinforced composite liner repair and deposited weld metal repair technologies were reviewed and evaluated for potential application for internal repair of gas transmission pipelines. Both are used to some extent for other applications and could be further developed for internal, local, structural repair of gas transmission pipelines. Principal conclusions from a survey of natural gas transmission industry pipeline operators can be summarized in terms of the following performance requirements for internal repair: (1) Use of internal repair is most attractive for river crossings, under other bodies of water, in difficult soil conditions, under highways, under congested intersections, and under railway crossings. (2) Internal pipe repair offers a strong potential advantage to the high cost of horizontal direct drilling when a new bore must be created to solve a leak or other problem. (3) Typical travel distances can be divided into three distinct groups: up to 305 m (1,000 ft.); between 305 m and 610 m (1,000 ft. and 2,000 ft.); and beyond 914 m (3,000 ft.). All three groups require pig-based systems. A despooled umbilical system would suffice for the first two groups which represents 81% of survey respondents. The third group would require an onboard self-contained power unit for propulsion and welding/liner repair energy needs. (4) The most common size range for 80% to 90% of operators surveyed is 508 mm (20 in.) to 762 mm (30 in.), with 95% using 558.8 mm (22 in.) pipe. Evaluation trials were conducted on pipe sections with simulated corrosion damage repaired with glass fiber-reinforced composite liners, carbon fiber-reinforced composite liners, and weld deposition. Additional un-repaired pipe sections were evaluated in the virgin condition and with simulated damage. Hydrostatic failure pressures for pipe sections repaired with glass fiber-reinforced composite liner were only marginally greater than that of pipe sections without

  4. Synthetic lethality between PAXX and XLF in mammalian development

    Science.gov (United States)

    Balmus, Gabriel; Barros, Ana C.; Wijnhoven, Paul W.G.; Lescale, Chloé; Hasse, Hélène Lenden; Boroviak, Katharina; le Sage, Carlos; Doe, Brendan; Speak, Anneliese O.; Galli, Antonella; Jacobsen, Matt; Deriano, Ludovic; Adams, David J.; Jackson, Stephen P.

    2016-01-01

    PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf−/− mice, Paxx−/− mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4−/− and Lig4−/− mice. Thus, combined loss of Paxx and Xlf is synthetic-lethal in mammals. PMID:27798842

  5. Bladder exstrophy repair

    Science.gov (United States)

    Bladder birth defect repair; Everted bladder repair; Exposed bladder repair; Repair of bladder exstrophy ... Bladder exstrophy repair involves two surgeries. The first surgery is to repair the bladder and the second one is to attach ...

  6. [The "lethal white foal" syndrome].

    Science.gov (United States)

    Blendinger, C; Müller, G; Bostedt, H

    1994-06-01

    The lethal white foal syndrome (congenital intestinal aganglionosis) was diagnosed by history, clinical signs and pathological findings in a female foal, born in March 1992, that was an offspring of two overo-spotted paint horses. The syndrome is a congenital innervation defect of the gastrointestinal tract. A literature review of this condition, relatively unknown in Germany, is given.

  7. Exogenous Oct4 in combination with valproic acid increased neural progenitor markers: an approach for enhancing the repair potential of the brain.

    Science.gov (United States)

    Dehghan, Samaneh; Asadi, Sareh; Hajikaram, Maryam; Soleimani, Masoud; Mowla, Seyed Javad; Fathollahi, Yaghoub; Ahmadiani, Abolhassan; Javan, Mohammad

    2015-02-01

    Attempts are aimed to introduce new approaches toward enhancing the brain's potential for repair in neurodegenerative diseases and traumatic injuries. Here we report an increased expression of pluripotency and progenitor markers within the brain following pretreatment with valproic acid (VPA) and in vivo transfection of inducible Oct4-expressing viral particles. Systemic administration of VPA was performed for one week prior to an intracerebroventricular injection of the Oct4-expressing vector into the right side of the brain. Oct4 expression was induced by doxycycline from day 1 post-transfection for an additional week. Real time-PCR and immunohistofluorescence were used for evaluation of marker expression. Real time-PCR analyses of samples collected from the area of transfection within the injected-lateral ventricle revealed increased expression of some stem cell and progenitor markers, which included endogenous Oct4, Nanog, Klf4, c-Myc, Pax6 and Sox1. Expressions of Oct4, SSEA1 and Nanog were further confirmed by immunohistofluorescence. The increased neural progenitor and pluripotency markers due to Oct4 overexpression did not lead to teratoma formation during a 100day follow-up. Our findings suggest that the application of Oct4 as a reprogramming factor in conjunction with VPA, an epigenetic modifier, might be a potential strategy for increasing the brain's capability to repair itself. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. INTERNAL REPAIR OF PIPELINES

    Energy Technology Data Exchange (ETDEWEB)

    Robin Gordon; Bill Bruce; Ian Harris; Dennis Harwig; George Ritter; Bill Mohr; Matt Boring; Nancy Porter; Mike Sullivan; Chris Neary

    2004-08-17

    The two broad categories of fiber-reinforced composite liner repair and deposited weld metal repair technologies were reviewed and evaluated for potential application for internal repair of gas transmission pipelines. Both are used to some extent for other applications and could be further developed for internal, local, structural repair of gas transmission pipelines. Principal conclusions from a survey of natural gas transmission industry pipeline operators can be summarized in terms of the following performance requirements for internal repair: (1) Use of internal repair is most attractive for river crossings, under other bodies of water, in difficult soil conditions, under highways, under congested intersections, and under railway. (2) Internal pipe repair offers a strong potential advantage to the high cost of horizontal direct drilling when a new bore must be created to solve a leak or other problem. (3) Typical travel distances can be divided into three distinct groups: up to 305 m (1,000 ft.); between 305 m and 610 m (1,000 ft. and 2,000 ft.); and beyond 914 m (3,000 ft.). All three groups require pig-based systems. A despooled umbilical system would suffice for the first two groups which represents 81% of survey respondents. The third group would require an onboard self-contained power unit for propulsion and welding/liner repair energy needs. (4) The most common size range for 80% to 90% of operators surveyed is 508 mm (20 in.) to 762 mm (30 in.), with 95% using 558.8 mm (22 in.) pipe. Evaluation trials were conducted on pipe sections with simulated corrosion damage repaired with glass fiber-reinforced composite liners, carbon fiber-reinforced composite liners, and weld deposition. Additional un-repaired pipe sections were evaluated in the virgin condition and with simulated damage. Hydrostatic failure pressures for pipe sections repaired with glass fiber-reinforced composite liner were only marginally greater than that of pipe sections without liners

  9. Endovascular repair of ruptured abdominal aortic aneurysm

    Directory of Open Access Journals (Sweden)

    Šarac Momir

    2014-01-01

    Full Text Available Introduction. Rupture of an abdominal aortic aneurysm (AAA is a potentially lethal state. Only half of patients with ruptured AAA reach the hospital alive. The alternative for open reconstruction of this condition is endovascular repair (EVAR. We presented a successful endovascular reapir of ruptured AAA in a patient with a number of comorbidities. Case report. A 60-year-old man was admitted to our institution due to diffuse abdominal pain with flatulence and belching. Initial abdominal ultrasonography showed an AAA that was confirmed on multislice computed tomography scan angiography which revealed a large retroperitoneal haematoma. Because of patient’s comorbidites (previous surgery of laryngeal carcinoma and one-third laryngeal stenosis, arterial hypertension and cardiomyopathy with left ventricle ejection fraction of 30%, stenosis of the right internal carotid artery of 80% it was decided that endovascular repair of ruptured AAA in local anaesthesia and analgosedation would be treatment of choice. Endovascular grafting was achieved with aorto-bi-iliac bifurcated excluder endoprosthesis with complete exclusion of the aneurysmal sac, without further enlargment of haemathoma and no contrast leakage. The postoperative course of the patient was eventless, without complications. On recall examination 3 months after, the state of the patient was well. Conclusion. The alternative for open reconstruction of ruptured AAA in haemodynamically stable patients with suitable anatomy and comorbidities could be emergency EVAR in local anesthesia. This technique could provide greater chances for survival with lower intraoperative and postoperative morbidity and mortality, as shown in the presented patient.

  10. Laparoscopic repair of postoperative perineal hernia.

    LENUS (Irish Health Repository)

    Ryan, Stephen

    2010-01-01

    Perineal hernias are infrequent complications following abdominoperineal operations. Various approaches have been described for repair of perineal hernias including open transabdominal, transperineal or combined abdominoperineal repairs. The use of laparoscopic transabdominal repair of perineal hernias is not well-described. We present a case report demonstrating the benefits of laparoscopic repair of perineal hernia following previous laparoscopic abdominoperineal resection (APR) using a nonabsorbable mesh to repair the defect. We have demonstrated that the use of laparoscopy with repair of the pelvic floor defect using a non absorbable synthetic mesh offers an excellent alternative with many potential advantages over open transabdominal and transperineal repairs.

  11. Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

    Directory of Open Access Journals (Sweden)

    Hicks Steven D

    2012-10-01

    Full Text Available Abstract Background Alcohol use disorders (AUDs lead to alterations in central nervous system (CNS architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1 was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5 showed a highly significant correlation with AUD-induced decreases in the volume of the left

  12. Turbulent kinetic energy in the right ventricle: Potential MR marker for risk stratification of adults with repaired Tetralogy of Fallot.

    Science.gov (United States)

    Fredriksson, Alexandru; Trzebiatowska-Krzynska, Aleksandra; Dyverfeldt, Petter; Engvall, Jan; Ebbers, Tino; Carlhäll, Carl-Johan

    2017-08-02

    To assess right ventricular (RV) turbulent kinetic energy (TKE) in patients with repaired Tetralogy of Fallot (rToF) and a spectrum of pulmonary regurgitation (PR), as well as to investigate the relationship between these 4D flow markers and RV remodeling. Seventeen patients with rToF and 10 healthy controls were included in the study. Patients were divided into two groups based on PR fraction: one lower PR fraction group (≤11%) and one higher PR fraction group (>11%). Field strength/sequences: 3D cine phase contrast (4D flow), 2D cine phase contrast (2D flow), and balanced steady-state free precession (bSSFP) at 1.5T. The RV volume was segmented in the morphologic short-axis images and TKE parameters were computed inside the segmented RV volume throughout diastole. Statistical tests: One-way analysis of variance with Bonferroni post-hoc test; unpaired t-test; Pearson correlation coefficients; simple and stepwise multiple regression models; intraclass correlation coefficient (ICC). The higher PR fraction group had more remodeled RVs (140 ± 25 vs. 107 ± 22 [lower PR fraction, P < 0.01] and 93 ± 15 ml/m(2) [healthy, P < 0.001] for RV end-diastolic volume index [RVEDVI]) and higher TKE values (5.95 ± 3.15 vs. 2.23 ± 0.81 [lower PR fraction, P < 0.01] and 1.91 ± 0.78 mJ [healthy, P < 0.001] for Peak Total RV TKE). Multiple regression analysis between RVEDVI and 4D/2D flow parameters showed that Peak Total RV TKE was the strongest predictor of RVEDVI (R(2)  = 0.47, P = 0.002). The 4D flow-specific TKE markers showed a slightly stronger association with RV remodeling than conventional 2D flow PR parameters. These results suggest novel hemodynamic aspects of PR in the development of late complications after ToF repair. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  13. Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations.

    Science.gov (United States)

    Hicks, Steven D; Lewis, Lambert; Ritchie, Julie; Burke, Patrick; Abdul-Malak, Ynesse; Adackapara, Nyssa; Canfield, Kelly; Shwarts, Erik; Gentile, Karen; Meszaros, Zsuzsa Szombathyne; Middleton, Frank A

    2012-10-25

    Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal gyrus and

  14. Sugar-coating wound repair: a review of FGF-10 and dermatan sulfate in wound healing and their potential application in burn wounds.

    Science.gov (United States)

    Plichta, Jennifer K; Radek, Katherine A

    2012-01-01

    Thousands of patients suffer from burn injuries each year, yet few therapies have been developed to accelerate the wound healing process. Most fibroblast growth factors (FGFs) have been extensively evaluated but only a few have been found to participate in the wound healing process. In particular, FGF-10 is robustly increased in the wound microenvironment after injury and has demonstrated some ability to promote wound healing in vitro and in vivo. Glycosaminoglycans are linear carbohydrates that participate in wound repair by influencing cytokine/growth factor localization and interaction with cognate receptors. Dermatan sulfate (DS) is the most abundant glycosaminoglycan in human wound fluid and has been postulated to be directly involved in the healing process. Recently, the combination of FGF-10 and DS demonstrated the potential to accelerate wound healing via increased keratinocyte proliferation and migration. Based on these preliminary studies, DS may serve as a cofactor for FGF-10, and together they are likely to expedite the healing process by stimulating keratinocyte activity. As a specific subtype of wounds, the overall healing process of burn injuries does not significantly differ from other types of wounds, where optimal repair results in matrix regeneration and complete reepithelialization. At present, standard burn treatment primarily involves topical application of antimicrobial agents, while no routine therapies target acceleration of reepithelialization, the key to wound closure. Thus, this novel therapeutic combination could be used in conjunction with some of the current therapies, but it would have the unique ability to initiate wound healing by stimulating keratinocyte epithelialization.

  15. Reduced repair capacity of a DNA clustered damage site comprised of 8-oxo-7,8-dihydro-2′-deoxyguanosine and 2-deoxyribonolactone results in an increased mutagenic potential of these lesions

    Energy Technology Data Exchange (ETDEWEB)

    Cunniffe, Siobhan [CRUK-MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ (United Kingdom); O’Neill, Peter, E-mail: peter.oneill@oncology.ox.ac.uk [CRUK-MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ (United Kingdom); Greenberg, Marc M. [Johns Hopkins University, Department of Chemistry, 3400 N. Charles St. , Baltimore, MD 21218 (United States); Lomax, Martine E. [CRUK-MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ (United Kingdom)

    2014-04-15

    Highlights: • A dL lesion is not repaired as effectively as an AP site. • The repair of a cluster with dL and 8-oxodGuo lesions is compromised. • Delayed repair of the cluster leads to an increase in mutation frequency. - Abstract: A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase β, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL.

  16. 3D bioprinting of neural stem cell-laden thermoresponsive biodegradable polyurethane hydrogel and potential in central nervous system repair.

    Science.gov (United States)

    Hsieh, Fu-Yu; Lin, Hsin-Hua; Hsu, Shan-Hui

    2015-12-01

    The 3D bioprinting technology serves as a powerful tool for building tissue in the field of tissue engineering. Traditional 3D printing methods involve the use of heat, toxic organic solvents, or toxic photoinitiators for fabrication of synthetic scaffolds. In this study, two thermoresponsive water-based biodegradable polyurethane dispersions (PU1 and PU2) were synthesized which may form gel near 37 °C without any crosslinker. The stiffness of the hydrogel could be easily fine-tuned by the solid content of the dispersion. Neural stem cells (NSCs) were embedded into the polyurethane dispersions before gelation. The dispersions containing NSCs were subsequently printed and maintained at 37 °C. The NSCs in 25-30% PU2 hydrogels (∼680-2400 Pa) had excellent proliferation and differentiation but not in 25-30% PU1 hydrogels. Moreover, NSC-laden 25-30% PU2 hydrogels injected into the zebrafish embryo neural injury model could rescue the function of impaired nervous system. However, NSC-laden 25-30% PU1 hydrogels only showed a minor repair effect in the zebrafish model. In addition, the function of adult zebrafish with traumatic brain injury was rescued after implantation of the 3D-printed NSC-laden 25% PU2 constructs. Therefore, the newly developed 3D bioprinting technique involving NSCs embedded in the thermoresponsive biodegradable polyurethane ink offers new possibilities for future applications of 3D bioprinting in neural tissue engineering.

  17. Potential Role of Dentin Sialoprotein by Inducing Dental Pulp Mesenchymal Stem Cell Differentiation and Mineralization for Dental Tissue Repair

    Directory of Open Access Journals (Sweden)

    Zhi Chen

    2010-09-01

    Full Text Available Introduction: Dentin sialoprotein (DSP is a dentin extracellular matrix protein, a unique marker of dentinogenesis and plays a vital role in odontoblast differentiation and dentin mineralization. Recently, studies have shown that DSP induces differentiation and mineralization of periodontal ligament stem cells and dental papilla mesenchymal cells in vitro and rescues dentin deficiency and increases enamel mineralization in animal models.The hypothesis: DSP as a nature therapeutic agent stimulates dental tissue repair by inducing endogenous dental pulp mesenchymal stem/progenitor cells into odontoblast-like cells to synthesize and to secrete dentin extracellular matrix forming new tertiary dentin as well as to regenerate a functional dentin-pulp complex. As DSP is a nature protein, and clinical procedure for DSP therapy is easy and simple, application of DSP may provide a new avenue for dentists with additional option for the treatment of substantially damaged vital teeth.Evaluation of the hypothesis: Dental caries is the most common dental disease. Deep caries and pulp exposure have been treated by various restorative materials with limited success. One promising approach is dental pulp stem/progenitor-based therapies to regenerate dentin-pulp complex and restore its functions by DSP induction in vivo.

  18. Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression

    Institute of Scientific and Technical Information of China (English)

    Guogen Mao; Fenghua Yuan; Kimberly Absher; C Darrell Jennings; Dianna S Howard; Craig T Jordan; Liya Gu

    2008-01-01

    Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.

  19. INTERNAL REPAIR OF PIPELINES

    Energy Technology Data Exchange (ETDEWEB)

    Robin Gordon; Bill Bruce; Ian Harris; Dennis Harwig; Nancy Porter; Mike Sullivan; Chris Neary

    2004-04-12

    The two broad categories of deposited weld metal repair and fiber-reinforced composite liner repair technologies were reviewed for potential application for internal repair of gas transmission pipelines. Both are used to some extent for other applications and could be further developed for internal, local, structural repair of gas transmission pipelines. Preliminary test programs were developed for both deposited weld metal repair and for fiber-reinforced composite liner repair. Evaluation trials have been conducted using a modified fiber-reinforced composite liner provided by RolaTube and pipe sections without liners. All pipe section specimens failed in areas of simulated damage. Pipe sections containing fiber-reinforced composite liners failed at pressures marginally greater than the pipe sections without liners. The next step is to evaluate a liner material with a modulus of elasticity approximately 95% of the modulus of elasticity for steel. Preliminary welding parameters were developed for deposited weld metal repair in preparation of the receipt of Pacific Gas & Electric's internal pipeline welding repair system (that was designed specifically for 559 mm (22 in.) diameter pipe) and the receipt of 559 mm (22 in.) pipe sections from Panhandle Eastern. The next steps are to transfer welding parameters to the PG&E system and to pressure test repaired pipe sections to failure. A survey of pipeline operators was conducted to better understand the needs and performance requirements of the natural gas transmission industry regarding internal repair. Completed surveys contained the following principal conclusions: (1) Use of internal weld repair is most attractive for river crossings, under other bodies of water, in difficult soil conditions, under highways, under congested intersections, and under railway crossings. (2) Internal pipe repair offers a strong potential advantage to the high cost of horizontal direct drilling (HDD) when a new bore must be created

  20. Non-lethal weapons and their characteristics

    OpenAIRE

    DAMJANOVIC DRAGAN Z.

    2015-01-01

    Non-lethal weapons, also called less-lethal weapons, less-than lethal weapons, non-deadly weapons, compliance weapons, or pain-inducing weapons are weapons intended to be less likely to kill a living target than conventional weapons. It is often understood that accidental, incidental, and correlative casualties are risked wherever force is applied, but non-lethal weapons try to minimise the risk as much as possible. Non-lethal weapons are used in combat situations to limit the escalation of c...

  1. NON-LETHAL WEAPONS AND THEIR CHARACTERISTICS

    OpenAIRE

    2015-01-01

    Non-lethal weapons, also called less-lethal weapons, less-than lethal weapons, non-deadly weapons, compliance weapons, or pain-inducing weapons are weapons intended to be less likely to kill a living target than conventional weapons. It is often understood that accidental, incidental, and correlative casualties are risked wherever force is applied, but non-lethal weapons try to minimise the risk as much as possible. Non-lethal weapons are used in combat situations to limit the escalation of c...

  2. Repair-dependent cell radiation survival and transformation: an integrated theory.

    Science.gov (United States)

    Sutherland, John C

    2014-09-07

    The repair-dependent model of cell radiation survival is extended to include radiation-induced transformations. The probability of transformation is presumed to scale with the number of potentially lethal damages that are repaired in a surviving cell or the interactions of such damages. The theory predicts that at doses corresponding to high survival, the transformation frequency is the sum of simple polynomial functions of dose; linear, quadratic, etc, essentially as described in widely used linear-quadratic expressions. At high doses, corresponding to low survival, the ratio of transformed to surviving cells asymptotically approaches an upper limit. The low dose fundamental- and high dose plateau domains are separated by a downwardly concave transition region. Published transformation data for mammalian cells show the high-dose plateaus predicted by the repair-dependent model for both ultraviolet and ionizing radiation. For the neoplastic transformation experiments that were analyzed, the data can be fit with only the repair-dependent quadratic function. At low doses, the transformation frequency is strictly quadratic, but becomes sigmodial over a wider range of doses. Inclusion of data from the transition region in a traditional linear-quadratic analysis of neoplastic transformation frequency data can exaggerate the magnitude of, or create the appearance of, a linear component. Quantitative analysis of survival and transformation data shows good agreement for ultraviolet radiation; the shapes of the transformation components can be predicted from survival data. For ionizing radiations, both neutrons and x-rays, survival data overestimate the transforming ability for low to moderate doses. The presumed cause of this difference is that, unlike UV photons, a single x-ray or neutron may generate more than one lethal damage in a cell, so the distribution of such damages in the population is not accurately described by Poisson statistics. However, the complete

  3. DNA replication, repair, and repair tests. [Rat; human leukocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lambert, B.

    1980-09-01

    The rate of inhibition and recovery of DNA synthesis can be used in a rapid assay system to detect genotoxic potentials of chemicals. Also, the observation that an agent stimulates DNA repair in a test system indicates its ability to cause damage in DNA. Different experimental approaches to the study of repair synthesis are discussed.

  4. Hypospadias repair

    Science.gov (United States)

    ... the problem. If the repair is not done, problems may occur later on such as: Difficulty controlling and directing urine stream A curve in the penis during erection Decreased fertility Embarrassment about appearance of penis Surgery ...

  5. Co-lethality studied as an asset against viral drug escape: the HIV protease case

    Directory of Open Access Journals (Sweden)

    Ollivier Emmanuelle

    2010-06-01

    Full Text Available Abstract Background Co-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL or a co-lethal. Like invariant positions, SL sets (SL linked couples are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic lethality. Results From an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap, 4 (in the cantilever and 5 (in the fulcrum amino acid positions were found. Conclusions These three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains. Reviewers This article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke.

  6. Inducible repair of oxidative DNA damage in Escherichia coli.

    Science.gov (United States)

    Demple, B; Halbrook, J

    Hydrogen peroxide is lethal to many cell types, including the bacterium Escherichia coli. Peroxides yield transient radical species that can damage DNA and cause mutations. Such partially reduced oxygen species are occasionally released during cellular respiration and are generated by lethal and mutagenic ionizing radiation. Because cells live in an environment where the threat of oxidative DNA damage is continual, cellular mechanisms may have evolved to avoid and repair this damage. Enzymes are known which evidently perform these functions. We report here that resistance to hydrogen peroxide toxicity can be induced in E. coli, that this novel induction is specific and occurs, in part, at the level of DNA repair.

  7. Femoral hernia repair

    Science.gov (United States)

    Femorocele repair; Herniorrhaphy; Hernioplasty - femoral ... During surgery to repair the hernia, the bulging tissue is pushed back in. The weakened area is sewn closed or strengthened. This repair ...

  8. Undescended testicle repair

    Science.gov (United States)

    Orchidopexy; Inguinal orchidopexy; Orchiopexy; Repair of undescended testicle; Cryptorchidism repair ... first year of life without treatment. Undescended testicle repair surgery is recommended for patients whose testicles do ...

  9. Inhibition of proliferation of osteosarcoma by nano calcium phosphates:potential hard tissue repair after tumor extraction

    Institute of Scientific and Technical Information of China (English)

    HU Qinghong; CAI Yurong; SHI Zbongli; YAN Weiqi; TANG Ruikang

    2007-01-01

    Spherical- or cylindrical-shaped nanosized cal-cium phosphate particles are considered as an integral part of biological hard tissues such as bone and tooth enamel.Thes ize effects of these nanoparticles were evaluated by cocultur-ing osteosarcoma (U2OS) cells on their films or in their aque-ous suspensions.Experimental results demonstrated that these nanophase minerals could inhibit the proliferations of U2OS significantly.The effects were increased with decreas-ing particle sizes,and the 20-nm sized calcium phosphate,the basic building blocks during bone/enamel formations,was the most effective inhibitor.The particle size is believed to play an important role on cellular behaviors and this in vitro study suggested the potential of calcium phosphate nanopar-ticles for use in therapeutic replacement and reconstruction of bone merits after tumor extractions.

  10. Biomimetic Preparation of Magnetite/Chitosan Nanocomposite via In Situ Composite Method——Potential Use in Magnetic Tissue Repair Domain

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    This study focused on the preparation of magnetic chitosan nanocomposite that has a potential application to bone repair and regeneration using an in situ composite method where chitosan membrane was used as the template and NaOH was used as the precipitant. X-ray diffraction analysis results show the formation of magnetite in the chitosan matrix. From the magnetic measurement, it could be concluded that the magnetic chitosan rods were superparamagnetic,and that this is the unique property of nanomagnetite. Macroscopical layer structure of the magnetic chitosan rods was observed from the photographs after mechanical test, and the microlayer structure of the rods was observed from the images of scanning electron microscopy. The mechanism for preparing the rods was discussed in detail. Transmission electron microscope was used to investigate the magnetite particles in the chitosan matrix and from the images it was concluded that the magnetite particles dispersed well in chitosan matrix with particle size of about 10 nm. The mechanical properties of the magnetic chitosan rods were measured and the blending strength was found to be 98.8 MPa. The mechanical properties did not decline when compared with those of the pure chitosan materials.

  11. Porous polymer scaffold for on-site delivery of stem cells--Protects from oxidative stress and potentiates wound tissue repair.

    Science.gov (United States)

    Geesala, Ramasatyaveni; Bar, Nimai; Dhoke, Neha R; Basak, Pratyay; Das, Amitava

    2016-01-01

    Wound healing by cell transplantation techniques often suffer setbacks due to oxidative stress encountered at injury sites. A porous polyethyleneglycol-polyurethane (PEG-PU) scaffold that facilitates cell delivery and boosts tissue repair was developed through semi-interpenetrating polymer network approach. The key physico-chemical properties assessed confirms these polymeric matrices are highly thermostable, barostable, degrade at an acidic pH (5.8), biodegradable, cytocompatible and possess excellent porosity. Mechanism of cellular penetration into porous polymer networks was evident by a ≥6 - fold increase in gene expression of MMP-13 and MMP-2 via activation of Akt and Erk. H2O2-induced apoptosis of mouse bone marrow stem cells (BMSCs) was abrogated in presence of polymer networks indicating a protective effect from oxidative stress. Transplantation of BMSC + PEG-PU at murine excisional splint wound site depicted significant increase in fibroblast proliferation, collagen deposition, anti-oxidant enzyme activities of catalase, SOD and GPx. Furthermore it significantly decreased expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, etc) with a concomitant increase in anti-inflammatory cytokines (IL-10, IL-13) at an early healing period of day 7. Finally, immunostaining revealed an enhanced engraftment and vascularity indicating an accelerated wound tissue closure. This pre-clinical study demonstrates the proof-of-concept and further necessitates their clinical evaluation as potential cell delivery vehicle scaffolds.

  12. Electromagnetic field stimulation potentiates endogenous myelin repair by recruiting subventricular neural stem cells in an experimental model of white matter demyelination.

    Science.gov (United States)

    Sherafat, Mohammad Amin; Heibatollahi, Motahareh; Mongabadi, Somayeh; Moradi, Fatemeh; Javan, Mohammad; Ahmadiani, Abolhassan

    2012-09-01

    Electromagnetic fields (EMFs) may affect the endogenous neural stem cells within the brain. The aim of this study was to assess the effects of EMFs on the process of toxin-induced demyelination and subsequent remyelination. Demyelination was induced using local injection of lysophosphatidylcholine within the corpus callosum of adult female Sprague-Dawley rats. EMFs (60 Hz; 0.7 mT) were applied for 2 h twice a day for 7, 14, or 28 days postlesion. BrdU labeling and immunostaining against nestin, myelin basic protein (MBP), and BrdU were used for assessing the amount of neural stem cells within the tissue, remyelination patterns, and tracing of proliferating cells, respectively. EMFs significantly reduced the extent of demyelinated area and increased the level of MBP staining within the lesion area on days 14 and 28 postlesion. EMFs also increased the number of BrdU- and nestin-positive cells within the area between SVZ and lesion as observed on days 7 and 14 postlesion. It seems that EMF potentiates proliferation and migration of neural stem cells and enhances the repair of myelin in the context of demyelinating conditions.

  13. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

    Science.gov (United States)

    Lima, Michelle; Bouzid, Hana; Soares, Daniele G; Selle, Frédéric; Morel, Claire; Galmarini, Carlos M; Henriques, João A P; Larsen, Annette K; Escargueil, Alexandre E

    2016-05-03

    Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.

  14. Intestinal obstruction repair

    Science.gov (United States)

    Repair of volvulus; Intestinal volvulus - repair; Bowel obstruction - repair ... Intestinal obstruction repair is done while you are under general anesthesia . This means you are asleep and DO NOT feel pain. ...

  15. Aortic aneurysm repair - endovascular

    Science.gov (United States)

    EVAR; Endovascular aneurysm repair - aorta; AAA repair - endovascular; Repair - aortic aneurysm - endovascular ... Endovascular aortic repair is done because your aneurysm is very large, growing quickly, or is leaking or bleeding. You may have ...

  16. Lethal and sub lethal effects of the biocide chlorhexidine on aquatic organisms.

    Science.gov (United States)

    Jesus, Fátima T; Oliveira, Rhaul; Silva, Andreia; Catarino, Ana L; Soares, Amadeu M V M; Nogueira, António J A; Domingues, Inês

    2013-11-01

    Chlorhexidine is among the most used biocides in Europe, however its toxicity to aquatic organisms is scarcely known. The main objective of this study was to assess the lethal and sub lethal effects of chlorhexidine digluconate (ChD) on four aquatic model organisms: the bacteria Vibrio fischeri, the algae Pseudokirchneriella subcapitata, the crustacean Daphnia magna and the embryos of the fish Danio rerio. ChD was very toxic to algae and crustaceans, with a 72 h-EC50 of 62.2 μg/l and a 48 h-EC50 of 45.0 μg/l, respectively. Toxicity to fish embryos and the bacteria was lower, with a 96 h-EC50 of 804.0 μg/l and a 15 min-EC50 of 1,694.0 μg/l, respectively. Concerning sub lethal effects on D. magna (feeding inhibition) a 6 h-EC50 of 503.7 μg/l was obtained. In fish, ChD caused developmental abnormalities, namely alterations in the amniotic fluid (48 h-EC20 of 753.6 μg/l) and early hatching. Moreover, enzymatic biomarkers on fish embryos showed an induction of cholinesterase activity in all ChD tested concentrations (80-900 μg/l). The catalase activity was also induced at the highest concentration tested (900 μg/l) whereas no changes were observed for glutathione-S-transferase and lactate dehydrogenase activities. The toxicity of ChD to the algae and crustacean raises concerns about its potential effects in aquatic food webs, since these organisms are in the base of trophic chains, and highlights the need for further studies on ChD toxicity to aquatic organisms.

  17. Motorcycle Repair.

    Science.gov (United States)

    Hein, Jim; Bundy, Mike

    This motorcycle repair curriculum guide contains the following ten areas of study: brake systems, clutches, constant mesh transmissions, final drives, suspension, mechanical starting mechanisms, electrical systems, fuel systems, lubrication systems, and overhead camshafts. Each area consists of one or more units of instruction. Each instructional…

  18. DNA DSB repair pathway choice: an orchestrated handover mechanism.

    Science.gov (United States)

    Kakarougkas, A; Jeggo, P A

    2014-03-01

    DNA double strand breaks (DSBs) are potential lethal lesions but can also lead to chromosome rearrangements, a step promoting carcinogenesis. DNA non-homologous end-joining (NHEJ) is the major DSB rejoining process and occurs in all cell cycle stages. Homologous recombination (HR) can additionally function to repair irradiation-induced two-ended DSBs in G2 phase. In mammalian cells, HR predominantly uses a sister chromatid as a template for DSB repair; thus HR functions only in late S/G2 phase. Here, we review current insight into the interplay between HR and NHEJ in G2 phase. We argue that NHEJ represents the first choice pathway, repairing approximately 80% of X-ray-induced DSBs with rapid kinetics. However, a subset of DSBs undergoes end resection and repair by HR. 53BP1 restricts resection, thereby promoting NHEJ. During the switch from NHEJ to HR, 53BP1 is repositioned to the periphery of enlarged irradiation-induced foci (IRIF) via a BRCA1-dependent process. K63-linked ubiquitin chains, which also form at IRIF, are also repositioned as well as receptor-associated protein 80 (RAP80), a ubiquitin binding protein. RAP80 repositioning requires POH1, a proteasome component. Thus, the interfacing barriers to HR, 53BP1 and RAP80 are relieved by POH1 and BRCA1, respectively. Removal of RAP80 from the IRIF core is required for loss of the ubiquitin chains and 53BP1, and for efficient replication protein A foci formation. We propose that NHEJ is used preferentially to HR because it is a compact process that does not necessitate extensive chromatin changes in the DSB vicinity.

  19. Turbine repair process, repaired coating, and repaired turbine component

    Energy Technology Data Exchange (ETDEWEB)

    Das, Rupak; Delvaux, John McConnell; Garcia-Crespo, Andres Jose

    2015-11-03

    A turbine repair process, a repaired coating, and a repaired turbine component are disclosed. The turbine repair process includes providing a turbine component having a higher-pressure region and a lower-pressure region, introducing particles into the higher-pressure region, and at least partially repairing an opening between the higher-pressure region and the lower-pressure region with at least one of the particles to form a repaired turbine component. The repaired coating includes a silicon material, a ceramic matrix composite material, and a repaired region having the silicon material deposited on and surrounded by the ceramic matrix composite material. The repaired turbine component a ceramic matrix composite layer and a repaired region having silicon material deposited on and surrounded by the ceramic matrix composite material.

  20. Comparison of the Osteogenic Potential of Mineral Trioxide Aggregate and Endosequence Root Repair Material in a 3-dimensional Culture System.

    Science.gov (United States)

    Rifaey, Hisham S; Villa, Max; Zhu, Qiang; Wang, Yu-Hsiung; Safavi, Kamran; Chen, I-Ping

    2016-05-01

    The ability to promote osteoblast differentiation is a desirable property of root-end filling materials. Several in vitro studies compare the cytotoxicity and physical properties between mineral trioxide aggregate (MTA) and Endosequence root repair material (ERRM), but not their osteogenic potential. Three-dimensional cultures allow cells to better maintain their physiological morphology and better resemble in vivo cellular response than 2-dimensional cultures. Here we examined the osteogenic potential of MTA and ERRM by using a commercially available 3-dimensional Alvetex scaffold. Mandibular osteoblasts were derived from 3-week-old male transgenic reporter mice where mature osteoblasts express green fluorescent protein (GFP) driven by a 2.3-kilobase type I collagen promoter (Col(I)-2.3). Mandibular osteoblasts were grown on Alvetex in direct contact with MTA, ERRM, or no material (negative control) for 14 days. Osteoblast differentiation was evaluated by expression levels of osteogenic genes by using quantitative polymerase chain reaction and by the spatial dynamics of Col(I)-2.3 GFP-positive mature osteoblasts within the Alvetex scaffolds by using 2-photon microscopy. ERRM significantly increased alkaline phosphatase (Alp) and bone sialoprotein (Bsp) expression compared with MTA and negative control groups. Both MTA and ERRM increased osterix (Osx) mRNA significantly compared with the negative control group. The percentage of Col(I)-2.3 GFP-positive cells over total cells within Alvetex was the highest in the ERRM group, followed by MTA and by negative controls. ERRM promotes osteoblast differentiation better than MTA and controls with no material in a 3-dimensional culture system. Alvetex scaffolds can be used to test endodontic materials. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  1. Lethal entanglement in baleen whales.

    Science.gov (United States)

    Cassoff, Rachel M; Moore, Kathleen M; McLellan, William A; Barco, Susan G; Rotsteins, David S; Moore, Michael J

    2011-10-06

    Understanding the scenarios whereby fishing gear entanglement of large whales induces mortality is important for the development of mitigation strategies. Here we present a series of 21 cases involving 4 species of baleen whales in the NW Atlantic, describing the available sighting history, necropsy observations, and subsequent data analyses that enabled the compilation of the manners in which entanglement can be lethal. The single acute cause of entanglement mortality identified was drowning from entanglement involving multiple body parts, with the animal's inability to surface. More protracted causes of death included impaired foraging during entanglement, resulting in starvation after many months; systemic infection arising from open, unresolved entanglement wounds; and hemorrhage or debilitation due to severe gear-related damage to tissues. Serious gear-induced injury can include laceration of large vessels, occlusion of the nares, embedding of line in growing bone, and massive periosteal proliferation of new bone in an attempt to wall off constricting, encircling lines. These data show that baleen whale entanglement is not only a major issue for the conservation of some baleen whale populations, but is also a major concern for the welfare of each affected individual.

  2. ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

    Energy Technology Data Exchange (ETDEWEB)

    Heravi, Mitra [Department of Human Genetics, McGill University, Montreal (Canada); Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Kumala, Slawomir [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Rachid, Zakaria; Jean-Claude, Bertrand J. [Cancer Drug Research Laboratory, McGill University Health Center, Montreal (Canada); Radzioch, Danuta [Department of Human Genetics, McGill University, Montreal (Canada); Muanza, Thierry M., E-mail: tmuanza@yahoo.com [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada)

    2015-06-01

    Purpose: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. Methods and Materials: The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Results: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. Conclusions: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings.

  3. Aircraft Propeller Hub Repair

    Energy Technology Data Exchange (ETDEWEB)

    Muth, Thomas R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Peter, William H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-02-13

    The team performed a literature review, conducted residual stress measurements, performed failure analysis, and demonstrated a solid state additive manufacturing repair technique on samples removed from a scrapped propeller hub. The team evaluated multiple options for hub repair that included existing metal buildup technologies that the Federal Aviation Administration (FAA) has already embraced, such as cold spray, high velocity oxy-fuel deposition (HVOF), and plasma spray. In addition the team helped Piedmont Propulsion Systems, LLC (PPS) evaluate three potential solutions that could be deployed at different stages in the life cycle of aluminum alloy hubs, in addition to the conventional spray coating method for repair. For new hubs, a machining practice to prevent fretting with the steel drive shaft was recommended. For hubs that were refurbished with some material remaining above the minimal material condition (MMC), a silver interface applied by an electromagnetic pulse additive manufacturing method was recommended. For hubs that were at or below the MMC, a solid state additive manufacturing technique using ultrasonic welding (UW) of thin layers of 7075 aluminum to the hub interface was recommended. A cladding demonstration using the UW technique achieved mechanical bonding of the layers showing promise as a viable repair method.

  4. Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.

    Science.gov (United States)

    Brown, Jessica S; O'Carrigan, Brent; Jackson, Stephen P; Yap, Timothy A

    2017-01-01

    Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations.

  5. Stem cells: potential source for retinal repair and regeneration Células tronco: fonte potencial para a regeneração retiniana

    Directory of Open Access Journals (Sweden)

    Leonardo Torquetti

    2007-03-01

    Full Text Available Stem cells have been studied in several fields of Medicine, and their applications are not too far from the clinical practice. Retinal impairment by neuronal death has been considered incurable due to the limited regenerative capacity of the central nervous system. The capacity of stem cells to regenerate tissues, as well as their plasticity makes them a potential source for retinal repair. The stem cells are a great promise for the therapy of inherited retinal disorders and retinal-neuronal degenerative diseases, such as retinitis pigmentosa and allied retinal dystrophies, which can result in blindness. Because of the accessibility, expansibility, and multipotentiality mesenchymal stem cells are expected to be useful for clinical applications, especially in regenerative medicine and tissue engineering. Mesenchymal stem cells are clonogenic, nonhematopoietic stem cells present in the bone marrow. Given the appropriate microenvironment, they could differentiate into cardiomyocytes or even into cells of nonmesodermal derivation including hepatocytes and neurons. So far, the results of a few studies are consistent with the belief that cell-based therapies using mesenchymal stem cells may be effective when it comes to retinal damaged tissue repair.Células-tronco têm sido estudadas em várias áreas da Medicina e suas aplicações brevemente deverão estar incorporadas à prática clínica. O dano retiniano pela morte neuronal é considerado incurável devido a pobre capacidade regenerativa do sistema nervoso central. A capacidade das células-tronco em regenerar tecidos, assim como sua plasticidade, faz que estas sejam uma fonte potencial de células para a regeneração retiniana. Células-tronco são muito promissoras para o tratamento das distrofias retinianas, como a retinose pigmentar e outras doenças neurodegenerativas, que podem evoluir para cegueira. As células-tronco mesenquimais são o tipo mais provável de células-tronco a serem

  6. Tumor clone dynamics in lethal prostate cancer.

    Science.gov (United States)

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.

  7. The effect of tissue surface modification with collagenase and addition of TGF-beta 3 on the healing potential of meniscal tears repaired with tissue glues in vitro

    NARCIS (Netherlands)

    Bochynska, Agnieszka Izabela; Hannink, Gerjon; Verhoeven, Renate; Grijpma, Dirk W.; Buma, Pieter

    The aim of the current in vitro study was to investigate if tissue surface modification with collagenase and addition of the TGF-beta 3 can increase the number of cells present in meniscus tears repaired with the use of newly developed tissue adhesives based on isocyanate-terminated block

  8. Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair

    NARCIS (Netherlands)

    Y.J. Choi (Yong Jun); H. Li (Han); M.Y. Son (Mi Young); X.-H. Wang (Xiao-Hong); J.L. Fornsaglio (Jamie L.); R.W. Sobol (Robert W.); M. Lee (Moonsook); J. Vijg (Jan); S. Imholz (Sandra); M.E.T. Dollé (Martijn); H. van Steeg (Harry); E. Reiling (Erwin); P. Hasty (Paul)

    2014-01-01

    textabstractKu70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB

  9. Mice lacking functional STAT1 are highly susceptible to lethal infection with Lassa virus.

    Science.gov (United States)

    Yun, Nadezhda E; Seregin, Alexey V; Walker, David H; Popov, Vsevolod L; Walker, Aida G; Smith, Jeanon N; Miller, Milagros; de la Torre, Juan C; Smith, Jennifer K; Borisevich, Viktoriya; Fair, Joseph N; Wauquier, Nadia; Grant, Donald S; Bockarie, Bayon; Bente, Dennis; Paessler, Slobodan

    2013-10-01

    Lassa fever (LF) is a potentially lethal human disease that is caused by the arenavirus Lassa virus (LASV). Annually, around 300,000 infections with up to 10,000 deaths occur in regions of Lassa fever endemicity in West Africa. Here we demonstrate that mice lacking a functional STAT1 pathway are highly susceptible to infection with LASV and develop lethal disease with pathology similar to that reported in humans.

  10. Generation of reactive oxygen species by lethal attacks from competing microbes

    OpenAIRE

    Dong, Tao G.; Dong, Shiqi; Catalano, Christy; Moore, Richard; Liang, Xiaoye; Mekalanos, John J.

    2015-01-01

    How microbes respond to lethal attacks from competing species is not fully understood. Here, we investigated the response of Escherichia coli to attacks from the type VI secretion system (T6SS), bacteriophage P1vir, and polymyxin B. We report that generation of reactive oxygen species (ROS) is a general outcome of potentially lethal activities mediated by contact-dependent or contact-independent interactions of aggressive competing bacterial species and phage. An ROS response gene, soxS, is h...

  11. Eye muscle repair - discharge

    Science.gov (United States)

    ... Lazy eye repair - discharge; Strabismus repair - discharge; Extraocular muscle surgery - discharge ... You or your child had eye muscle repair surgery to correct eye muscle ... term for crossed eyes is strabismus. Children most often ...

  12. Ventral hernia repair

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/007661.htm Ventral hernia repair To use the sharing features on this page, please enable JavaScript. Ventral hernia repair is surgery to repair a ventral hernia. ...

  13. Brain aneurysm repair

    Science.gov (United States)

    ... aneurysm repair; Dissecting aneurysm repair; Endovascular aneurysm repair - brain; Subarachnoid hemorrhage - aneurysm ... Your scalp, skull, and the coverings of the brain are opened. A metal clip is placed at ...

  14. DNA repair deficiency in neurodegeneration

    DEFF Research Database (Denmark)

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    : homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage......Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...

  15. Local Morphological Response of the Distal Femoral Articular–Epiphyseal Cartilage Complex of Young Foals to Surgical Stab Incision and Potential Relevance to Cartilage Injury and Repair in Children

    Science.gov (United States)

    Hendrickson, Eli H.S.; Ekman, Stina; Carlson, Cathy S.; Dolvik, Nils I.

    2013-01-01

    Objective: Describe the local morphological response of the articular–epiphyseal cartilage complex to surgical stab incision in the distal femur of foals, with emphasis on the relationship between growth cartilage injury, enchondral ossification, and repair. Design: Nine foals were induced into general anesthesia at the age of 13 to 15 days. Four full-thickness stab incision defects were created in the cartilage on the lateral aspect of the lateral trochlear ridge of the left distal femur. Follow-up examination was carried out from 1 to 49 days postoperatively, including examination of intact bones, sawed slabs, and histological sections. Results: Incision defects filled with cells displaying fibroblast-, chondrocyte-, and osteoblast-like characteristics, potentially validating the rationale behind the drilling of stable juvenile osteochondritis dissecans lesions in children. Incisions induced necrosis within the cartilage on the margins at all depths of the defects. Sharp dissection may therefore be contraindicated in cartilage repair in young individuals. Incisions caused a focal delay in enchondral ossification in 2 foals, apparently related to the orientation of the incision defect relative to the direction of ossification. Defects became progressively surrounded by subchondral bone, in which granulation tissue containing clasts and foci of osteoblast-like cells was observed. Continued enchondral ossification was therefore likely to result in healing of uncomplicated defects to morphologically normal bone. Conclusions: Epiphyseal growth cartilage injury had the potential to exert a negative effect on enchondral ossification. Enchondral ossification exerted a beneficial effect on repair. This relationship warrants consideration in future studies of cartilage injury and repair within the articular–epiphyseal cartilage complex of all species. PMID:26069670

  16. The characteristic of lethality as an indicator of combinad infections

    Directory of Open Access Journals (Sweden)

    V. V. Nechaev

    2016-01-01

    Full Text Available The Combined Socially Important Infections (CSII in St. Petersburg are result of accumulation of chroniogenic potential of HIV infection, tuberculosis and chronic viral hepatitis B and C. The analysis of a lethality from the combined infection (CI for the long-term period in dynamics by years, showed to age and sexual groups and other signs that it exceeds that from tuberculosis by 2,4 times, from chronic hepatitis by 7,5 times. High level of a lethality of persons of young age, sharp growth of tuberculosis of intra chest, intra belly lymph nodes, frequent generalization of process with involvement in process of a liver, a spleen, kidneys testifies to the leading role of HIV infection in failures of diseases. The system and algorithm of proofs about the reasons of lethal outcomes of SI have to be based on representative selections. For this purpose it is necessary to carry out registration of HIV infection not only in the AIDS centers, but also regional in the form of the uniform register SI (HIV+TB+HIC or HIB for the purpose of complex impact on epidemic process.

  17. Lethality Index 2008-2014: Less shootings, same lethality, more opacity

    Directory of Open Access Journals (Sweden)

    Carlos Silva Forné

    2017-07-01

    Full Text Available This article evaluates the use of lethal force by Mexican federal security forces during shootings with presumed members of organized crime from 2008-2014. The authors use official data and press reports on deaths and wounded in shootings to construct indicators such as the number of dead civilians over the number of dead officials from the federal security forces and the number of dead civilians over the number of wounded civilians. In a context where certain factors that contribute to an excessive use of force become more common, the results of the study show a growing use of lethal force. This raises questions over the possible excessive use of lethal force as a normal or systematic practice. The study also shows a growing context of opacity in the infor­mation available to evaluate the use of lethal force and the general lack of a legal framework to regulate the use of lethal force in Mexico.

  18. Combination of CD34-positive cell subsets with infarcted myocardium-like matrix stiffness: a potential solution to cell-based cardiac repair.

    Science.gov (United States)

    Zhang, Shuning; Ma, Xin; Yao, Kang; Zhu, Hong; Huang, Zheyong; Shen, Li; Qian, Juying; Zou, Yunzeng; Sun, Aijun; Ge, Junbo

    2014-06-01

    Detection of the optimal cell transplantation strategy for myocardial infarction (MI) has attracted a great deal of attention. Commitment of engrafted cells to angiogenesis within damaged myocardium is regarded as one of the major targets in cell-based cardiac repair. Bone marrow-derived CD34-positive cells, a well-characterized population of stem cells, might represent highly functional endothelial progenitor cells and result in the formation of new blood vessels. Recently, physical microenvironment (extracellular matrix stiffness) around the engrafted cells was found to exert an essential impact on their fate. Stem cells are able to feel and respond to the tissue-like matrix stiffness to commit to a relevant lineage. Notably, the infarct area after MI experiences a time-dependent stiffness change from flexible to rigid. Our previous observations demonstrated myocardial stiffness-dependent differentiation of the unselected bone marrow-derived mononuclear cells (BMMNCs) along endothelial lineage cells. Myocardial stiffness (~42 kPa) within the optimal time domain of cell engraftment (at week 1 to 2) after MI provided a more favourable physical microenvironment for cell specification and cell-based cardiac repair. However, the difference in tissue stiffness-dependent cell differentiation between the specific cell subsets expressing and no expressing CD34 phenotype remains uncertain. We presumed that CD34-positive cell subsets facilitated angiogenesis and subsequently resulted in cardiac repair under induction of infarcted myocardium-like matrix stiffness compared with CD34-negative cells. If the hypothesis were true, it would contribute greatly to detect the optimal cell subsets for cell therapy and to establish an optimized therapy strategy for cell-based cardiac repair.

  19. Evaluation of Non-Lethal Effects of N2 Bubbles on Marine Mammal Health and the Potential Role of Immune Activity in Facilitating the Development of Dive Related Injury

    Science.gov (United States)

    2015-09-30

    Marine Mammal Health and the Potential Role of Immune Activity in Facilitating the Development of Dive Related Injury Laura Thompson & Tracy Romano...gas bubbles on immune function in marine mammals and to address the hypothesis that a less reactive immune system serves a protective role against...marine mammal blood samples following in vitro exposure to N2 bubbles. 2) Monitor changes in complement components (complement activation) in marine

  20. Lethal effects of Helianthemum lippii (L.) on Acanthamoeba castellanii cysts in vitro.

    Science.gov (United States)

    Badria, F A; Hetta, M H; Sarhan, Rania M; Ezz El-Din, M H

    2014-06-01

    Acanthamoeba spp. commonly cause Acanthamoeba keratitis which is typically associated with the wear of contact lenses. Therefore, finding an economic, efficient, and safe therapy of natural origin is of outmost importance. This study examined the in vitro lethal potential of ethyl acetate and methanol extracts of Helianthemum lippii (L.) (sun roses) against Acanthamoeba castellanii cysts isolated from patients with amoebic keratitis. Both extracts proved to be potent as regard to their lethal effects on A. castellanii cysts with comparable results to chlorhexidine. The ethyl acetate was more promising with cumulative lethality. It showed a highly significant lethal percentage along the duration of treatment. The analysis of the more potent ethyl acetate extract revealed the presence of 2.96 mg/100 g of total phenolics, 0.289 mg/100 ml of total flavonoids and 37 mg/100 mg of total tannins which highlighted their phytomedicinal role.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  3. DNA damage and repair in white blood cells at occupational exposure

    Energy Technology Data Exchange (ETDEWEB)

    Georgieva, R T; Zaharieva, E K; Rupova, I M; Acheva, A R; Nikolov, V N [Department of Radiobiology, National Center of Radiobiology and Radiation Protection, Sofia, 1756 (Bulgaria)], E-mail: r.georgieva@ncrrp.org

    2008-02-01

    : The present work was aimed at finding appropriate biomarkers applicable in molecular epidemiological surveys of occupationally exposed individuals and/or population in order to prove low dose effects. Blood samples were taken from NPP workers, in the 'strict regimen' area (exposed group) and from the administration staff (control group). The spontaneous and induced (exposed to a challenge dose of 2,0 Gy gamma irradiation) DNA repair synthesis in leucocytes, the level of DNA damage by single cell gel-electrophoresis in lymphocytes and the concentration of malonedialdehyde in blood serum, were analyzed. A significant decrease of potentially lethal damage in leucocytes as well as reduction of DNA double strand breaks level in lymphocytes of persons with 'mean annual dose' lower or equal to 5 mSv/a was found, compared to the control group. A higher repair capacity corresponding to elevated protein synthesis after a challenging dose of 2,0 Gy gamma rays and a significant decrease in the level of oxidative stress in the blood plasma were established in persons from the same group. The present investigation showed that annual doses not higher than twice the natural radiation background exert positive effects on DNA damage and repair, increase cellular resistance and decrease oxidative stress.

  4. UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae.

    Science.gov (United States)

    Kozmin, S; Slezak, G; Reynaud-Angelin, A; Elie, C; de Rycke, Y; Boiteux, S; Sage, E

    2005-09-20

    UVA (320-400 nm) radiation constitutes >90% of the environmentally relevant solar UV radiation, and it has been proposed to have a role in skin cancer and aging. Because of the popularity of UVA tanning beds and prolonged periods of sunbathing, the potential deleterious effect of UVA has emerged as a source of concern for public health. Although generally accepted, the impact of DNA damage on the cytotoxic, mutagenic, and carcinogenic effect of UVA radiation remains unclear. In the present study, we investigated the sensitivity of a panel of yeast mutants affected in the processing of DNA damage to the lethal and mutagenic effect of UVA radiation. The data show that none of the major DNA repair pathways, such as base excision repair, nucleotide excision repair, homologous recombination, and postreplication repair, efficiently protect yeast from the lethal action of UVA radiation. In contrast, the results show that the Ogg1 DNA glycosylase efficiently prevents UVA-induced mutagenesis, suggesting the formation of oxidized guanine residues. Furthermore, sequence analysis of UVA-induced canavanine-resistant mutations reveals a bias in favor of GC-->TA events when compared with spontaneous or H(2)O(2)-, UVC-, and gamma-ray- induced canavanine-resistant mutations in the WT strain. Taken together, our data point out a major role of oxidative DNA damage, mostly 7,8-dihydro-8-oxoguanine, in the genotoxicity of UVA radiation in the yeast Saccharomyces cerevisiae. Therefore, the capacity of skin cells to repair 7,8-dihydro-8-oxoguanine may be a key parameter in the mutagenic and carcinogenic effect of UVA radiation in humans.

  5. Mutagenesis of Neisseria gonorrhoeae: absence of error-prone repair

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, L.A.; Yasbin, R.E.

    1984-10-01

    The lethal and mutagenic effects of various mutagens on Neisseria gonorrhoeae were investigated. Lethality studies demonstrated that N. gonorrhoeae was relatively sensitive to ethyl methanesulfonate, UV light, and methyl methanesulfonate. Although N. gonorrhoeae was readily mutated by ethyl methanesulfonate and N-methyl-n'-nitro-N-nitrosoguanidine for the three genetic markers assayed, no increase in the mutation frequency was observed for any of the selective markers after UV irradiation of methyl methanesulfonate treatment. These results suggest than N. gonorrhoeae lacks an error-prone repair mechanism.

  6. DNA repair. [UV radiation

    Energy Technology Data Exchange (ETDEWEB)

    Setlow, R.

    1978-01-01

    Some topics discussed are as follows: difficulty in extrapolating data from E. coli to mammalian systems; mutations caused by UV-induced changes in DNA; mutants deficient in excision repair; other postreplication mechanisms; kinds of excision repair systems; detection of repair by biochemical or biophysical means; human mutants deficient in repair; mutagenic effects of UV on XP cells; and detection of UV-repair defects among XP individuals. (HLW)

  7. Targeted gene repair – in the arena

    OpenAIRE

    2003-01-01

    The development of targeted gene repair is under way and, despite some setbacks, shows promise as an alternative form of gene therapy. This approach uses synthetic DNA molecules to activate and direct the cell’s inherent DNA repair systems to correct inborn errors. The progress of this technique and its therapeutic potential are discussed in relation to the treatment of genetic diseases.

  8. Guidebook for non-lethal experimentation

    NARCIS (Netherlands)

    Paulissen, J.J.M.; Rahimi, R.

    2011-01-01

    In the 2009-2011 timeframe, NATO conducts a capability based assessment of Non-Lethal Weapon (NLW) systems. The work, performed by the RTO study team SAS-078, involves the development of NLW requirement descriptions, which are put against a set of NLW systems. Gaps are likely to occur, indicating th

  9. Lack of dominant lethality in mice following 1-bromopropane treatment.

    Science.gov (United States)

    Yu, Wook-Joon; Kim, Jong-Choon; Chung, Moon-Koo

    2008-03-29

    1-Bromopropane (1-BP) is widely used in spray adhesives, precision cleaner, and degreaser. This study was conducted to investigate the potential of 1-BP to induce dominant lethality in mice. 1-BP was orally administered to males at doses of 300 and 600 mg/kg for 10 days before mating. Cyclophosphamide was used as a positive control (PC), which was administered intraperitoneally to males at 40 mg/kg for 5 days. The vehicle control (VC) group received corn oil only. Thereafter, males were mated with untreated females during six sequential mating periods of a week each. Males were sacrificed at the end of mating and so were the pregnant females on days 15-17 of gestation. Clinical signs, gross findings, mating index, gestation index, the numbers of corpora lutea, implantations, live fetuses, resorptions and dead fetuses, pre- and post-implantation losses, and dominant lethal mutation rate were examined. There were no treatment-related changes in clinical signs, gross findings, mating index, gestation index, number of corpora lutea and implantations, pre-implantation loss, live fetuses, resorptions, dead fetuses, post-implantation loss at any 1-BP doses tested. In the PC group, there were no treatment-related changes in mating index, gestation index, number of corpora lutea, and dead fetuses. However, a decrease in the number of implantations and an increase in pre-implantation loss were observed during the first 2 weeks as compared to those of the VC group. No treatment-related changes were observed in the third to sixth weeks. Increases in resorptions, fetal deaths and post-implantation loss, and a decrease in the number of live fetuses were observed in the first 3 weeks of the PC group compared to those of the VC group. However, no treatment-related changes were observed during the forth to sixth weeks. An increase in dominant lethal mutation rate was observed in 1-3 weeks of mating of the PC group, but there was no significant difference in 1-6 weeks of mating of

  10. Cholesterol Metabolism and Prostate Cancer Lethality.

    Science.gov (United States)

    Stopsack, Konrad H; Gerke, Travis A; Sinnott, Jennifer A; Penney, Kathryn L; Tyekucheva, Svitlana; Sesso, Howard D; Andersson, Swen-Olof; Andrén, Ove; Cerhan, James R; Giovannucci, Edward L; Mucci, Lorelei A; Rider, Jennifer R

    2016-08-15

    Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785-90. ©2016 AACR.

  11. An immunochemical approach to the study of DNA damage and repair

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, S.S. (Vermont Univ., Burlington, VT (United States). Dept. of Microbiology and Molecular Genetics); Erlanger, B.F. (Columbia Univ., New York, NY (United States). Dept. of Microbiology)

    1992-05-01

    The overall objective of this project has been to develop immunochemical methods to quantitate unique DNA base damages in order to facilitate studies on radiation-induced damage production and repair. Specifically, we have been using antibodies raised to damaged bases to quantitate unique lesions in model systems in order to evaluate their potential biological consequences. Our approach has been to synthesize modified nucleotides or nucleosides, conjugate them to protein carriers, and use the conjugates as immunogens in rabbits or to prepare monoclonal antibodies. We have been studying damages that are stable radiolysis products found in X-irradiated DNA and thus of potential biological consequence. Our aim is to build an in vitro and in vivo data base on the interactions between model DNA lesions and such cellular enzymes as DNA polymerases and repair endonucleases. Initial studies have focused on pyrimidine ring saturation products (thymine glycol.and dihydrothymine), products resulting from ring fragmentation or base loss (urea, {Beta}-ureidoisobutyric acid, abasic sites), 7-hydro-8-oxopurines, and more recently, cytosine radiolysis products. These modified bases serve as useful models for examining the potential lethal and/or mutagenic (carcinogenic) effects of the products of DNA radiolysis.

  12. Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair.

    Directory of Open Access Journals (Sweden)

    Yong Jun Choi

    Full Text Available Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS to repair DNA double strand breaks (DSBs through the nonhomologous end joining (NHEJ pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70(-/- cells and ku80(-/- cells also appeared to have a defect in base excision repair (BER. BER corrects base lesions, apurinic/apyrimidinic (AP sites and single stand breaks (SSBs utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1 and DNA Polymerase β (Pol β. In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80 and/or free Ku80 (not bound to Ku70 possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80(-/- mice had a shorter life span than dna-pkcs(-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT, an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER.

  13. Immunohistochemical expression of BRCA1 and lethal prostate cancer

    Science.gov (United States)

    Fiorentino, Michelangelo; Judson, Gregory; Penney, Kathryn; Flavin, Richard; Stark, Jennifer; Fiore, Christopher; Fall, Katja; Martin, Neil; Ma, Jing; Sinnott, Jennifer; Giovannucci, Edward; Stampfer, Meir; Sesso, Howard D.; Kantoff, Philip W.; Finn, Stephen; Loda, Massimo; Mucci, Lorelei

    2011-01-01

    BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell-cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell-cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumors samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1 positive tumors had substantially increased tumor proliferation index compared to negative tumors (47.0 Ki67 positive nuclei vs. 10.3, p=0.0016), and were more likely to develop lethal cancer compared to BRCA1 negative tumors (Hazard ratio=4.6; 95% Confidence interval: 2.4, 8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell-cycle control and demonstrate that BRCA1 is a marker of clinical prostate cancer prognosis. PMID:20388772

  14. [Medical aspects of common non-lethal weapons].

    Science.gov (United States)

    Kunz, Sebastian Niko; Grove, Christina; Monticelli, Fabio

    2014-03-01

    The development and provision of non-lethal weapons (NLW) allow military and law enforcement personnel to exploit gradual engagement in countering potentially hazardous threats. Chemical, kinetic and electrical weapons systems are used to curb violence in civilian crowds. With inappropriate usage, these technologies can cause potentially fatal injuries that are not only of clinical, but also of legal relevance. In this context, the practicing physician is faced with treatment as well as assessment issues of new forms of injuries. In order to assure medical care and to be able to draw competent expert's conclusions, a detailed knowledge of the medical effects of these NLW is necessary. The review at hand presents today's most popular NLW and gives an overview of their possible injury potential and required treatments.

  15. Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.

    Science.gov (United States)

    Mori, Tomohisa; Ito, Shinobu; Namiki, Mizuho; Suzuki, Tadashi; Kobayashi, Shizuko; Matsubayashi, Kenji; Sawaguchi, Toshiko

    2007-07-17

    An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine.

  16. Changes in DNA repair during aging

    Science.gov (United States)

    Gorbunova, Vera; Seluanov, Andrei; Mao, Zhiyong; Hine, Christpher

    2007-01-01

    DNA is a precious molecule. It encodes vital information about cellular content and function. There are only two copies of each chromosome in the cell, and once the sequence is lost no replacement is possible. The irreplaceable nature of the DNA sets it apart from other cellular molecules, and makes it a critical target for age-related deterioration. To prevent DNA damage cells have evolved elaborate DNA repair machinery. Paradoxically, DNA repair can itself be subject to age-related changes and deterioration. In this review we will discuss the changes in efficiency of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) and double-strand break (DSB) repair systems during aging, and potential changes in DSB repair pathway usage that occur with age. Mutations in DNA repair genes and premature aging phenotypes they cause have been reviewed extensively elsewhere, therefore the focus of this review is on the comparison of DNA repair mechanisms in young versus old. PMID:17913742

  17. Dorsal variant blister aneurysm repair.

    Science.gov (United States)

    Couldwell, William T; Chamoun, Roukoz

    2012-01-01

    Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique. It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases. The video can be found here: http://youtu.be/crUreWGQdGo.

  18. INTERNAL REPAIR OF PIPELINES REVIEW & EVALUATION OF INTERNAL PIPELINE REPAIR TRIALS REPORT

    Energy Technology Data Exchange (ETDEWEB)

    Robin Gordon; Bill Bruce; Ian Harris; Dennis Harwig; George Ritter; Bill Mohr; Matt Boring; Nancy Porter; Mike Sullivan; Chris Neary

    2004-09-01

    The two broad categories of fiber-reinforced composite liner repair and deposited weld metal repair technologies were reviewed and evaluated for potential application for internal repair of gas transmission pipelines. Both are used to some extent for other applications and could be further developed for internal, local, structural repair of gas transmission pipelines. Evaluation trials were conducted on pipe sections with simulated corrosion damage repaired with glass fiber-reinforced composite liners, carbon fiber-reinforced composite liners, and weld deposition. Additional un-repaired pipe sections were evaluated in the virgin condition and with simulated damage. Hydrostatic failure pressures for pipe sections repaired with glass fiber-reinforced composite liner were only marginally greater than that of pipe sections without liners, indicating that this type of liner is generally ineffective at restoring the pressure containing capabilities of pipelines. Failure pressure for pipe repaired with carbon fiber-reinforced composite liner was greater than that of the un-repaired pipe section with damage, indicating that this type of liner is effective at restoring the pressure containing capability of pipe. Pipe repaired with weld deposition failed at pressures lower than that of un-repaired pipe in both the virgin and damaged conditions, indicating that this repair technology is less effective at restoring the pressure containing capability of pipe than a carbon fiber-reinforced liner repair. Physical testing indicates that carbon fiber-reinforced liner repair is the most promising technology evaluated to-date. Development of a comprehensive test plan for this process is recommended for use in the next phase of this project.

  19. Refeeding syndrome: a forgotten and potentially lethal entity.

    Science.gov (United States)

    Aissaoui, Y; Hammi, S; Tagajdid, R; Chkoura, K; Boughalem, M

    2016-05-01

    Refeeding syndrome (RS) is defined as the fluid, electrolyte, metabolic, and clinical disturbances that occur after nutrition of patients who have been undernourished or fasting for a prolonged period. This syndrome has been recognized for several decades but is most often overlooked and underdiagnosed by health professionals. The authors report a RS in a patient subjected to prolonged fasting after being kidnapped by a criminal gang. Refeeding resulted in severe hypophosphatemia, neurological impairments, and hematologic disorders. The patient died due to septic shock with multiple organ failure secondary to aspiration pneumonia. In this case, the failure to recognize RS was decisive in the fatal outcome. Professionals must be aware of this disease to prevent and treat it properly.

  20. Life-threatening hyperkalemia: a potentially lethal drug combination.

    Science.gov (United States)

    Juvet, Tristan; Gourineni, Venkata C; Ravi, Sandeep; Zarich, Stuart W

    2013-09-01

    Hyperkalemia is commonly seen in the elderly and is occasionally fatal. Inadvertently combining potassium sparing medications can result in profound hyperkalemia which may result in cardiac dysrhythmias, especially in the setting of chronic kidney disease. An 85 year-old woman on a drug regimen of sotalol, valsartan, spironolactone, and trimethoprim-sulfamethoxazole presented to the emergency department with hypotension and bradycardia. Presumptive treatment for hyperkalemia was started based on her initial electrocardiogram. This diagnosis was later confirmed with a serum potassium value of 10.1 mmol/L. Following pharmacologic treatment, emergency hemodialysis was performed and the patient subsequently recovered. It is known that several drug classes can cause hyperkalemia, with elderly patients at a higher risk of developing this side effect. It is believed that this was a major contributor to the degree of hyperkalemia seen in this patient.

  1. Patterson-Lowry rhizomelic dysplasia: a potentially lethal bone dysplasia?

    Energy Technology Data Exchange (ETDEWEB)

    Kamoda, T.; Nakajima, R.; Matsui, A. [Dept. of Paediatrics, Univ. of Tsukuba, Ibaraki (Japan); Nishimura, G. [Dept. of Radiology, Nasu Chuou Hospital, Tochigi (Japan)

    2001-02-01

    We report a Japanese boy, who is considered as having Patterson-Lowry rhizomelic dysplasia, a rare, as yet undefined, skeletal dysplasia. The diagnosis was warranted by the constellation of skeletal abnormalities - mild platyspondyly, hypoplastic ilia, broad proximal femora with prominent lesser trochanters, mild brachymetacarpalia and, most importantly, rhizomelic shortening of the upper limbs with lateral bowing, medial cortical thickening, and medial metaphyseal notching of the humeri. Our patient, unlike previously reported patients, had respiratory distress and died suddenly of unknown cause in late infancy. Our experience may imply the heterogeneity or phenotypic variability of Patterson-Lowry rhizomelic dysplasia. (orig.)

  2. 'Jamaican Stone': A potentially lethal remedy for delaying ejaculation.

    Science.gov (United States)

    Díaz-Antón, Belén; Alonso-Deniz, Guillermo; Perez-Vela, Jose Luis; Molina-Martín de Nicolás, Javier; Rubio-Alonso, Belen; Jurado-Román, Alfonso; Miguel-Gutierrez, Ana; Martin-Asenjo, Roberto

    2017-02-01

    Poisoning by ingestion of 'Jamaican Stone', a kind of cardioactive steroid, is extremely rare. However, mortality is very high. For this reason, when it occurs, an early and accurate diagnosis represents a critical challenge for clinicians. We present an unusual case of electrical storm caused by this substance. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Lethal midline granuloma syndrome: a diagnostic dilemma

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Bruno Niemeyer de Freitas; Bahia, Paulo Roberto Valle [Radiology, Hospital Universitario Clementino Fraga Filho - Universidade Federal do Rio de Janeiro (HUCFF-UFRJ), Rio de Janeiro, RJ (Brazil); Oliveira, Ana Luiza Vianna Sobral de Magalhaes [Resident of Medical Practice, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil); Marchon Junior, Joao Luiz [Unit of Computed Tomography, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil)

    2012-11-15

    The rare lethal midline granuloma syndrome is difficult to diagnose because of the wide array of related diseases and lack of knowledge by the majority of physicians. In the present report, the authors describe the case of a patient with this disease, caused by squamous cell carcinoma, drawing attention to differential diagnoses and to clinical and radiological findings that may be useful to define the diagnosis. (author)

  4. Brine shrimp lethality assay of Bacopa monnieri.

    Science.gov (United States)

    D'Souza, Prashanth; Deepak, Mundkinajeddu; Rani, Padmaja; Kadamboor, Sandhya; Mathew, Anjana; Chandrashekar, Arun P; Agarwal, Amit

    2002-03-01

    Successive petroleum ether, chloroform, ethanol and water extracts, a saponin rich fraction (SRF) and bacoside A isolated from Bacopa monnieri were tested for brine shrimp lethality. Successive ethanol extracts and SRF showed potent activity. Bacoside A showed the maximum activity with a LC(50) of 38.3 microg/mL. The results confirmed the previous reports of an anticancer effect of Bacopa monnieri and suggest bacoside A as the active constituent.

  5. Lethal Interpersonal Violence in the Middle Pleistocene

    OpenAIRE

    Nohemi Sala; Juan Luis Arsuaga; Ana Pantoja-Pérez; Adrián Pablos; Ignacio Martínez; Quam, Rolf M.; Asier Gómez-Olivencia; José María Bermúdez de Castro; Eudald Carbonell

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force ...

  6. Lethality in Desbuquois dysplasia: three new cases

    Energy Technology Data Exchange (ETDEWEB)

    Hall, B.D. [Department of Pediatrics, University of Kentucky College of Medicine, Lexington (United States)

    2001-01-01

    Three new cases of Desbuquois syndrome in two brothers and a sporadic male, all of whom died in early infancy, are presented to emphasize the high rate (33 %) of lethality in this variable, but serious skeletal dysplasia. Including the three presented patients and 10 of the 36 cases in the literature who died, most did so between birth and 7 months and from respiratory-related problems. Neonatal and infancy survivors should be monitored closely, particularly relative to their pulmonary status. (orig.)

  7. Complement component 5 promotes lethal thrombosis

    Science.gov (United States)

    Mizuno, Tomohiro; Yoshioka, Kengo; Mizuno, Masashi; Shimizu, Mie; Nagano, Fumihiko; Okuda, Tomoyuki; Tsuboi, Naotake; Maruyama, Shoichi; Nagamatsu, Tadashi; Imai, Masaki

    2017-01-01

    Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45–75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis. PMID:28205538

  8. Lethal interpersonal violence in the Middle Pleistocene.

    Science.gov (United States)

    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.

  9. Lethal interpersonal violence in the Middle Pleistocene.

    Directory of Open Access Journals (Sweden)

    Nohemi Sala

    Full Text Available Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.

  10. Pectus excavatum repair

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002949.htm Pectus excavatum repair To use the sharing features on this page, please enable JavaScript. Pectus excavatum repair is surgery to correct pectus excavatum . This ...

  11. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway.

    Science.gov (United States)

    Rosado, Ivan V; Langevin, Frédéric; Crossan, Gerry P; Takata, Minoru; Patel, Ketan J

    2011-11-13

    Metabolism is predicted to generate formaldehyde, a toxic, simple, reactive aldehyde that can damage DNA. Here we report a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway. These results define a fundamental role for the combined action of formaldehyde catabolism and DNA cross-link repair in vertebrate cell survival.

  12. Genetic and biochemical characterization of human AP endonuclease 1 mutants deficient in nucleotide incision repair activity.

    Directory of Open Access Journals (Sweden)

    Aurore Gelin

    Full Text Available BACKGROUND: Human apurinic/apyrimidinic endonuclease 1 (APE1 is a key DNA repair enzyme involved in both base excision repair (BER and nucleotide incision repair (NIR pathways. In the BER pathway, APE1 cleaves DNA at AP sites and 3'-blocking moieties generated by DNA glycosylases. In the NIR pathway, APE1 incises DNA 5' to a number of oxidatively damaged bases. At present, physiological relevance of the NIR pathway is fairly well established in E. coli, but has yet to be elucidated in human cells. METHODOLOGY/PRINCIPAL FINDING: We identified amino acid residues in the APE1 protein that affect its function in either the BER or NIR pathway. Biochemical characterization of APE1 carrying single K98A, R185A, D308A and double K98A/R185A amino acid substitutions revealed that all mutants exhibited greatly reduced NIR and 3'-->5' exonuclease activities, but were capable of performing BER functions to some extent. Expression of the APE1 mutants deficient in the NIR and exonuclease activities reduced the sensitivity of AP endonuclease-deficient E. coli xth nfo strain to an alkylating agent, methylmethanesulfonate, suggesting that our APE1 mutants are able to repair AP sites. Finally, the human NIR pathway was fully reconstituted in vitro using the purified APE1, human flap endonuclease 1, DNA polymerase beta and DNA ligase I proteins, thus establishing the minimal set of proteins required for a functional NIR pathway in human cells. CONCLUSION/SIGNIFICANCE: Taken together, these data further substantiate the role of NIR as a distinct and separable function of APE1 that is essential for processing of potentially lethal oxidative DNA lesions.

  13. When "Other" Initiate Repair.

    Science.gov (United States)

    Schegloff, Emanuel A.

    2000-01-01

    Elaborates on the locus of other-initiated repair, and reports on a number of environments in which others initiate repair turns later than the one directly following the trouble-source turn. Describes several ways that other initiation of repair, which occurs in next-turn position, may be delayed within that position. (Author/VWL)

  14. Potential risk of esophageal squamous cell carcinoma due to nucleotide excision repair XPA and XPC gene variants and their interaction among themselves and with environmental factors.

    Science.gov (United States)

    Rafiq, Rumaisa; Bhat, Gulzar Ahmad; Lone, Mohd Maqbool; Masood, Akbar; Dar, Nazir Ahmad

    2016-08-01

    The association of nucleotide excision repair (NER) gene polymorphisms with esophageal squamous cell carcinoma (ESCC) is inconclusive. The aim of the current study was to assess the association of repair gene xeroderma pigmentosum A (XPA) (rs-1800975) and xeroderma pigmentosum C (XPC) (rs-2228000) polymorphisms with ESCC risk as well as modifying effects of environmental factors. The genotyping was done in 450 confirmed ESCC cases and equal number of individually matched controls by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and direct sequencing methods. Conditional logistic regression models were used to assess the genotypic associations and interactions. A high ESCC risk was found in subjects who carried the homozygous minor allele of XPA (odds ratio (OR) = 3.57; 95 % confidence interval (CI) = 1.76-7.23), and the risk was higher when analysis was limited to participants who were ever smokers (OR = 4.22; 95 % CI = 2.01-8.88), lived in adobe houses (OR = 8.42; 95 % CI = 3.74-18.95), consumed large volumes of salt tea (OR = 7.42; 95 % CI = 3.30-16.69), or had a positive family history of cancer (FHC) (OR = 9.47; 95 % CI = 4.67-19.20). In case of XPC, a homozygous minor allele also showed strong association with ESCC risk (OR = 4.43; 95 % CI = 2.41-8.16). We again observed a very strong effect of the above environmental factors in elevating the risk of ESCC. Further, the variant genotypes of both genes in combination showed an increased risk towards ESCC (OR = 7.01; 95 % CI = 3.14-15.64) and such association was synergistically significant. Salt tea consumption showed an interaction with genotypes of XPA and XPC. However, an interaction with FHC was significant in the case of XPA genotype only. XPA and XPC genotypes are associated with an increased risk of ESCC, and such association was reasonably modulated by different exposures.

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

    Science.gov (United States)

    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.

  16. Nitric Oxide: Genomic Instability And Synthetic Lethality

    Directory of Open Access Journals (Sweden)

    Vasily A. Yakovlev

    2015-08-01

    Loss or inhibition of Poly(ADP-ribose polymerase 1 (PARP1 activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DSB by the transcription machinery. In BRCA-positive cells, DSB are repaired by HRR, but they cannot be properly repaired in BRCA1-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. Our data demonstrated that combination of NO-donors with PARP inhibitors significantly sensitized the BRCA1-positive cancer cells to DNA-damaging agents.

  17. Application potential of bone marrow mesenchymal stem cell (BMSCs) based tissue-engineering for spinal cord defect repair in rat fetuses with spina bifida aperta.

    Science.gov (United States)

    Li, Xiaoshuai; Yuan, Zhengwei; Wei, Xiaowei; Li, Hui; Zhao, Guifeng; Miao, Jiaoning; Wu, Di; Liu, Bo; Cao, Songying; An, Dong; Ma, Wei; Zhang, Henan; Wang, Weilin; Wang, Qiushi; Gu, Hui

    2016-04-01

    Spina bifida aperta are complex congenital malformations resulting from failure of fusion in the spinal neural tube during embryogenesis. Despite surgical repair of the defect, most patients who survive with spina bifida aperta have a multiple system handicap due to neuron deficiency of the defective spinal cord. Tissue engineering has emerged as a novel treatment for replacement of lost tissue. This study evaluated the prenatal surgical approach of transplanting a chitosan-gelatin scaffold seeded with bone marrow mesenchymal stem cells (BMSCs) in the healing the defective spinal cord of rat fetuses with retinoic acid induced spina bifida aperta. Scaffold characterisation revealed the porous structure, organic and amorphous content. This biomaterial promoted the adhesion, spreading and in vitro viability of the BMSCs. After transplantation of the scaffold combined with BMSCs, the defective region of spinal cord in rat fetuses with spina bifida aperta at E20 decreased obviously under stereomicroscopy, and the skin defect almost closed in many fetuses. The transplanted BMSCs in chitosan-gelatin scaffold survived, grew and expressed markers of neural stem cells and neurons in the defective spinal cord. In addition, the biomaterial presented high biocompatibility and slow biodegradation in vivo. In conclusion, prenatal transplantation of the scaffold combined with BMSCs could treat spinal cord defect in fetuses with spina bifida aperta by the regeneration of neurons and repairmen of defective region.

  18. In vitro multipotentiality and characterization of human unfractured traumatic hemarthrosis-derived progenitor cells: A potential cell source for tissue repair.

    Science.gov (United States)

    Lee, Sang Yang; Miwa, Masahiko; Sakai, Yoshitada; Kuroda, Ryosuke; Matsumoto, Tomoyuki; Iwakura, Takashi; Fujioka, Hiroyuki; Doita, Minoru; Kurosaka, Masahiro

    2007-03-01

    Mesenchymal progenitor cells (MPCs) are a very attractive tool in the context of repair and regeneration of musculoskeletal tissue damaged by trauma. The most common source of MPCs to date has been the bone marrow, but aspirating bone marrow from the patient is an invasive procedure. In an attempt to search for alternative sources of MPCs that could be obtained with minimal invasion, we looked into traumatic hemarthrosis of the knee. In this study, we determined whether a population of multipotent MPCs could be isolated from acute traumatic knee hemarthrosis in the absence of intra-articular fractures. Mononuclear cells were isolated from the aspirated hemarthrosis by density gradient separation, and cultured. We were able to obtain plastic adherent fibroblast-like cells from the mononuclear cell fractions. Flow cytometry analysis revealed that the adherent fibroblast-like cells were consistently positive for CD29, CD44, CD105, and CD166, and were negative for CD14, CD34, and CD45. These were similar to control bone marrow stromal cells. These cells could differentiate in vitro into osteogenic, adipogenic, and chondrogenic cells in the presence of lineage-specific induction factors. In conclusion, acute unfractured traumatic hemarthrosis of the knee contains MPCs with multipotentiality. Because knee hemarthrosis is easy to harvest with minimal pain and without unnecessary invasion, we regard hemarthrosis-derived cells as an additional progenitor cell source for future tissue engineering and cell-based therapy in knee injuries.

  19. Leg ulcer and osteomyelitis due to methicillin-susceptible Staphylococcus aureus infection after fracture repair treatment: a case highlighting the potential role of prostaglandin E₁ vasodilator.

    Science.gov (United States)

    Bentivegna, Erminia; Citarrella, Emanuele; Vivaldi, Roberto; De Luca, Dario; Maira, Giovanna Grazia; Casuccio, Alessandra; Di Carlo, Paola

    2015-03-01

    Prostaglandins appear to reduce biofilm formation and chronicization of infections, and stimulate a rapid and effective clearance of infecting micro-organisms. We report a case of recovery from methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis after multidisciplinary management with antibiotics, anti-thrombotics and prostaglandin E1 (PGE1) vasodilator, in a patient with tibial plateau fracture repaired with internal fixation devices. A 47-year-old HIV-negative male with chronic ulcer on the proximal third of the left leg was admitted to the Orthopaedic Unit of the Orestano Clinic in Palermo, Italy, for suspected osteomyelitis. A biopsy of the skin ulcer and blood cultures were performed and resulted positive for MSSA. Labelled leukocyte scintigraphy confirmed osteomyelitis. No clinical improvement was observed after combined antibiotic treatment with rifampicin plus trimethoprim-sulfamethoxazole. The patient underwent a 4-day therapeutic cycle: PGE1 (alprostadil 60 mg/day IV) combined with nadroparin calcium plus gentamicin, followed by treatment with aminaftone plus sulodexide plus levofloxacin. At discharge, the patient's painful symptoms had completely resolved and the ulcer had cicatrized; recovery from osteomyelitis was confirmed by scintigraphy. This treatment protocol including PGE1 may result in a significant improvement in quality of life and functional status of patients with a reduction in direct and indirect costs and economic benefit for the National Health Service.

  20. Novel neutralizing monoclonal antibodies protect rodents against lethal filovirus challenges

    Directory of Open Access Journals (Sweden)

    Caleb D. Marceau

    2014-01-01

    Full Text Available Filoviruses are the causative agents of lethal hemorrhagic fever in human and non-human primates (NHP. The family of Filoviridae is composed of three genera, Ebolavirus, Marburgvirus and Cuevavirus. There are currently no approved vaccines or antiviral therapeutics for the treatment of filovirus infections in humans. Passive transfer of neutralizing antibodies targeting the Ebola virus (EBOV glycoprotein (GP has proven effective in protecting mice, guinea pigs and NHP from lethal challenges with EBOV. In this study, we generated two neutralizing monoclonal antibodies (MAbs, termed S9 and M4 that recognize the GP of EBOV or multiple strains of Marburg virus (MARV, respectively. We characterized the putative binding site of S9 as a linear epitope on the glycan cap of the GP1 subunit of the EBOV-GP. The M4 antibody recognizes an unknown conformational epitope on MARV-GP. Additionally, we demonstrated the post-exposure protection potential of these antibodies in both the mouse and guinea pig models of filovirus infection. These data indicate that MAbs S9 and M4 would be good candidates for inclusion in an antibody cocktail for the treatment of filovirus infections.

  1. Approach to the classical radiation biology. Ionizing radiation effects and repair mechanism of DNA double strand breaks

    Energy Technology Data Exchange (ETDEWEB)

    Utsumi, Hiroshi [Kyoto Univ., Kumatori, Osaka (Japan). Research Reactor Inst

    2000-09-01

    Split-dose recovery has been observed under a variety of experimental conditions in many cell systems and believed to be the recovery of sublethal damage (SLD). It is considered to be one of the most widespread and important cellular responses in clinical radiotherapy. To study the molecular mechanism of this recovery, we analyzed the knockout mutants KU70{sup -/-}, RAD54{sup -/-}, and KU70{sup -/-}/ RAD54{sup -/-} of the chicken B-cell line, DT40. Rad54 participates in the homologous recombinational (HR) repair of DNA double-strand breaks (DSB), while Ku proteins are involved in non-homologous end-joining (NHEJ). Split-dose recovery was observed in the parent DT40 and KU70{sup -/-} cells. Moreover the split-dose survival enhancement had all of the characteristics of SLD recovery that had been demonstrated earlier: e.g., the reappearance of the shoulder of the survival curve with dose fractionation; repair at 25degC; and inhibition by the antibiotic actinomycin D. These results strongly suggest that SLD recovery is due to DSB repair via or mediated by HR, and that these breaks constitute SLD. The tonicity-sensitive potentially lethal damage (PLD) recovery was also found only in DT40 and KU70 {sup -/-} cells. Delayed-plating PLD recovery may be controlled by NHEJ repair that works through the cell cycle. These results lead to the conclusion that the repair of DSBs could explain the classical operational recovery phenomena. We have also investigated RBE/LET using those mutants. (author)

  2. Repair, Evaluation, Maintenance, and Rehabilitation Research Program. Geotechnical Applications of the Self Potential (SP) Method. Report 4. Numerical Modeling of SP Anomalies: Documentation of Program SPPC and Applications

    Science.gov (United States)

    1990-03-01

    Vicksburg, MS Fitterman, D. V., and Corwin, R. F. 1982. "Inversion of Self Potential Data from the Cerro Prieto Geothermal Field, Mexico," Geophysics, Vol...POTENTIAL (SP) METHOD Report 4 NUMERICAL MODELING OF SP ANOMALIES : DOCUMENTATION OF PROGRAM SPPC AND APPLICATIONS by Michael J. Wilt Engineering Geosciences...version of program SPXCPL which calculates the self potential anomaly due to fluid and therma’ sources in geologic media. Fluid and heat flow

  3. Content-Related Repairing of Inconsistencies in Distributed Data

    Institute of Scientific and Technical Information of China (English)

    Yue-Feng Du; De-Rong Shen; Tie-Zheng Nie; Yue Kou; Ge Yu

    2016-01-01

    Conditional functional dependencies (CFDs) are a critical technique for detecting inconsistencies while they may ignore some potential inconsistencies without considering the content relationship of data. Content-related conditional functional dependencies (CCFDs) are a type of special CFDs, which combine content-related CFDs and detect potential inconsistencies by putting content-related data together. In the process of cleaning inconsistencies, detection and repairing are interactive: 1) detection catches inconsistencies, 2) repairing corrects caught inconsistencies while may bring new incon-sistencies. Besides, data are often fragmented and distributed into multiple sites. It consequently costs expensive shipment for inconsistencies cleaning. In this paper, our aim is to repair inconsistencies in distributed content-related data. We propose a framework consisting of an inconsistencies detection method and an inconsistencies repairing method, which work iteratively. The detection method marks the violated CCFDs for computing the inconsistencies which should be repaired preferentially. Based on the repairing-cost model presented in this paper, we prove that the minimum-cost repairing using CCFDs is NP-complete. Therefore, the repairing method heuristically repairs the inconsistencies with minimum cost. To improve the efficiency and accuracy of repairing, we propose distinct values and rules sequences. Distinct values make less data shipments than real data for communication. Rules sequences determine appropriate repairing sequences to avoid some incorrect repairs. Our solution is proved to be more effective than CFDs by empirical evaluation on two real-life datasets.

  4. Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections

    Directory of Open Access Journals (Sweden)

    Nithiuthai S

    2004-09-01

    research and adds support to the prediction that partially effective vaccines may select for increasingly virulent malaria parasite strains. By contrast, there was no consistent correlation between transmission and sub-lethal anaemia, a more common outcome of malaria infection. However, overall, the data are not inconsistent with the recent proposal that sub-lethal effects may impose an upper limit on virulence. Moreover, clone specific differences in transmission phenotypes linked to anaemia do suggest that there is considerable adaptive potential relating anaemia and transmission that may lead to uncertain consequences following intervention strategies.

  5. Mutation induced extinction in finite populations: lethal mutagenesis and lethal isolation.

    Directory of Open Access Journals (Sweden)

    C Scott Wylie

    Full Text Available Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate "semi-conservatively," e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U, and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N. However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of "lethal isolation." Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently

  6. DNA damage by reactive species: Mechanisms, mutation and repair.

    Science.gov (United States)

    Jena, N R

    2012-07-01

    DNA is continuously attacked by reactive species that can affect its structure and function severely. Structural modifications to DNA mainly arise from modifications in its bases that primarily occur due to their exposure to different reactive species. Apart from this, DNA strand break, inter- and intra-strand crosslinks and DNA-protein crosslinks can also affect the structure of DNA significantly. These structural modifications are involved in mutation, cancer and many other diseases. As it has the least oxidation potential among all the DNA bases, guanine is frequently attacked by reactive species, producing a plethora of lethal lesions. Fortunately, living cells are evolved with intelligent enzymes that continuously protect DNA from such damages. This review provides an overview of different guanine lesions formed due to reactions of guanine with different reactive species. Involvement of these lesions in inter- and intra-strand crosslinks, DNA-protein crosslinks and mutagenesis are discussed. How certain enzymes recognize and repair different guanine lesions in DNA are also presented.

  7. DNA damage by reactive species: Mechanisms, mutation and repair

    Indian Academy of Sciences (India)

    N R Jena

    2012-07-01

    DNA is continuously attacked by reactive species that can affect its structure and function severely. Structural modifications to DNA mainly arise from modifications in its bases that primarily occur due to their exposure to different reactive species. Apart from this, DNA strand break, inter- and intra-strand crosslinks and DNA–protein crosslinks can also affect the structure of DNA significantly. These structural modifications are involved in mutation, cancer and many other diseases. As it has the least oxidation potential among all the DNA bases, guanine is frequently attacked by reactive species, producing a plethora of lethal lesions. Fortunately, living cells are evolved with intelligent enzymes that continuously protect DNA from such damages. This review provides an overview of different guanine lesions formed due to reactions of guanine with different reactive species. Involvement of these lesions in inter- and intra-strand crosslinks, DNA–protein crosslinks and mutagenesis are discussed. How certain enzymes recognize and repair different guanine lesions in DNA are also presented.

  8. Percutaneous mitral valve repair.

    Science.gov (United States)

    Gillinov, A Marc; Liddicoat, John R

    2006-01-01

    Surgical mitral valve repair is the procedure of choice to treat mitral regurgitation of all etiologies. Whereas annuloplasty is the cornerstone of mitral valve repair, a variety of other surgical techniques are utilized to correct dysfunction of the leaflets and subvalvular apparatus; in most cases, surgical repair entails application of multiple repair techniques in each patient. Preclinical studies and early human experience have demonstrated that some of these surgical repair techniques can be performed using percutaneous approaches. Specifically, there has been great progress in the development of novel technology to facilitate percutaneous annuloplasty and percutaneous edge-to-edge repair. The objectives of this report were to (1) discuss the surgical foundations for these percutaneous approaches; (2) review device design and experimental and clinical results of percutaneous valve repair; and (3) address future directions, including the key challenges of patient selection and clinical trial design.

  9. Other-initiated repair in Siwu

    Directory of Open Access Journals (Sweden)

    Dingemanse Mark

    2015-02-01

    Full Text Available This article describes the interactional patterns and linguistic structures associated with other-initiated repair in Siwu, a Kwa language spoken in eastern Ghana. Other-initiated repair is the set of techniques used by people to deal with problems in speaking, hearing and understanding. Formats for repair initiation in Siwu exploit language-specific resources like question words and noun class morphology. At the same time, the basic structure of the system bears a strong similarity to other-initiated repair in other languages. Practices described for Siwu thus are potentially of broader relevance to the study of other-initiated repair. This article documents how different prosodic realisations of repair initiators may index social actions and features of the speech event; how two distinct roles of repetition in repair initiators are kept apart by features of turn design; and what kinds of items can be treated as ‘dispensable’ in resayings. By charting how other-initiated repair uses local linguistic resources and yet is shaped by interactional needs that transcend particular languages, this study contributes to the growing field of pragmatic typology: the study of systems of language use and the principles that shape them.

  10. A novel plant glutathione S-transferase/peroxidase suppresses Bax lethality in yeast

    DEFF Research Database (Denmark)

    Kampranis, S C; Damianova, R; Atallah, M

    2000-01-01

    for the identification of plant genes, which inhibit either directly or indirectly the lethal phenotype of Bax. Using this method a number of cDNA clones were isolated, the more potent of which encodes a protein homologous to the class theta glutathione S-transferases. This Bax-inhibiting (BI) protein was expressed......The mammalian inducer of apoptosis Bax is lethal when expressed in yeast and plant cells. To identify potential inhibitors of Bax in plants we transformed yeast cells expressing Bax with a tomato cDNA library and we selected for cells surviving after the induction of Bax. This genetic screen allows...

  11. The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

    Science.gov (United States)

    Sharma, Hari Shanker; Menon, Preeti K; Lafuente, José Vicente; Aguilar, Zoraida P; Wang, Y Andrew; Muresanu, Dafin Fior; Mössler, Herbert; Patnaik, Ranjana; Sharma, Aruna

    2014-01-01

    Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions. However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition. Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.

  12. Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.

    Science.gov (United States)

    Fedier, Andre; Erdmann, Ruediger; Boulikas, Teni; Fink, Daniel

    2006-11-01

    Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.

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

    Science.gov (United States)

    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.

  14. Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.

    Science.gov (United States)

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin; Metcalf, Jordan Patrick

    2012-12-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.

  15. Potentials of manufacture and repair of nickel base turbine components used in aero engines and power plants by laser metal deposition and laser drilling

    Institute of Scientific and Technical Information of China (English)

    I.Kelbassa; K.Walther; L.Trippe; W.Meiners; C.Over

    2007-01-01

    High pressure turbine (HPT) parts like blades and vanes with integrated cooling channels are challenging concerning overhaul and repair.So far damaged parts have to be replaced by the operator.The aim is to design and implement a refurbishment process chain to avoid scrapping of used parts.This process chain implies three different laser applications 1.Direct Laser Forming (DLF),2.Laser Metal Deposition (LMD) and 3.Laser Drilling (LD).The laser processing was extended in the last years towards application near materials like Nickel and Titanium base alloys.Concerning LMD and DLF the achieved results are investigated regarding macro and micro structure,hardness,defects (e.g.cracks,bonding defects,porosity) and contamination with atmospheric elements (e.g.O, N,C and H) are presented for Titanium alloys like Ti-6Al-4V,Ti-6246 and Ti-17 as well as for Nickel base alloys like Inconel 718 and Rene 80.Suitable process parameters are presented with the achieved static (tensile) and dynamic mechanical properties (HCF) and compared to those of heat treated raw materials.One innovative solution (manufacturing case) is to fabricate the small and complex shaped geometrical elements by LMD and/or DLF.By LMD these elements are built-up directly.With DLF the elements are manufactured separately in the DLF machine and connected by a subsequent joining technique with the large parts.With DLF small complex shaped parts like combustor swirlers,HPT blades and vanes with internal cooling channels are manufactured completely.LMD and DLF can be used in combination with subsequent LD.Depending on the application two different drilling techniques by dominant melt ejection-percussion drilling and trepanning-are classified and characterised.The drilling techniques are exemplarily presented for stainless steel and nickel base alloys (diameter 0.2~0.6 mm,aspect ratio<30,inclination up to 60°) using pulsed laser radiation (Nd:YAG,1064 nm,0.5~1 ms).The experimental results of coaxial

  16. Chronic pain after childhood groin hernia repair

    DEFF Research Database (Denmark)

    Aasvang, Eske Kvanner; Kehlet, Henrik

    2007-01-01

    BACKGROUND: In contrast to the well-described 10% risk of chronic pain affecting daily activities after adult groin hernia repair, chronic pain after childhood groin hernia repair has never been investigated. Studies of other childhood surgery before the age of 3 months suggest a risk of increased...... pain responsiveness later in life, but its potential relationship to chronic pain in adult life is unknown. METHODS: This was a nationwide detailed questionnaire study of chronic groin pain in adults having surgery for a groin hernia repair before the age of 5 years (n = 1075). RESULTS: The response...

  17. Suicide Intent and Accurate Expectations of Lethality: Predictors of Medical Lethality of Suicide Attempts

    Science.gov (United States)

    Brown, Gregory K.; Henriques, Gregg R.; Sosdjan, Daniella; Beck, Aaron T.

    2004-01-01

    The degree of intent to commit suicide and the severity of self-injury were examined in individuals (N = 180) who had recently attempted suicide. Although a minimal association was found between the degree of suicide intent and the degree of lethality of the attempt, the accuracy of expectations about the likelihood of dying was found to moderate…

  18. Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

    Science.gov (United States)

    Dadhania, Vivekkumar P.; Bhushan, Bharat

    2017-01-01

    Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection. PMID:28210203

  19. In vitro cell culture lethal dose submitted to gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Moreno, Carolina S.; Rogero, Sizue O.; Rogero, Jose Roberto [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)], e-mail: carolina_sm@hotmail.com; Ikeda, Tamiko I.; Cruz, Aurea S. [Instituto Adolfo Lutz, Sao Paulo, SP (Brazil)

    2009-07-01

    The present study was designed to evaluate the in vitro effect of gamma radiation in cell culture of mouse connective tissue exposed to different doses of gamma radiation and under several conditions. The cell viability was analyzed by neutral red uptake methodology. This assay was developed for establish a methodology to be used in the future in the study of resveratrol radioprotection. Resveratrol (3,4',5- trihydroxystilbene), a phenolic phytoalexin that occurs naturally in some spermatophytes, such as grapevines, in response to injury as fungal infections and exposure to ultraviolet light. In the wines this compound is found at high levels and is considered one of the highest antioxidant constituents. The intense antioxidant potential of resveratrol provides many pharmacological activities including cardioprotection, chemoprevention and anti-tumor effects. Our results demonstrated that {sup 60}Co gamma radiation lethal dose (LD50) on NCTC clone 929 cells was about 340Gy. (author)

  20. DEK is required for homologous recombination repair of DNA breaks

    DEFF Research Database (Denmark)

    Smith, Eric A; Gole, Boris; Willis, Nicholas A

    2017-01-01

    -deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout...... mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK...... filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition....

  1. Optimality in DNA repair.

    Science.gov (United States)

    Richard, Morgiane; Fryett, Matthew; Miller, Samantha; Booth, Ian; Grebogi, Celso; Moura, Alessandro

    2012-01-07

    DNA within cells is subject to damage from various sources. Organisms have evolved a number of mechanisms to repair DNA damage. The activity of repair enzymes carries its own risk, however, because the repair of two nearby lesions may lead to the breakup of DNA and result in cell death. We propose a mathematical theory of the damage and repair process in the important scenario where lesions are caused in bursts. We use this model to show that there is an optimum level of repair enzymes within cells which optimises the cell's response to damage. This optimal level is explained as the best trade-off between fast repair and a low probability of causing double-stranded breaks. We derive our results analytically and test them using stochastic simulations, and compare our predictions with current biological knowledge.

  2. Differences between the cell populations from the peritenon and the tendon core with regard to their potential implication in tendon repair

    NARCIS (Netherlands)

    Cadby, Jennifer A; Buehler, Evelyne; Godbout, Charles; van Weeren, P René; Snedeker, Jess G

    2014-01-01

    The role of intrinsic and extrinsic healing in injured tendons is still debated. In this study, we characterized cell plasticity, proliferative capacity, and migration characteristics as proxy measures of healing potential in cells derived from the peritenon (extrinsic healing) and compared these to

  3. An immunochemical approach to the study of DNA damage and repair. Technical progress report, May 1, 1989--April 30, 1992

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, S.S. [Vermont Univ., Burlington, VT (United States). Dept. of Microbiology and Molecular Genetics; Erlanger, B.F. [Columbia Univ., New York, NY (United States). Dept. of Microbiology

    1992-05-01

    The overall objective of this project has been to develop immunochemical methods to quantitate unique DNA base damages in order to facilitate studies on radiation-induced damage production and repair. Specifically, we have been using antibodies raised to damaged bases to quantitate unique lesions in model systems in order to evaluate their potential biological consequences. Our approach has been to synthesize modified nucleotides or nucleosides, conjugate them to protein carriers, and use the conjugates as immunogens in rabbits or to prepare monoclonal antibodies. We have been studying damages that are stable radiolysis products found in X-irradiated DNA and thus of potential biological consequence. Our aim is to build an in vitro and in vivo data base on the interactions between model DNA lesions and such cellular enzymes as DNA polymerases and repair endonucleases. Initial studies have focused on pyrimidine ring saturation products (thymine glycol.and dihydrothymine), products resulting from ring fragmentation or base loss (urea, {Beta}-ureidoisobutyric acid, abasic sites), 7-hydro-8-oxopurines, and more recently, cytosine radiolysis products. These modified bases serve as useful models for examining the potential lethal and/or mutagenic (carcinogenic) effects of the products of DNA radiolysis.

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

    Directory of Open Access Journals (Sweden)

    Blanford Simon

    2012-11-01

    Full Text Available Abstract Background 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. Methods 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. Results and conclusions 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

  5. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Directory of Open Access Journals (Sweden)

    Erhong Meng

    2015-07-01

    Full Text Available Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair. Aberrant activation of the Hedgehog (Hh signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  6. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A., E-mail: lsamant@uab.edu [Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, WTI320D, 1824 6th Avenue South, Birmingham, AL 35233 (United States)

    2015-07-21

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  7. Lethality in PARP-1/Ku80 double mutant mice reveals physiologicalsynergy during early embryogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Henrie, Melinda S.; Kurimasa, Akihiro; Burma, Sandeep; Menissier-de Murcia, Josiane; de Murcia, Gilbert; Li, Gloria C.; Chen,David J.

    2002-09-24

    Ku is an abundant heterodimeric nuclear protein, consisting of 70-kDa and 86-kDa tightly associated subunits that comprise the DNA binding component of DNA-dependent protein kinase. Poly(ADP)ribose polymerase-1 (PARP-1) is a 113-kDa protein that catalyzes the synthesis of poly(ADP-ribose) on target proteins. Both Ku and PARP-1 recognize and bind to DNA ends. Ku functions in the non-homologous end joining (NHEJ) repair pathway whereas PARP-1 functions in the single strand break repair and base excision repair (BER) pathways. Recent studies have revealed that PARP-1 and Ku80 interact in vitro. To determine whether the association of PARP-1 and Ku80 has any physiological significance or synergistic function in vivo, mice lacking both PARP-1 and Ku80 were generated. The resulting offspring died during embryonic development displaying abnormalities around the gastrulation stage. In addition, PARP-1-/-Ku80-/- cultured blastocysts had an increased level of apoptosis. These data suggest that the functions of both Ku80 and PARP-1 are essential for normal embryogenesis and that a loss of genomic integrity leading to cell death through apoptosis is likely the cause of the embryonic lethality observed in these mice.

  8. Adipose-Derived Stem Cells: A Review of Signaling Networks Governing Cell Fate and Regenerative Potential in the Context of Craniofacial and Long Bone Skeletal Repair

    Directory of Open Access Journals (Sweden)

    Kshemendra Senarath-Yapa

    2014-05-01

    Full Text Available Improvements in medical care, nutrition and social care are resulting in a commendable change in world population demographics with an ever increasing skew towards an aging population. As the proportion of the world’s population that is considered elderly increases, so does the incidence of osteodegenerative disease and the resultant burden on healthcare. The increasing demand coupled with the limitations of contemporary approaches, have provided the impetus to develop novel tissue regeneration therapies. The use of stem cells, with their potential for self-renewal and differentiation, is one potential solution. Adipose-derived stem cells (ASCs, which are relatively easy to harvest and readily available have emerged as an ideal candidate. In this review, we explore the potential for ASCs to provide tangible therapies for craniofacial and long bone skeletal defects, outline key signaling pathways that direct these cells and describe how the developmental signaling program may provide clues on how to guide these cells in vivo. This review also provides an overview of the importance of establishing an osteogenic microniche using appropriately customized scaffolds and delineates some of the key challenges that still need to be overcome for adult stem cell skeletal regenerative therapy to become a clinical reality.

  9. Alleged lethal sorcery in East Timor.

    Science.gov (United States)

    Pollanen, Michael S

    2004-01-01

    A wide range of cultural and social perspectives exists on the concept of sudden and unexpected death. In countries, without a formal system of death investigation, sudden death is shrouded in mysticism often based on traditional belief systems. This cultural perspective on sudden death is often at variance with medical and forensic concepts and may include explanations such as sorcery, magic, and voodoo. In this case report, the postmortem findings in an alleged victim of lethal 'black magic', known as ema halo by the indigenous people of East Timor, is described. The alleged victim died suddenly in front of witnesses. At autopsy, marked dilation of a bicuspid aortic valve with annuloaortic ectasia and a sinus of Valsalva aneurysm was found after exhumation of the body. The findings mitigated the local belief in witchcraft and established a natural manner of death.

  10. Lethal photosensitization of biofilm-grown bacteria

    Science.gov (United States)

    Wilson, Michael

    1997-12-01

    Antibacterial agents are increasingly being used for the prophylaxis and treatment of oral diseases. As these agents can be rendered ineffective by resistance development in the target organisms there is a need to develop alternative antimicrobial approaches. Light-activated antimicrobial agents release singlet oxygen and free radicals which can kill adjacent bacteria and a wide range of cariogenic and periodontopathogenic bacteria has been shown to be susceptible to such agents. In the oral cavity these organisms are present as biofilms (dental plaques) which are less susceptible to traditional antimicrobial agents than bacterial suspensions. The results of these studies have shown that biofilm-grown oral bacteria are also susceptible to lethal photosensitization although the light energy doses required are grater than those needed to kill the organisms when they are grown as aqueous suspensions.

  11. Drug facilitated sexual assault with lethal outcome

    DEFF Research Database (Denmark)

    Mehling, Lena-Maria; Johansen, Sys Stybe; Wang, Xin

    2016-01-01

    A very serious case of DFSA (drug facilitated sexual assault) is presented, in which a six-year-old girl died following sedation with γ-hydroxybutyric acid (GHB). She had been sexually abused by a relative. Samples of cardiac blood, bile, vitreous humour, liver, kidney, brain tissues and hair were...... segments of hair - up to 12 cm distant from the hair scalp - GHB concentrations were higher than the overall found endogenous range of 2-3 ng/mg. Police investigations revealed that the uncle had also administered GHB to the older half-sister. Therefore, a sample of her hair was analysed accordingly......, but unremarkable results were obtained. Comparing our toxicological results with police investigations and the offender's statements it can be assumed that the 6-year-old girl had ingested GHB. By exclusion of other causes of death a lethal intoxication with GHB could be confirmed....

  12. Repairs of composite structures

    Science.gov (United States)

    Roh, Hee Seok

    Repair on damaged composite panels was conducted. To better understand adhesively bonded repair, the study investigates the effect of design parameters on the joint strength. The design parameters include bondline length, thickness of adherend and type of adhesive. Adhesives considered in this study were tested to measure their tensile material properties. Three types of adhesively bonded joints, single strap, double strap, and single lap joint were considered under changing bondline lengths, thickness of adherend and type of adhesive. Based on lessons learned from bonded joints, a one-sided patch repair method for composite structures was conducted. The composite patch was bonded to the damaged panel by either film adhesive FM-73M or paste adhesive EA-9394 and the residual strengths of the repaired specimens were compared under varying patch sizes. A new repair method using attachments has been suggested to enhance the residual strength. Results obtained through experiments were analyzed using finite element analysis to provide a better repair design and explain the experimental results. It was observed that the residual strength of the repaired specimen was affected by patch length. Method for rapid repairs of damaged composite structures was investigated. The damage was represented by a circular hole in a composite laminated plate. Pre-cured composite patches were bonded with a quick-curing commercial adhesive near (rather than over) the hole. Tensile tests were conducted on specimens repaired with various patch geometries. The test results showed that, among the methods investigated, the best repair method restored over 90% of the original strength of an undamaged panel. The interfacial stresses in the adhesive zone for different patches were calculated in order to understand the efficiencies of the designs of these patch repairs. It was found that the composite patch that yielded the best strength had the lowest interfacial peel stress between the patch and

  13. Human induced pluripotent cells resemble embryonic stem cells demonstrating enhanced levels of DNA repair and efficacy of nonhomologous end-joining

    Energy Technology Data Exchange (ETDEWEB)

    Fan Jinshui; Robert, Carine [Department of Radiation Oncology, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 7-023A, Baltimore, MD 21201 (United States); Jang, Yoon-Young; Liu Hua; Sharkis, Saul; Baylin, Stephen Bruce [Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21231-1000 (United States); Rassool, Feyruz Virgilia, E-mail: frassool@som.umaryland.edu [Department of Radiation Oncology, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 7-023A, Baltimore, MD 21201 (United States)

    2011-08-01

    Highlights: {yields} iPSC and hESC demonstrate a similar cell cycle profile, with increased S phase cells and decreased G0/G1. {yields} iPSC and hESC increased ROS and decreased DSBs, compared with differentiated parental cells. {yields} iPSC and hESC demonstrate elevated DSB repair activity, including nonhomologous end-joining, compared with differentiated parental cells. {yields} iPSC however show a partial apoptotic response to DNA damage, compared to hESC. {yields} DNA damage responses may constitute important markers for the efficacy of iPSC reprogramming. - Abstract: To maintain the integrity of the organism, embryonic stem cells (ESC) need to maintain their genomic integrity in response to DNA damage. DNA double strand breaks (DSBs) are one of the most lethal forms of DNA damage and can have disastrous consequences if not repaired correctly, leading to cell death, genomic instability and cancer. How human ESC (hESC) maintain genomic integrity in response to agents that cause DSBs is relatively unclear. Adult somatic cells can be induced to 'dedifferentiate' into induced pluripotent stem cells (iPSC) and reprogram into cells of all three germ layers. Whether iPSC have reprogrammed the DNA damage response is a critical question in regenerative medicine. Here, we show that hESC demonstrate high levels of endogenous reactive oxygen species (ROS) which can contribute to DNA damage and may arise from high levels of metabolic activity. To potentially counter genomic instability caused by DNA damage, we find that hESC employ two strategies: First, these cells have enhanced levels of DNA repair proteins, including those involved in repair of DSBs, and they demonstrate elevated nonhomologous end-joining (NHEJ) activity and repair efficacy, one of the main pathways for repairing DSBs. Second, they are hypersensitive to DNA damaging agents, as evidenced by a high level of apoptosis upon irradiation. Importantly, iPSC, unlike the parent cells they are derived

  14. DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents.

    NARCIS (Netherlands)

    B.J. Glassner (Brian); G. Weeda (Geert); J.M. Allan (James); J.L.M. Broekhof (Jose'); N.H.E. Carls (Nick); I. Donker (Ingrid); B.P. Engelward (Bevin); R.J. Hampson (Richard); R. Hersmus (Remko); M.J. Hickman (Mark); R.B. Roth (Richard); H.B. Warren (Henry); M.M. Wu (Mavis); J.H.J. Hoeijmakers (Jan); L.D. Samson (Leona)

    1999-01-01

    textabstractWe have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransf

  15. Differentiation of lethal and non lethal prostate cancer:PSA and PSA isoforms and kinetics

    Institute of Scientific and Technical Information of China (English)

    H Ballentine Carter

    2012-01-01

    Prostate-specific antigen (PSA) testing for the early diagnosis of prostate cancer has led to a decrease in cancer mortality.However,the high prevalence of low-grade prostate cancer and its long natural history,competing causes of death in older men and treatment patterns of prostate cancer,have led to dramatic overtreatment of the disease.Improved markers of prostate cancer lethality are needed to reduce the overtreatment of prostate cancer that leads to a reduced quality of life without extending life for a high proportion of men.The PSA level prior to treatment is routinely used in multivariable models to predict prostate cancer aggressiveness.PSA isoforms and PSA kinetics have been associated with more aggressive phenotypes,but are not routinely employed as part of prediction tools prior to treatment.PSA kinetics is a valuable marker of lethality post treatment and routinely used in determining the need for salvage therapy.

  16. Effects of lethal and non-lethal malaria on the mononuclear phagocyte system

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Tosta

    1983-03-01

    Full Text Available The effects ofone non-lethal species ofmalarialparasite, Plasmodium yoelii, and one lethal species, P. berghei, on the mononuclear phagocyte system (MPS of BALB/c mice were studied. P. yoelii caused a greater and more sustained expansion and activation of the MPS, and the two major populations of spleen phagocytic cells-red pulp and marginal zone macrophages - exhibited a greater increase in numbers in this infection. During the course of P. berghei mataria, the spleen was progressively occupied by haematopoietic tissue and, at the terminal stage of infection, an extensive depletion of lymphocytes and macrophages was apparent. The possibility was suggested that the outcome of mataria may be inftuenced by the particular way the parasite interacts with the MPS.

  17. Potential of Glutathione Antioxidant in the Hippocampus Repair: Preliminary Study on Bioactive Materials Antiaging of Snakehead Fish (Channa striata in Animal Models of Aging

    Directory of Open Access Journals (Sweden)

    Sunarno Sunarno

    2014-12-01

    Full Text Available Snakehead fish meat contains active ingredients with anti-aging potential that serves as a precursor of glutathione. The ability of glutathione as an antiaging opportunities in the utilization of fish meat, especially snakehead fish. Snakehead fish meat contains several important amino acids, such as glutamine, cysteine​​, and glycine so the potential to be developed for the production of food that is nutritious and healthy. This study examines the essential amino acid composition of the antioxidant glutathione precursors found in snakehead fish from Rawa Pening Central Java to increase glutathione in the body and brain. The results showed that every 100g of snakehead fish meat from Rawa Pening containing glutamine (32.39%, cysteine ​​(6.61%, and glycine (9.69%. Snakehead fish meat extract given at a dose of 30 ml/kg/day in both types of animal models of aging effect on the increase in the content of glutathione and glutathione precursors, both in blood and hippocampus. Increased glutathione precursor of the most high to low, respectively glutamine, glycine, and cysteine​​. Availability of essential amino acids can support increased glutathione in the brain. This is indicated by an increase in glutathione hippocampus in both animal models, both on chronological aging or aging due to oxidative stress, respectively (0.822 and 0.359 mol/g bb compared to control tissue.

  18. Workshop on DNA repair.

    NARCIS (Netherlands)

    A.R. Lehmann (Alan); J.H.J. Hoeijmakers (Jan); A.A. van Zeeland (Albert); C.M.P. Backendorf (Claude); B.A. Bridges; A. Collins; R.P.D. Fuchs; G.P. Margison; R. Montesano; E. Moustacchi; A.T. Natarajan; M. Radman; A. Sarasin; E. Seeberg; C.A. Smith; M. Stefanini (Miria); L.H. Thompson; G.P. van der Schans; C.A. Weber (Christine); M.Z. Zdzienika

    1992-01-01

    textabstractA workshop on DNA repair with emphasis on eukaryotic systems was held, under the auspices of the EC Concerted Action on DNA Repair and Cancer, at Noordwijkerhout (The Netherlands) 14-19 April 1991. The local organization of the meeting was done under the auspices of the Medical Genetic C

  19. Laparoscopic lumbar hernia repair.

    Science.gov (United States)

    Madan, Atul K; Ternovits, Craig A; Speck, Karen E; Pritchard, F Elizabeth; Tichansky, David S

    2006-04-01

    Lumbar hernias are rare clinical entities that often pose a challenge for repair. Because of the surrounding anatomy, adequate surgical herniorraphy is often difficult. Minimally invasive surgery has become an option for these hernias. Herein, we describe two patients with lumbar hernias (one with a recurrent traumatic hernia and one with an incisional hernia). Both of these hernias were successfully repaired laparoscopically.

  20. Mutation Induced Extinction in Finite Populations: Lethal Mutagenesis and Lethal Isolation

    OpenAIRE

    C Scott Wylie; Shakhnovich, Eugene I.

    2012-01-01

    Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate “semi-conservatively,” e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathoge...

  1. DNA repair protocols

    DEFF Research Database (Denmark)

    Bjergbæk, Lotte

    In its 3rd edition, this Methods in Molecular Biology(TM) book covers the eukaryotic response to genomic insult including advanced protocols and standard techniques in the field of DNA repair. Offers expert guidance for DNA repair, recombination, and replication. Current knowledge of the mechanisms...... that regulate DNA repair has grown significantly over the past years with technology advances such as RNA interference, advanced proteomics and microscopy as well as high throughput screens. The third edition of DNA Repair Protocols covers various aspects of the eukaryotic response to genomic insult including...... recent advanced protocols as well as standard techniques used in the field of DNA repair. Both mammalian and non-mammalian model organisms are covered in the book, and many of the techniques can be applied with only minor modifications to other systems than the one described. Written in the highly...

  2. Syn-lethality: an integrative knowledge base of synthetic lethality towards discovery of selective anticancer therapies.

    Science.gov (United States)

    Li, Xue-juan; Mishra, Shital K; Wu, Min; Zhang, Fan; Zheng, Jie

    2014-01-01

    Synthetic lethality (SL) is a novel strategy for anticancer therapies, whereby mutations of two genes will kill a cell but mutation of a single gene will not. Therefore, a cancer-specific mutation combined with a drug-induced mutation, if they have SL interactions, will selectively kill cancer cells. While numerous SL interactions have been identified in yeast, only a few have been known in human. There is a pressing need to systematically discover and understand SL interactions specific to human cancer. In this paper, we present Syn-Lethality, the first integrative knowledge base of SL that is dedicated to human cancer. It integrates experimentally discovered and verified human SL gene pairs into a network, associated with annotations of gene function, pathway, and molecular mechanisms. It also includes yeast SL genes from high-throughput screenings which are mapped to orthologous human genes. Such an integrative knowledge base, organized as a relational database with user interface for searching and network visualization, will greatly expedite the discovery of novel anticancer drug targets based on synthetic lethality interactions. The database can be downloaded as a stand-alone Java application.

  3. DESARDA’S NO MESH REPAIR VERSUS LICHTENSTEIN’S OPEN MESH REPAIR OF INGUINAL HERNIA: A COMPARATIVE STUDY

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    Zaheer

    2015-09-01

    Full Text Available BACKGROUND : The tissue - based techniques are still acceptable for primary inguinal hernia repair according to the European Hernia Society guidelines. Desarda’s no mesh technique, introduced in 2001, is a hernia repair method using an undetached strip of external oblique Apo neurosis . This study compared outcomes after hernia repair with Desarda (D and mesh - based Lichtenstein (L techniques. METHODS : A total of 100 patients were randomly assigned to the D or L group (50 each. The primary outcomes measured were post - operative pain ( D ay1 and day 7, mean hospital stay (in days, return to basic activity (in days and recurrence. RESULTS : During the follow - up, no recurrences were observed in each group (p = 1.000. Average duration of the Desarda’s repair was 65.64 minutes, while the Lichtenstein repair lasted for 65.76 minutes. Mean VAS on 1 st post - operative day was significantly less in Desarda’s repair (2.86 than Lichenstein’s repair (3.50, (p=0.0004. Mean hospital stay was less in Desarda’s repair (2.58 days versus Lichtenstein’s repair (3.90 days p=0.0001. Return to basic physical activity was earlier in Desarda’s repair (7.04 days than Lichenstein’s repair (11.30 days, (p=<0.0001. However there was no recurrence in either group in 18 months follow up. CONCLUSIONS : The Desarda’s and Lichtenstein’s methods of primary inguinal hernia repair do not differ in the means of procedure complexity, surgery time and complication profile. However the return to basic physical activity was earlier in Desarda’s repair. Desarda’s no mesh repair is equally safe and more cost effective than Lichtenstein’s repair. The technique may potentially increase the number of tissue - based methods a vailable for treating inguinal hernias.

  4. Repair and regeneration in endodontics.

    Science.gov (United States)

    Lin, L M; Rosenberg, P A

    2011-10-01

    The ideal objective of treatment of established diseases, including irreversible pulpitis and apical periodontitis, is to achieve wound healing. Wound healing can result in repair or regeneration. The ultimate goal of wound healing is to restore the original architecture and biological function of the injured tissue or organ. Although humans are equipped with powerful innate and adaptive immune defence mechanisms, many intrinsic and extrinsic factors can affect wound healing. Complete regeneration following injury in humans can occur only in the pre-natal foetus within 24 weeks of gestation. Post-natal wounds including irreversible pulpitis or apical periodontitis always heal by repair or by a combination of repair and regeneration. Somatic cells, such as fibroblasts, macrophages, cementoblasts and osteoblasts, in the pulp and periapical tissues have limited potential for regeneration following injury and lack of telomerase. Wound healing of irreversible pulpitis and apical periodontitis requires recruitment and differentiation of progenitor/stem cells into tissue-committed somatic cells. Stem cell differentiation is regulated by intrinsic factors and extrinsic micro-environmental cues. Functionality of stem cells appears to show an age-related decline because of the change in intrinsic properties and diminished signals within the extrinsic local and systemic environment that modulate the function of stem cells or their progeny. Infection induces an immuno-inflammatory response and tissue destruction, which hinders the potential of tissue regeneration. Therefore, prevention, early detection and treatment of inflammation/infection of pulpal and periapical disease can enhance regeneration and minimize the repair of pulpal and periapical tissues after endodontic therapy. © 2011 International Endodontic Journal.

  5. 40 CFR 798.5450 - Rodent dominant lethal assay.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Rodent dominant lethal assay. 798.5450 Section 798.5450 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES... lethality, high pregnancy frequency and high implant numbers are recommended. (ii) Age. Healthy,...

  6. Genetic interaction motif finding by expectation maximization – a novel statistical model for inferring gene modules from synthetic lethality

    Directory of Open Access Journals (Sweden)

    Ye Ping

    2005-12-01

    Full Text Available Abstract Background Synthetic lethality experiments identify pairs of genes with complementary function. More direct functional associations (for example greater probability of membership in a single protein complex may be inferred between genes that share synthetic lethal interaction partners than genes that are directly synthetic lethal. Probabilistic algorithms that identify gene modules based on motif discovery are highly appropriate for the analysis of synthetic lethal genetic interaction data and have great potential in integrative analysis of heterogeneous datasets. Results We have developed Genetic Interaction Motif Finding (GIMF, an algorithm for unsupervised motif discovery from synthetic lethal interaction data. Interaction motifs are characterized by position weight matrices and optimized through expectation maximization. Given a seed gene, GIMF performs a nonlinear transform on the input genetic interaction data and automatically assigns genes to the motif or non-motif category. We demonstrate the capacity to extract known and novel pathways for Saccharomyces cerevisiae (budding yeast. Annotations suggested for several uncharacterized genes are supported by recent experimental evidence. GIMF is efficient in computation, requires no training and automatically down-weights promiscuous genes with high degrees. Conclusion GIMF effectively identifies pathways from synthetic lethality data with several unique features. It is mostly suitable for building gene modules around seed genes. Optimal choice of one single model parameter allows construction of gene networks with different levels of confidence. The impact of hub genes the generic probabilistic framework of GIMF may be used to group other types of biological entities such as proteins based on stochastic motifs. Analysis of the strongest motifs discovered by the algorithm indicates that synthetic lethal interactions are depleted between genes within a motif, suggesting that synthetic

  7. Lethal and Sublethal Effects of Insecticides on the Egg Parasitoid Telenomus podisi (Hymenoptera: Platygastridae).

    Science.gov (United States)

    Turchen, L M; Golin, V; Butnariu, A R; Guedes, R N C; Pereira, M J B

    2016-02-01

    Insecticide use remains controversial, and subjected to increasing environmental and health concerns, even when recent insecticide groups are considered. Neonicotinoids and even bioinsecticides are in the forefront of discussions regarding their nontarget safety. The ubiquitous focus on the lethal effects of insecticides on nontarget species has been expanding to sublethal effects, as sublethal exposure extends for a longer time and affects a broader range of (nontarget) species. Here we explored the lethal and sublethal effects of a lambda-cyhalothrin + thiamethoxan mixture, the neonicotinoid imidacloprid, and the bioinsecticide azadirachtin on the egg parasitoid Telenomus podisi Ashmead, an important parasitoid of stink bug Euschistus heros (F.), a key soybean pest in neotropical America. Contact with dry insecticide residue on glass surface and (parasitized and healthy) host egg immersion exposure bioassays were performed, assessing their acute lethal effects, and their potential sublethal impairment of parasitism, adult emergence, and fertility of the egg parasitoid. Both imidacloprid and the insecticide mixture exhibited high acute lethal activity toward the parasitoid under contact with dry insecticide residue. These insecticides compromised parasitism and wasp emergence when exposure took place before parasitism. In contrast, azadirachtin did not affect adult survival. However, this bioinsecticide compromised parasitism and progeny production, impairing the female parasitoid reproductive potential. Our results indicate strong negative effects of imidacloprid, and specially of the mixture lambda-cyhalthrin + thiamethoxan. However, even azadirachtin, which exhibited low acute lethality, exhibited significant negative sublethal effects on parasitism and population growth of egg parasitoid, cautioning against their use and the need of semifield and field assessments to confirm such an impact. © The Authors 2015. Published by Oxford University Press on behalf of

  8. Bacterial Factors Associated with Lethal Outcome of Enteropathogenic Escherichia coli Infection: Genomic Case-Control Studies.

    Directory of Open Access Journals (Sweden)

    Michael S Donnenberg

    2015-05-01

    Full Text Available Typical enteropathogenic Escherichia coli (tEPEC strains were associated with mortality in the Global Enteric Multicenter Study (GEMS. Genetic differences in tEPEC strains could underlie some of the variability in clinical outcome.We produced draft genome sequences of all available tEPEC strains from GEMS lethal infections (LIs and of closely matched EPEC strains from GEMS subjects with non-lethal symptomatic infections (NSIs and asymptomatic infections (AIs to identify gene clusters (potential protein encoding sequences sharing ≥90% nucleotide sequence identity associated with lethality.Among 14,412 gene clusters identified, the presence or absence of 392 was associated with clinical outcome. As expected, more gene clusters were associated with LI versus AI than LI versus NSI. The gene clusters more prevalent in strains from LI than those from NSI and AI included those encoding proteins involved in O-antigen biogenesis, while clusters encoding type 3 secretion effectors EspJ and OspB were among those more prevalent in strains from non-lethal infections. One gene cluster encoding a variant of an NleG ubiquitin ligase was associated with LI versus AI, while two other nleG clusters had the opposite association. Similar associations were found for two nleG gene clusters in an additional, larger sample of NSI and AI GEMS strains.Particular genes are associated with lethal tEPEC infections. Further study of these factors holds potential to unravel the mechanisms underlying severe disease and to prevent adverse outcomes.

  9. Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells.

    Science.gov (United States)

    Pollok, Simone; Pfeiffer, Ann-Catherine; Lobmann, Ralf; Wright, Catherine S; Moll, Ingrid; Martin, Patricia E M; Brandner, Johanna M

    2011-04-01

    During early wound healing (WH) events Connexin 43 (Cx43) is down-regulated at wound margins. In chronic wound margins, including diabetic wounds, Cx43 expression is enhanced suggesting that down-regulation is important for WH. We previously reported that the Cx43 mimetic peptide Gap27 blocks Cx43 mediated intercellular communication and promotes skin cell migration of infant cells in vitro. In the present work we further investigated the molecular mechanism of Gap27 action and its therapeutic potential to improve WH in skin tissue and diabetic and non-diabetic cells. Ex vivo skin, organotypic models and human keratinocytes/fibroblasts of young and old donors and of diabetic and non-diabetic origin were used to assess the impact of Gap27 on cell migration, proliferation, Cx43 expression, localization, phosphorylation and hemichannel function. Exposure of ex vivo WH models to Gap27 decreased dye spread, accelerated WH and elevated cell proliferation. In non-diabetic cell cultures Gap27 decreased dye uptake through Cx hemichannels and after scratch wounding cells showed enhanced migration and proliferation. Cells of diabetic origin were less susceptible to Gap27 during early passages. In late passages these cells showed responses comparable to non-diabetic cells. The cause of the discrepancy between diabetic and non-diabetic cells correlated with decreased Cx hemichannel activity in diabetic cells but excluded differences in Cx43 expression, localization and Ser368-phosphorylation. These data emphasize the importance of Cx43 in WH and support the concept that Gap27 could be a beneficial therapeutic to accelerate normal WH. However, its use in diabetic WH may be restricted and our results highlight differences in the role of Cx43 in skin cells of different origin.

  10. Free Biceps Tendon Autograft to Augment Arthroscopic Rotator Cuff Repair

    OpenAIRE

    Obma, Padraic R.

    2013-01-01

    Arthroscopic rotator cuff repairs have become the standard of treatment for all sizes of tears over the past several years. Current healing rates reported in the literature are quite good, but improving the healing potential of rotator cuff repairs remains a challenging problem. There has been an increase recently in the use of augmentation of rotator cuff repairs with xenografts or synthetics for large and massive tears. Biceps tenodesis is often indicated as part of the treatment plan while...

  11. Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy.

    Science.gov (United States)

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A; Leppla, Stephen H; Johnson, Alan T

    2010-11-15

    Sub-nanomolar small molecule inhibitors of anthrax lethal factor have been identified using SAR and Merck L915 (4) as a model compound. One of these compounds (16) provided 100% protection in a rat lethal toxin model of anthrax disease.

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

    NARCIS (Netherlands)

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

    2016-01-01

    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 pe

  13. Advances of stem cell based-therapeutic approaches for tendon repair

    Directory of Open Access Journals (Sweden)

    Lidi Liu

    2017-04-01

    The translational potential of this article: This paper reviews recent progress on stem cell-based therapeutic approaches for tendon repair, which highlights its translational potential and challenges.

  14. Salvage hypospadias repairs

    Directory of Open Access Journals (Sweden)

    Sripathi V

    2008-01-01

    Full Text Available Aim: Review of our experience and to develop an algorithm for salvage procedures in the management of hypospadias cripples and treatment of urethral strictures following hypospadias repair. Methods: This is a retrospective review of hypospadias surgeries over a 41-month period. Out of a total 168 surgeries, 20 were salvage/re-operative repairs. In three children a Duplay repair was feasible, while in four others a variety of single-stage repairs could be done. The repair was staged in seven children - buccal mucosal grafts (BMGs in five, buccal mucosal tube in one, and skin graft in one. Five children with dense strictures were managed by dorsal BMG inlay grafting in one, vascularized tunical onlay grafting on the ventrum in one, and a free tunical patch in one. Three children were treated by internal urethrotomy and stenting for four weeks with a poor outcome. Results: The age of children ranged from 1.5-15 years (mean 4.5. Follow-up ranged from 3 months to 3.5 years. Excellent results were obtained in 10 children (50% with a well-surfaced erect penis and a slit-like meatus. Glans closure could not be achieved and meatus was coronal in three. Two children developed fistulae following a Duplay repair and following a staged BMG. Three repairs failed completely - a composite repair broke down, a BMG tube stenosed with a proximal leak, and a stricture recurred with loss of a ventral free tunical graft. Conclusions: In salvage procedures performed on hypospadias cripples, a staged repair with buccal mucosa as an inlay in the first stage followed by tubularization 4-6 months later provides good results. A simple algorithm to plan corrective surgery in failed hypospadias cases and obtain satisfactory results is devised.

  15. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival.

    Science.gov (United States)

    Tinkum, Kelsey L; Stemler, Kristina M; White, Lynn S; Loza, Andrew J; Jeter-Jones, Sabrina; Michalski, Basia M; Kuzmicki, Catherine; Pless, Robert; Stappenbeck, Thaddeus S; Piwnica-Worms, David; Piwnica-Worms, Helen

    2015-12-22

    Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.

  16. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

    Science.gov (United States)

    Tinkum, Kelsey L.; Stemler, Kristina M.; White, Lynn S.; Loza, Andrew J.; Jeter-Jones, Sabrina; Michalski, Basia M.; Kuzmicki, Catherine; Pless, Robert; Stappenbeck, Thaddeus S.; Piwnica-Worms, David; Piwnica-Worms, Helen

    2015-01-01

    Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy. PMID:26644583

  17. The effects of altered fractionation schedules on the survival of human cell lines differing in their proliferative activity and repair capacity

    Energy Technology Data Exchange (ETDEWEB)

    Konefal, J.B.; Taylor, Y.C. (Washington Univ. School of Medicine, St. Louis, MO (USA))

    1989-11-01

    Plateau phase cultures of human cell lines were used as model systems to study the relative influences of proliferation and repair on the effectiveness of altered fractionation schedules. A human normal diploid fibroblast cell line (AG1522) which has a high capacity to repair potentially lethal radiation damage (PLD) and very little proliferative activity when grown to confluence was compared to human tumor cell lines which maintain significant cell-cycle activity in plateau phase. The human fibrosarcoma cell line, HT1080, used in the present study exhibited a much greater rate of turnover than the normal fibroblasts as determined from tritiated thymidine incorporation (5 day labeling index of 66% vs 20%) and no PLD repair, as determined by delayed plating experiments, in plateau phase. Twenty Gy were delivered to both cell lines over 5 days in 3 regimens: one 4 Gy fraction/day, two 2 Gy fractions/day with a 2 hr interval between doses, and two 2 Gy fractions/day with a 6 hr interval between doses. Although the normal fibroblasts demonstrated the greatest sparing between acute single doses and one 4 Gy fraction/day, there was little additional benefit (increased survival) from the increased dose fractionation. In contrast, the twice daily fractionation schedules resulted in significant differential sparing of the fibrosarcoma cells compared to the normal fibroblasts. With the 6 hr interval between doses, the survival advantages of the cell line with the slow turnover rate and high PLD repair capacity were completely lost. Split-dose experiments indicated slightly less sublethal damage repair in the fibrosarcoma cell line, but for both cell lines recovery was complete in 2 hr. DNA distributions were measured by flow cytometry and long term labeling index measurements performed in parallel with the multifraction radiation survival studies.

  18. Cancer TARGETases: DSB repair as a pharmacological target.

    Science.gov (United States)

    Samadder, Pounami; Aithal, Rakesh; Belan, Ondrej; Krejci, Lumir

    2016-05-01

    Cancer is a disease attributed to the accumulation of DNA damages due to incapacitation of DNA repair pathways resulting in genomic instability and a mutator phenotype. Among the DNA lesions, double stranded breaks (DSBs) are the most toxic forms of DNA damage which may arise as a result of extrinsic DNA damaging agents or intrinsic replication stress in fast proliferating cancer cells. Accurate repair of DSBs is therefore paramount to the cell survival, and several classes of proteins such as kinases, nucleases, helicases or core recombinational proteins have pre-defined jobs in precise execution of DSB repair pathways. On one hand, the proper functioning of these proteins ensures maintenance of genomic stability in normal cells, and on the other hand results in resistance to various drugs employed in cancer therapy and therefore presents a suitable opportunity for therapeutic targeting. Higher relapse and resistance in cancer patients due to non-specific, cytotoxic therapies is an alarming situation and it is becoming more evident to employ personalized treatment based on the genetic landscape of the cancer cells. For the success of personalized treatment, it is of immense importance to identify more suitable targetable proteins in DSB repair pathways and also to explore new synthetic lethal interactions with these pathways. Here we review the various alternative approaches to target the various protein classes termed as cancer TARGETases in DSB repair pathway to obtain more beneficial and selective therapy.

  19. Repair of 8-methoxypsoralen monoadducts and diadducts in bacteriophages and bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Belogurov, A.A.; Zuev, A.V.; Zavil' gel' skii, G.B.

    1976-01-01

    The combined action of 8-methoxypsoralen (8-MOP) and light with lambda greater than 310 nm on bacteriophages and bacteria results in the formation of the following two types of photo-products in the DNA: monoadducts, in which 8-MOP is covalently bound to a pyrimidine base, and diadducts or cross links, in which 8-MOP is covalently bound to two pyrimidines from complementary strands. The method of repeated irradiation has been proposed for analyzing the degree of lethality of the photoproducts in DNA. According to this method, the preparation is freed of free 8-MOP molecules after the first irradiation and then irradiated for a second time. In this case the monoadducts are converted into cross linkages between the strands. Approximately 3-10(-9) cross links/Dalton-min form in Escherichia coli DNA during the first irradiation. The rate of the formation of cross links drops by a factor of about 2 during the repeated irradiation. It has been shown that the 8-MOP monoadducts are repaired by the uvr system just as efficiently as are lethal photoproducts of the cyclobutane pyrimidine dimer type. Lethal cross linkages in bacteria and phages are repaired by the joint action of the uvr, recA, and lex systems. A scheme has been proposed for the repair of cross linkages in one genome by these systems. The photoreactivating enzyme is inactive on DNA subjected to the combined action of 8-MOP and light. The kinetics of the repair of monadducts in bacteria and phages with various defects in the repair systems have been studied. It has been shown that the products of genes recA and lex take part in the repair process according to an excision-resynthesis method. The use of the method of repeated irradiation with 8-MOP as an express method for detecting repair systems of the uvr type in cells has been proposed.

  20. Lethal altruists: itineraries along the dark outskirts of moralistic prosociality.

    Science.gov (United States)

    Tobeña, Adolf

    2009-06-01

    Suicide bombers are the most spectacular example of an impregnable morality toward one's own group that co-exists alongside a radical amorality toward members of another group. Suicide bombers carry out massacres with the utter conviction that they are acting in accordance with values associated with the greatest good. Suicidal attacks are conceived as a form of lethal altruism, a damaging drift from human cooperative tendencies and one that requires a detailed understanding. Strong altruism is a main component of a cluster of temperamental traits that may distinguish individuals with propensities to put themselves at the threshold of major progroupal sacrifices. Among all populations there will be pockets of extreme moralizing altruists willing to make high investments in others, investments involving great personal risk. A research framework is outlined to study other constitutionally based traits (dominance, boldness, aggressiveness, machiavellianism, narcissism, messianism, credulity/religiosity) that may also contribute to the different roles played by self-recruited members in combative cells that in turn are crucial for the ties they establish and the tactics employed. Individually oriented research may reveal profiles distinguishing between potential inducers and performers of martyrdom. As a rule, machiavellistic leaders do not usually squander their personal choices on group commitments; on the contrary, their gift for simulating altruism is used for individual gains. Potential martyrs, on the other hand, are by definition squanderers. Evidence accrued in recent years in fields going from behavioral economics to cognitive neuroimaging makes such an endeavor feasible.

  1. Key tissue targets responsible for anthrax toxin-induced-lethality

    Science.gov (United States)

    Liu, Shihui; Zhang, Yi; Moayeri, Mahtab; Liu, Jie; Crown, Devorah; Fattah, Rasem; Wein, Alexander N.; Yu, Zu-Xi; Finkel, Toren; Leppla, Stephen H.

    2014-01-01

    Summary Bacillus anthracis, the causative agent of anthrax disease, is lethal due to the actions of two exotoxins, anthrax lethal toxin (LT) and edema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occur through damage to distinct cell-types; while targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Surprisingly, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not appear to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems. PMID:23995686

  2. Progress of peripheral nerve repair

    Institute of Scientific and Technical Information of China (English)

    陈峥嵘

    2002-01-01

    Study on repair of peripheral nerve injury has been proceeding over a long period of time. With the use of microsurgery technique since 1960s,the quality of nerve repair has been greatly improved. In the past 40 years, with the continuous increase of surgical repair methods, more progress has been made on the basic research of peripheral nerve repair.

  3. Achilles tendon repair

    Science.gov (United States)

    Achilles tendon rupture-surgery; Percutaneous Achilles tendon rupture repair ... To fix your torn Achilles tendon, the surgeon will: Make a cut down the back of your heel Make several small cuts rather than one large cut ...

  4. Diaphragmatic hernia repair - slideshow

    Science.gov (United States)

    ... presentations/100014.htm Diaphragmatic hernia repair - series—Normal anatomy To use the sharing ... Overview The chest cavity includes the heart and lungs. The abdominal cavity includes the liver, the stomach, ...

  5. Eye muscle repair - slideshow

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/presentations/100062.htm Eye muscle repair - series—Normal anatomy To use the sharing ... the eyeball to the eye socket. The external muscles of the eye are found behind the conjunctiva. ...

  6. Tracheoesophageal fistula repair - slideshow

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/presentations/100103.htm Tracheoesophageal fistula repair - series—Normal anatomy To use the sharing ... Editorial team. Related MedlinePlus Health Topics Esophagus Disorders Fistulas Tracheal Disorders A.D.A.M., Inc. is ...

  7. Inguinal hernia repair - slideshow

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/presentations/100027.htm Inguinal hernia repair - series—Normal anatomy To use the sharing ... to slide 4 out of 4 Overview A hernia occurs when part of an organ protrudes through ...

  8. Pectus excavatum repair - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100035.htm Pectus excavatum repair - series—Normal anatomy To use the sharing ... Go to slide 4 out of 4 Overview Pectus excavatum is a deformity of the front of the ...

  9. Hiatal hernia repair - slideshow

    Science.gov (United States)

    ... presentations/100028.htm Hiatal hernia repair - series—Normal anatomy To use the sharing features on ... Overview The esophagus runs through the diaphragm to the stomach. It functions to carry food from the mouth ...

  10. Repairing ceramic insulating tiles

    Science.gov (United States)

    Dunn, B. R.; Laymance, E. L.

    1980-01-01

    Fused-silica tiles containing large voids or gauges are repaired without adhesives by plug insertion method. Tiles are useful in conduits for high-temperature gases, in furnaces, and in other applications involving heat insulation.

  11. Rotator cuff repair - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100229.htm Rotator cuff repair - series—Normal anatomy To use the sharing ... to slide 4 out of 4 Overview The rotator cuff is a group of muscles and tendons that ...

  12. Cleft lip repair - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100010.htm Cleft lip repair - series—Normal anatomy To use the sharing ... abnormal opening in the middle of the upper lip. A cleft palate is an opening in the roof of ...

  13. Are high-lethality suicide attempters with bipolar disorder a distinct phenotype?

    Science.gov (United States)

    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

    2009-01-01

    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.

  14. Grey Repairable System Analysis

    Institute of Scientific and Technical Information of China (English)

    Renkuan Guo; Charles Ernie Love

    2006-01-01

    In this paper, we systematically discuss the basic concepts of grey theory, particularly the grey differential equation and its mathematical foundation, which is essentially unknown in the reliability engineering community. Accordingly,we propose a small-sample based approach to estimate repair improvement effects by partitioning system stopping times into intrinsic functioning times and repair improvement times. An industrial data set is used for illustrative purposes in a stepwise manner.

  15. The Application of Polysaccharide Biocomposites to Repair Cartilage Defects

    Directory of Open Access Journals (Sweden)

    Feng Zhao

    2014-01-01

    Full Text Available Owing to own nature of articular cartilage, it almost has no self-healing ability once damaged. Despite lots of restore technologies having been raised in the past decades, no repair technology has smoothly substituted for damaged cartilage using regenerated cartilage tissue. The approach of tissue engineering opens a door to successfully repairing articular cartilage defects. For instance, grafting of isolated chondrocytes has huge clinical potential for restoration of cartilage tissue and cure of chondral injury. In this paper, SD rats are used as subjects in the experiments, and they are classified into three groups: natural repair (group A, hyaluronic acid repair (group B, and polysaccharide biocomposites repair (hyaluronic acid hydrogel containing chondrocytes, group C. Through the observation of effects of repairing articular cartilage defects, we concluded that cartilage repair effect of polysaccharide biocomposites was the best at every time point, and then the second best was hyaluronic acid repair; both of them were better than natural repair. Polysaccharide biocomposites have good biodegradability and high histocompatibility and promote chondrocytes survival, reproduction, and spliting. Moreover, polysaccharide biocomposites could not only provide the porous network structure but also carry chondrocytes. Consequently hyaluronic acid-based polysaccharide biocomposites are considered to be an ideal biological material for repairing articular cartilage.

  16. Engineered repressible lethality for controlling the pink bollworm, a lepidopteran pest of cotton.

    Directory of Open Access Journals (Sweden)

    Neil I Morrison

    Full Text Available The sterile insect technique (SIT is an environmentally friendly method of pest control in which insects are mass-produced, irradiated and released to mate with wild counterparts. SIT has been used to control major pest insects including the pink bollworm (Pectinophora gossypiella Saunders, a global pest of cotton. Transgenic technology has the potential to overcome disadvantages associated with the SIT, such as the damaging effects of radiation on released insects. A method called RIDL (Release of Insects carrying a Dominant Lethal is designed to circumvent the need to irradiate insects before release. Premature death of insects' progeny can be engineered to provide an equivalent to sterilisation. Moreover, this trait can be suppressed by the provision of a dietary antidote. In the pink bollworm, we generated transformed strains using different DNA constructs, which showed moderate-to-100% engineered mortality. In permissive conditions, this effect was largely suppressed. Survival data on cotton in field cages indicated that field conditions increase the lethal effect. One strain, called OX3402C, showed highly penetrant and highly repressible lethality, and was tested on host plants where its larvae caused minimal damage before death. These results highlight a potentially valuable insecticide-free tool against pink bollworm, and indicate its potential for development in other lepidopteran pests.

  17. Engineered Repressible Lethality for Controlling the Pink Bollworm, a Lepidopteran Pest of Cotton

    Science.gov (United States)

    Morrison, Neil I.; Simmons, Gregory S.; Fu, Guoliang; O’Connell, Sinead; Walker, Adam S.; Dafa’alla, Tarig; Walters, Michelle; Claus, John; Tang, Guolei; Jin, Li; Marubbi, Thea; Epton, Matthew J.; Harris, Claire L.; Staten, Robert T.; Miller, Ernest; Miller, Thomas A.; Alphey, Luke

    2012-01-01

    The sterile insect technique (SIT) is an environmentally friendly method of pest control in which insects are mass-produced, irradiated and released to mate with wild counterparts. SIT has been used to control major pest insects including the pink bollworm (Pectinophora gossypiella Saunders), a global pest of cotton. Transgenic technology has the potential to overcome disadvantages associated with the SIT, such as the damaging effects of radiation on released insects. A method called RIDL (Release of Insects carrying a Dominant Lethal) is designed to circumvent the need to irradiate insects before release. Premature death of insects’ progeny can be engineered to provide an equivalent to sterilisation. Moreover, this trait can be suppressed by the provision of a dietary antidote. In the pink bollworm, we generated transformed strains using different DNA constructs, which showed moderate-to-100% engineered mortality. In permissive conditions, this effect was largely suppressed. Survival data on cotton in field cages indicated that field conditions increase the lethal effect. One strain, called OX3402C, showed highly penetrant and highly repressible lethality, and was tested on host plants where its larvae caused minimal damage before death. These results highlight a potentially valuable insecticide-free tool against pink bollworm, and indicate its potential for development in other lepidopteran pests. PMID:23226548

  18. Laparoscopic mesh repair of parahiatal hernia: a case report.

    Science.gov (United States)

    Lew, Pei Shi; Wong, Andrew Siang Yih

    2013-08-01

    We report a case of a primary parahiatal hernia that was repaired laparoscopically with a composite mesh. A 51-year-old woman presented with vomiting and epigastric pain. CT scan showed a giant paraesophageal hernia with intrathoracic gastric volvulus. Intraoperatively, a diaphragmatic muscular defect was found lateral to an attenuated left crus of the diaphragm, distinct from the normal esophageal hiatus. The defect ring was fibrotic, making a tension-free primary repair difficult. A laparoscopic mesh repair was performed with a composite mesh, which was covered with the hernia sac to prevent potential erosion into the esophagus or stomach. Recovery was uneventful and the patient was discharged on the 5 days postoperatively. She remained asymptomatic at subsequent follow-up. Laparoscopic repair of parahiatal hernia can be safely performed. In circumstances where a large or fibrotic defect prevents a tension-free primary repair, the use of a composite mesh can provide effective repair of the hernia.

  19. Lethal and sub-lethal responses of native freshwater mussels exposed to granular Bayluscide®, a sea lamprey larvicide

    Science.gov (United States)

    Newton, Teresa; Boogaard, Michael A.; Gray, Brian R.; Hubert, Terrance D.; Schloesser, Nicholas

    2017-01-01

    The invasive sea lamprey (Petromyzon marinus) poses a substantial threat to fish communities in the Great Lakes. Efforts to control sea lamprey populations typically involve treating tributary streams with lampricides on a recurring cycle. The presence of a substantial population of larval sea lampreys in the aquatic corridor between Lakes Huron and Erie prompted managers to propose a treatment using the granular formulation of Bayluscide® that targets larval sea lampreys that reside in sediments. However, these treatments could cause adverse effects on native freshwater mussels—imperiled animals that also reside in sediments. We estimated the risk of mortality and sub-lethal effects among eight species of adult and sub-adult mussels exposed to Bayluscide® for durations up to 8 h to mimic field applications. Mortality was appreciable in some species, especially in sub-adults (range, 23–51%). The lethal and sub-lethal effects were positively associated with the duration of exposure in most species and life stage combinations. Estimates of the median time of exposure that resulted in lethal and sub-lethal effects suggest that sub-adults were often affected by Bayluscide® earlier than adults. Siphoning activity and burrowing position of mussels during exposure may have moderated the uptake of Bayluscide® and may have influenced lethal and sub-lethal responses. Given that the various species and life stages were differentially affected, it will be difficult to predict the effects of Bayluscide® treatments on mussels.

  20. Fentanyl-Laced 'Norco' Is Lethal, Report Warns

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_160158.html Fentanyl-Laced 'Norco' Is Lethal, Report Warns New street ... study involving the drug. The street drug combines fentanyl -- the synthetic opioid painkiller linked to the death ...

  1. New type of lethal short-limbed dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Nairn, E.R.; Chapman, S.

    1989-05-01

    Details are presented of a most unusual osteo-chondrodysplasia which presents with lethal neonatal short-limbed dwarfism, defective ossification and nodular calcification with cartilage. The features resemble one case previously described in the literature.

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

    Science.gov (United States)

    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.

  3. Perinatal-lethal Gaucher disease presenting as hydrops fetalis.

    Science.gov (United States)

    BenHamida, Emira; Ayadi, Imene; Ouertani, Ines; Chammem, Maroua; Bezzine, Ahlem; BenTmime, Riadh; Attia, Leila; Mrad, Ridha; Marrakchi, Zahra

    2015-01-01

    Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis. Less common signs of the disease are hepatosplenomegaly, ichthyosis and arthrogryposis. We report a case of Gaucher's disease (type 2) diagnosed in a newborn who presented with Hydrops Fetalis.

  4. Testicular trauma secondary to less-lethal kinetic energy munitions.

    Science.gov (United States)

    Kavoussi, Parviz K; Hermans, Michael R

    2006-06-01

    Many cases of testicular trauma secondary to munitions have been reported. We report a case of a 37-year-old man who suffered testicular trauma as a result of a less-lethal munition projectile. With the advent, and increased use, of less-lethal munitions by the military and law enforcement agencies, more of these new subsets of genitourinary trauma patients who will require care are sure to result.

  5. Life-saving electroconvulsive therapy in a patient with near-lethal catatonia.

    Science.gov (United States)

    Girardi, Paolo; Rapinesi, Chiara; Cuomo, Ilaria; Kotzalidis, Giorgio D; Del Casale, Antonio; Serata, Daniele; Campi, Sandra; Caloro, Matteo; De Chiara, Lavinia; Tamorri, Stefano Maria; Scatena, Paola; Caccia, Federica; Bersani, Francesco Saverio; Carbonetti, Paolo; Vento, Alessandro; Dimitri-Valente, Giorgia; Tatarelli, Roberto; Fensore, Claudio; Ferracuti, Stefano; Angeletti, Gloria

    2012-01-01

    A young woman with bipolar I disorder and comorbid catatonia on enteral nutrition from several months, developed a form of near-lethal catatonia with weight loss, pressure sores, muscle atrophy, electrolyte imbalance, and depression of vital signs. A compulsory treatment was necessary, and informed consent was obtained from her mother for electroconvulsive therapy (ECT). After 7 ECT sessions, the patient recovered and resumed feeding. ECT may save the life of a patient with catatonia provided that legal obstacles are overcome. Clinicians should carefully evaluate patients with near-lethal catatonia, taking into account the risk of pulmonary embolism and other fatal events. The medical-legal issues, which vary across state regulations, should be addressed in detail to avoid unnecessary and potentially harmful delay in intervention.

  6. Detecting and Correcting Speech Repairs

    CERN Document Server

    Heeman, P A; Heeman, Peter; Allen, James

    1994-01-01

    Interactive spoken dialog provides many new challenges for spoken language systems. One of the most critical is the prevalence of speech repairs. This paper presents an algorithm that detects and corrects speech repairs based on finding the repair pattern. The repair pattern is built by finding word matches and word replacements, and identifying fragments and editing terms. Rather than using a set of prebuilt templates, we build the pattern on the fly. In a fair test, our method, when combined with a statistical model to filter possible repairs, was successful at detecting and correcting 80\\% of the repairs, without using prosodic information or a parser.

  7. An endogenous antitoxin to the lethal venom of the funnel web spider, Atrax robustus, in rabbit sera.

    Science.gov (United States)

    Sheumack, D D; Comis, A; Claassens, R; Mylecharane, E J; Spence, I; Howden, M E

    1991-01-01

    1. An endogenous antitoxin fraction was isolated from non-immune rabbit sera by affinity chromatography with robustoxin bound to the solid support. 2. Robustoxin is the sole lethal toxin in the venom of the male funnel web spider, Atrax robustus. 3. The fraction was found to contain IgG and IgM immunoglobulins. 4. This fraction prevented or reversed the lethal actions of the crude venom in newborn mice, in mouse phrenic nerve-hemidiaphragm preparations, and in anaesthetized monkeys. 5. The antitoxin fraction is of potential value in the therapy of human envenomation by A. robustus.

  8. Toxicity and sub-lethal effect of endemic plants from family Anacardiaceae on oviposition behavior of Aedes albopictus

    Directory of Open Access Journals (Sweden)

    Wan Fatma Zuharah

    2015-08-01

    Conclusions: These results clearly indicate that the acetone extract of G. renghas could be served as potential larvicide, whereas M. fasciculiflora has better sub-lethal effect for oviposition deterrence and against Ae. albopictus as an oviciding agent.

  9. Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Jianzhong Li

    2015-08-01

    Full Text Available Hong Shan Capsule (HSC, a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI. Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage.

  10. Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats.

    Science.gov (United States)

    Li, Jianzhong; Xu, Jing; Xu, Weiheng; Qi, Yang; Lu, Yiming; Qiu, Lei; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

    2015-08-12

    Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage.

  11. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation.

    Directory of Open Access Journals (Sweden)

    Claudia Lange

    Full Text Available BACKGROUND: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. METHODS AND FINDINGS: Mouse mesenchymal stromal cells (mMSCs were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i decreased proinflammatory, ECM formation and adhesion properties and (ii boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. CONCLUSIONS: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis

  12. miRNA control of tissue repair and regeneration.

    Science.gov (United States)

    Sen, Chandan K; Ghatak, Subhadip

    2015-10-01

    Tissue repair and regeneration rely on the function of miRNA, molecular silencers that enact post-transcriptional gene silencing of coding genes. Disruption of miRNA homeostasis is developmentally lethal, indicating that fetal tissue development is tightly controlled by miRNAs. Multiple critical facets of adult tissue repair are subject to control by miRNAs, as well. Sources of cell pool for tissue repair and regeneration are diverse and provided by processes including cellular dedifferentiation, transdifferentiation, and reprogramming. Each of these processes is regulated by miRNAs. Furthermore, induced pluripotency may be achieved by miRNA-based strategies independent of transcription factor manipulation. The observation that miRNA does not integrate into the genome makes miRNA-based therapeutic strategies translationally valuable. Tools to manipulate cellular and tissue miRNA levels include mimics and inhibitors that may be specifically targeted to cells of interest at the injury site. Here, we discuss the extraordinary importance of miRNAs in tissue repair and regeneration based on emergent reports and rapid advances in miRNA-based therapeutics.

  13. Interparietal hernias after open retromuscular hernia repair.

    Science.gov (United States)

    Carbonell, A M

    2008-12-01

    The retromuscular or sublay repair of ventral hernias, popularized by Rives and Stoppa, requires that a layer of tissue be reapproximated dorsal to the mesh to separate the bowel from the prosthetic. This is the first report of two patients who developed bowel obstruction resulting from interparietal incarceration between the posterior rectus sheath and the prosthetic graft through a defect in this dorsal layer. Both patients underwent open retromuscular hernia repair, one with lightweight polypropylene mesh, the other with human acellular dermal matrix. Postoperatively (day 3 and day 42, respectively), the patients developed signs of bowel obstruction. Computed tomography demonstrated the herniation of the small bowel into the potential space between the prosthesis and the posterior rectus sheath. The first patient underwent successful laparoscopic repair, while the second patient had an open operation to reduce the incarcerated bowel and repair the defect. In the patient convalescing from an uneventful retromuscular hernia repair who develops signs and symptoms of a bowel obstruction, there should be a high index of suspicion that an interparietal hernia may have formed, with the small bowel herniated into the surgically created space between the prosthetic and the posterior rectus sheath.

  14. DNA repair responses in human skin cells

    Energy Technology Data Exchange (ETDEWEB)

    Hanawalt, P.C.; Liu, S.C.; Parsons, C.S.

    1981-07-01

    Sunlight and some environmental chemical agents produce lesions in the DNA of human skin cells that if unrepaired may interfere with normal functioning of these cells. The most serious outcome of such interactions may be malignancy. It is therefore important to develop an understanding of mechanisms by which the lesions may be repaired or tolerated without deleterious consequences. Our models for the molecular processing of damaged DNA have been derived largely from the study of bacterial systems. Some similarities but significant differences are revealed when human cell responses are tested against these models. It is also of importance to learn DNA repair responses of epidermal keratinocytes for comparison with the more extensive studies that have been carried out with dermal fibroblasts. Our experimental results thus far indicate similarities for the excision-repair of ultraviolet-induced pyrimidine dimers in human keratinocytes and fibroblasts. Both the monoadducts and the interstrand crosslinks produced in DNA by photoactivated 8-methoxypsoralen (PUVA) can be repaired in normal human fibroblasts but not in those from xeroderma pigmentosum patients. The monoadducts, like pyrimidine dimers, are probably the more mutagenic/carcinogenic lesions while the crosslinks are less easily repaired and probably result in more effective blocking of DNA function. It is suggested that a split-dose protocol that maximizes the production of crosslinks while minimizing the yield of monoadducts may be more effective and potentially less carcinogenic than the single ultraviolet exposure regimen in PUVA therapy for psoriasis.

  15. DNA repair variants and breast cancer risk.

    Science.gov (United States)

    Grundy, Anne; Richardson, Harriet; Schuetz, Johanna M; Burstyn, Igor; Spinelli, John J; Brooks-Wilson, Angela; Aronson, Kristan J

    2016-05-01

    A functional DNA repair system has been identified as important in the prevention of tumour development. Previous studies have hypothesized that common polymorphisms in DNA repair genes could play a role in breast cancer risk and also identified the potential for interactions between these polymorphisms and established breast cancer risk factors such as physical activity. Associations with breast cancer risk for 99 single nucleotide polymorphisms (SNPs) from genes in ten DNA repair pathways were examined in a case-control study including both Europeans (644 cases, 809 controls) and East Asians (299 cases, 160 controls). Odds ratios in both additive and dominant genetic models were calculated separately for participants of European and East Asian ancestry using multivariate logistic regression. The impact of multiple comparisons was assessed by correcting for the false discovery rate within each DNA repair pathway. Interactions between several breast cancer risk factors and DNA repair SNPs were also evaluated. One SNP (rs3213282) in the gene XRCC1 was associated with an increased risk of breast cancer in the dominant model of inheritance following adjustment for the false discovery rate (P breast cancer risk or their modification by breast cancer risk factors were observed.

  16. Groin hernia repair in young males: mesh or sutured repair?

    DEFF Research Database (Denmark)

    Bisgaard, T; Bay-Nielsen, M; Kehlet, H

    2010-01-01

    Large-scale data for the optimal inguinal hernia repair in younger men with an indirect hernia is not available. We analysed nationwide data for risk of reoperation in younger men after a primary repair using a Lichtenstein operation or a conventional non-mesh hernia repair....

  17. Cleft lip and palate repair

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002979.htm Cleft lip and palate repair To use the sharing features on this page, please enable JavaScript. Cleft lip and cleft palate repair is surgery to fix birth defects ...

  18. Abdominal aortic aneurysm repair - open

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007392.htm Abdominal aortic aneurysm repair - open To use the sharing features on this page, please enable JavaScript. Open abdominal aortic aneurysm repair is surgery to fix a widened part ...

  19. Nanomaterials promise better bone repair

    OpenAIRE

    Qifei Wang; Jianhua Yan; Junlin Yang; Bingyun Li

    2016-01-01

    Nanomaterials mimicking the nano-features of bones and offering unique smart functions are promising for better bone fracture repair. This review provides an overview of the current state-of-the-art research in developing and using nanomaterials for better bone fracture repair. This review begins with a brief introduction of bone fracture repair processes, then discusses the importance of vascularization, the role of growth factors in bone fracture repair, and the failure of bone fracture rep...

  20. Laparoscopic repair of femoral hernia

    OpenAIRE

    Yang, Xue-Fei; Liu, Jia-Lin

    2016-01-01

    Laparoscopic repair of inguinal hernia is mini-invasive and has confirmed effects. Femoral hernia could be repaired through the laparoscopic procedures for inguinal hernia. These procedures have clear anatomic view in the operation and preoperatively undiagnosed femoral hernia could be confirmed and treated. Lower recurrence ratio was reported in laparoscopic procedures compared with open procedures for repair of femoral hernia. The technical details of laparoscopic repair of femoral hernia, ...

  1. A multivariate model of stakeholder preference for lethal cat management.

    Science.gov (United States)

    Wald, Dara M; Jacobson, Susan K

    2014-01-01

    Identifying stakeholder beliefs and attitudes is critical for resolving management conflicts. Debate over outdoor cat management is often described as a conflict between two groups, environmental advocates and animal welfare advocates, but little is known about the variables predicting differences among these critical stakeholder groups. We administered a mail survey to randomly selected stakeholders representing both of these groups (n=1,596) in Florida, where contention over the management of outdoor cats has been widespread. We used a structural equation model to evaluate stakeholder intention to support non-lethal management. The cognitive hierarchy model predicted that values influenced beliefs, which predicted general and specific attitudes, which in turn, influenced behavioral intentions. We posited that specific attitudes would mediate the effect of general attitudes, beliefs, and values on management support. Model fit statistics suggested that the final model fit the data well (CFI=0.94, RMSEA=0.062). The final model explained 74% of the variance in management support, and positive attitudes toward lethal management (humaneness) had the largest direct effect on management support. Specific attitudes toward lethal management and general attitudes toward outdoor cats mediated the relationship between positive (pstakeholder intention to support non-lethal cat management. Our findings suggest that stakeholders can simultaneously perceive both positive and negative beliefs about outdoor cats, which influence attitudes toward and support for non-lethal management.

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

    Directory of Open Access Journals (Sweden)

    Samuel M Williams

    Full Text Available 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.

  3. Overexpression of dilp2 causes nutrient-dependent semi-lethality in Drosophila

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    Yukiko eSato-Miyata

    2014-04-01

    Full Text Available Insulin/insulin-like growth factor (IGF plays an important role as a systemic regulator of metabolism in multicellular organisms. Hyperinsulinemia, a high level of blood insulin, is often associated with impaired physiological conditions such as hypoglycemia, insulin resistance, and diabetes. However, due to the complex pathophysiology of hyperinsulinemia, the causative role of excess insulin/IGF signaling has remained elusive. To investigate the biological effects of a high level of insulin in metabolic homeostasis and physiology, we generated flies overexpressing Drosophila insulin-like peptide 2 (Dilp2, which has the highest potential of promoting tissue growth among the Ilp genes in Drosophila. In this model, a UAS-Dilp2 transgene was overexpressed under control of sd-Gal4 that drives expression predominantly in developing imaginal wing discs. Overexpression of Dilp2 caused semi-lethality, which was partially suppressed by mutations in the insulin receptor (InR or Akt1, suggesting that dilp2-induced semi-lethality is mediated by the PI3K/Akt1 signaling. We found that dilp2-overexpressing flies exhibited intensive autophagy in fat body cells. Interestingly, the dilp2-induced autophagy as well as the semi-lethality was partially rescued by increasing the protein content relative to glucose in the media. Our results suggest that excess insulin/IGF signaling impairs the physiology of animals, which can be ameliorated by controlling the nutritional balance between proteins and carbohydrates, at least in flies.

  4. Deciphering the Mechanisms of Developmental Disorders (DMDD: a new programme for phenotyping embryonic lethal mice

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    Timothy Mohun

    2013-05-01

    International efforts to test gene function in the mouse by the systematic knockout of each gene are creating many lines in which embryonic development is compromised. These homozygous lethal mutants represent a potential treasure trove for the biomedical community. Developmental biologists could exploit them in their studies of tissue differentiation and organogenesis; for clinical researchers they offer a powerful resource for investigating the origins of developmental diseases that affect newborns. Here, we outline a new programme of research in the UK aiming to kick-start research with embryonic lethal mouse lines. The ‘Deciphering the Mechanisms of Developmental Disorders’ (DMDD programme has the ambitious goal of identifying all embryonic lethal knockout lines made in the UK over the next 5 years, and will use a combination of comprehensive imaging and transcriptomics to identify abnormalities in embryo structure and development. All data will be made freely available, enabling individual researchers to identify lines relevant to their research. The DMDD programme will coordinate its work with similar international efforts through the umbrella of the International Mouse Phenotyping Consortium [see accompanying Special Article (Adams et al., 2013] and, together, these programmes will provide a novel database for embryonic development, linking gene identity with molecular profiles and morphology phenotypes.

  5. Ribavirin Protects Syrian Hamsters against Lethal Hantavirus Pulmonary Syndrome — After Intranasal Exposure to Andes Virus

    Science.gov (United States)

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

    2013-01-01

    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. PMID:24217424

  6. Ribavirin Protects Syrian Hamsters against Lethal Hantavirus Pulmonary Syndrome — After Intranasal Exposure to Andes Virus

    Directory of Open Access Journals (Sweden)

    Jay W. Hooper

    2013-11-01

    Full Text Available 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.

  7. The lethal ovitrap: a response to the resurgence of dengue and chikungunya.

    Science.gov (United States)

    Zeichner, Brian C; Debboun, Mustapha

    2011-01-01

    There has been a global resurgence in dengue fever since the 1960s and now more than one third of the world's population lives in dengue endemic areas. Chikungunya, another mosquito-borne disease, had been limited to sub-Saharan Africa and Southeast Asia, but recently spread to Italy and France, raising concerns that it could spread to many more countries in Europe and the Americas. There are currently no vaccines available to prevent infection with either virus and medical care is limited to symptomatic and supportive treatments. Suppression of the mosquito vector populations reduces disease transmission, however, the tools currently available to control the main vectors of dengue and chikungunya are inadequate. Larval control is very labor intensive and pesticide sprays do not adequately penetrate the microhabitats where adult mosquitoes are sequestered. The lethal ovitrap addresses these shortcomings by luring the potentially viremic female mosquitoes to an egg laying site where they are exposed to a toxic insecticide dose. It is a safe, environmentally sound, economical, and simple means of dengue and chikungunya vector control whose efficacy has been documented in 9 research papers. Management programs using the lethal ovitrap have been shown to halt dengue and chikungunya transmission. Efforts are underway to mass produce the lethal ovitrap under the registered trade name Trap-N-Kill which will ensure its availability to our armed forces deployed in dengue and chikungunya endemic areas.

  8. Effect of 8-MOP plus UVA treatment on survival and repair of plasmid pBR322; Efecto del tratamiento con 8-MOP mas UVA en la supervivencia y reparacion de pBR322

    Energy Technology Data Exchange (ETDEWEB)

    Bauluz, C.; Vidania, R. de

    1991-07-01

    We have studied the lethality produced in pBR322 DNA after PUVA treatment (8-MOP+UVA). As recipients, we used a collection of E. coli strains differing in their repair capacities and analysed the involvement of several DNA repair pathways in the removal of plasmid lesions. We have also studied the effect of UVA radiation alone, in order to determine more precisely the effect attributable only to psoralen molecules. Results showed a strong lethal effect derived from PUVA treatment; however, some plasmid recovery was achieved in bacterial hosts proficient in Excision repair and SOS repair. Another repair pathway, only detectable at high density of lesions, appeared to be relevant for the removal of 8-MOP:DNA adducts.(Author) 11 refs.

  9. Effects of lethal and non-lethal malaria on the mononuclear phagocyte system

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Tosta

    1983-03-01

    Full Text Available The effects ofone non-lethal species ofmalarialparasite, Plasmodium yoelii, and one lethal species, P. berghei, on the mononuclear phagocyte system (MPS of BALB/c mice were studied. P. yoelii caused a greater and more sustained expansion and activation of the MPS, and the two major populations of spleen phagocytic cells-red pulp and marginal zone macrophages - exhibited a greater increase in numbers in this infection. During the course of P. berghei mataria, the spleen was progressively occupied by haematopoietic tissue and, at the terminal stage of infection, an extensive depletion of lymphocytes and macrophages was apparent. The possibility was suggested that the outcome of mataria may be inftuenced by the particular way the parasite interacts with the MPS.Estudou-se o efeito da infecção causada por espécie letal (Plasmodium berghei e não- letal (P. yoelii de plasmódio sobre o sistema de fagócitos mononucleares de camundongo BALB/c. O P. yoelii causou maior e mais prolongada expansão e ativação do sistema de macrófagos. As duas mais importantes populações de fagócitos esplênicos - macrófagos de polpa vermelha e da zona marginal - exibiam maior aumento do número de células nesta infecção. Durante a evolução da malária por P. berghei, o baço foi progressivamente ocupado por tecido hematopoiético e, na fase terminal da infecção, observou-se significativa depleção dos linfócitos e macrófagos esplênicos. Os dados apresentados indicam que a evolução da malária depende do tipo de interação entre o plasmódio e o sistema de fagócitos mononucleares.

  10. Regulation of DNA repair mechanism in human glioma xenograft cells both in vitro and in vivo in nude mice.

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    Shivani Ponnala

    Full Text Available BACKGROUND: Glioblastoma Multiforme (GBM is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ repair mechanism plays a major role in double strand break (DSB repair in mammalian cells. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU and MMP9-cathepsin B (pMC shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls. CONCLUSION/SIGNIFICANCE: Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential

  11. Crossover suppressors and balanced recessive lethals in Caenorhabditis elegans. [Nematode

    Energy Technology Data Exchange (ETDEWEB)

    Herman, R.K.

    1978-01-01

    Two dominant suppressors of crossing over have been identified following x-ray treatment of the small nematode C. elegans. They suppress crossing over in linkage group II (LGII) about 100-fold and 50-fold and are both tightly linked to LGII markers. One, called C1, segregates independently of all other linkage groups and is homozygous fertile. The other is a translocation involving LGII and X. The translocation also suppresses crossing over along the right half of X and is homozygous lethal. C1 has been used as a balancer of LGII recessive lethal and sterile mutations induced by EMS. The frequencies of occurrence of lethals and steriles were approximately equal. Fourteen mutations were assigned to complementation groups and mapped. They tended to map in the same region where LGII visibles are clustered.

  12. Lethal effects of short-wavelength visible light on insects.

    Science.gov (United States)

    Hori, Masatoshi; Shibuya, Kazuki; Sato, Mitsunari; Saito, Yoshino

    2014-12-09

    We investigated the lethal effects of visible light on insects by using light-emitting diodes (LEDs). The toxic effects of ultraviolet (UV) light, particularly shortwave (i.e., UVB and UVC) light, on organisms are well known. However, the effects of irradiation with visible light remain unclear, although shorter wavelengths are known to be more lethal. Irradiation with visible light is not thought to cause mortality in complex animals including insects. Here, however, we found that irradiation with short-wavelength visible (blue) light killed eggs, larvae, pupae, and adults of Drosophila melanogaster. Blue light was also lethal to mosquitoes and flour beetles, but the effective wavelength at which mortality occurred differed among the insect species. Our findings suggest that highly toxic wavelengths of visible light are species-specific in insects, and that shorter wavelengths are not always more toxic. For some animals, such as insects, blue light is more harmful than UV light.

  13. Recombinant raccoon pox vaccine protects mice against lethal plague

    Science.gov (United States)

    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??104LD50). 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. ?? 2002 Elsevier Science Ltd. All rights reserved.

  14. Platinum drugs and DNA repair mechanisms in lung cancer.

    Science.gov (United States)

    Bonanno, Laura; Favaretto, Adolfo; Rosell, Rafael

    2014-01-01

    The standard first-line treatment for around 80% of newly-diagnosed advanced non-small cell lung cancer (NSCLC) is chemotherapy. Currently, patients are allocated to chemotherapy on the basis of clinical conditions, comorbidities and histology. If feasible, platinum-based chemotherapy is considered as the most efficacious option. Due to the heterogeneity in terms of platinum-sensitivity among patients with NSCLC, great efforts have been made in order to identify molecular predictive markers of platinum resistance. Based on the mechanism of action of platinum, several components of DNA repair pathways have been investigated as potential predictive markers. The main DNA repair pathways involved in the repair of platinum-induced DNA damage are nucleotide excision repair and homologous recombination. The most studied potential predictive markers of platinum-sensitivity are Excision Repair Cross Complementing-1 (ERCC1) and Brest Cancer Type-I Susceptibility protein (BRCA1); however, increasing biological knowledge about DNA repair pathways suggests the potential clinical usefulness of integrated analysis of multiple DNA repair components.

  15. Potential Long-Term Complications of Endovascular Stent Grafting for Blunt Thoracic Aortic Injury

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    Larry E. Miller

    2012-01-01

    Full Text Available Blunt thoracic aortic injury (BTAI is a rare, but lethal, consequence of rapid deceleration events. Most victims of BTAI die at the scene of the accident. Of those who arrive to the hospital alive, expedient aortic intervention significantly improves survival. Thoracic endovascular aortic repair (TEVAR has been accepted as the standard of care for BTAI at many centers, primarily due to the convincing evidence of lower mortality and morbidity in comparison to open surgery. However, less attention has been given to potential long-term complications of TEVAR for BTAI. This paper focuses on these complications, which include progressive aortic expansion with aging, inadequate stent graft characteristics, device durability concerns, long-term radiation exposure concerns from follow-up computed tomography scans, and the potential for (Victims of Modern Imaging Technology VOMIT.

  16. Impact of acute alcohol consumption on lethality of suicide methods.

    Science.gov (United States)

    Park, C Hyung Keun; Yoo, Seong Ho; Lee, Jaewon; Cho, Sung Joon; Shin, Min-Sup; Kim, Eun Young; Kim, Se Hyun; Ham, Keunsoo; Ahn, Yong Min

    2017-05-01

    The influence of acute alcohol consumption on the factors related to suicide remains understudied. Thus, the present study investigated the relationship between blood alcohol content (BAC) and the lethality of suicide methods. Autopsy data on 315 South Korean suicide completers with a positive BAC were collected from a nationwide pool between May 2015 and November 2015, and the methods were dichotomised as suicide methods of low lethality (SMLL; drug/chemical overdose and sharp objects, n=67) and suicide methods of high lethality (SMHL; everything else, n=243). BAC at the time of autopsy and various suicide-related factors of these two groups were compared with logistic regression analyses. Compared to suicide completers with a BAC in the lowest range of 0.011-0.049%, suicide completers with a BAC in the range of 0.150-0.199% were more likely to use SMHL (odds ratio [OR]: 3.644, 95% confidence interval [CI]: 1.221-10.874). Additionally, the adoption of SMHL was significantly associated with the absence of a psychiatric illness (OR: 0.433, 95% CI: 0.222-0.843) and a younger age; the OR for high BAC among subjects in their 40s was 0.266 (95% CI: 0.083-0.856); in their 50s, 0.183 (95% CI: 0.055-0.615); and in their 60s, 0.057 (95% CI: 0.015-0.216). The relationship between BAC and suicide method lethality was represented by a bell-shaped pattern in which suicide methods of high lethality were more likely to be used by suicide completers with mid-range BAC levels. The increased impulsivity and impairments in particular executive functions, including planning and organization, associated with acute alcohol use may influence the selection of a particular suicide method based on its lethality. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Prenatal diagnosis of lethal osteogenesis imperfecta in twin pregnancy.

    Science.gov (United States)

    Morin, L R; Herlicoviez, M; Loisel, J C; Jacob, B; Feuilly, C; Stanescu, V

    1991-06-01

    Lethal osteogenesis imperfecta was diagnosed at 27 weeks amenorrea in one fetus of a bichorial twin pregnancy. Sonographic findings included: short-limb dwarfism, hypotrophy and hypoechoic bones. The affected fetus was so translucent that only the normal fetus could be seen on plain in utero radiography. The affected fetus died immediately after birth. Postmortem radiography and histology were typical of lethal osteogenesis imperfecta of type IIA. Aids to the etiological diagnosis of in utero dwarfism are presented. Sonographic features correlated with neonatal death are described.

  18. Development of non-lethal methods for investigation of actinide uptake by wildlife

    Energy Technology Data Exchange (ETDEWEB)

    Johansen, M.; Child, D.; Davis, E.; Harrison, J.; Hotchkis, M.; Payne, T.; Thiruvoth, S. [Australian Nuclear Science and Technology Org. (Australia); Wood, M. [University of Salford (United Kingdom)

    2014-07-01

    There is growing interest in the use of non-lethal methods in radioecology and an International Union of Radioecology Task Group has been established to facilitate international cooperation in this field (http://iur-uir.org/en/task-groups/id-19-non-lethal-methods-in-radioecology). In this paper, we evaluate the use of lethally-, and non-lethally obtained samples (various body tissues, excreta and blood withdrawals as well as parasites and found bones) as indicators of contamination. Samples of mammals and reptiles were collected from the semi-arid former weapons test site at Maralinga, Australia and analysed for thorium, plutonium, and uranium isotopes by accelerator mass spectrometry and alpha-spectrometry. Most samples were of low mass and presented analytical challenges as a result. The plutonium concentrations in blood withdrawn from the marginal ear veins of Oryctolagus cuniculus (European rabbit) were successfully analysed using small samples (0.2 -7.9 ml, below the ∼10 ml threshold for safe extraction of blood from these rabbits). The results demonstrate that small-volume blood samples can serve as indicators of the presence of plutonium absorbed within other tissues (e.g., muscle, bone). However, the magnitude of the blood plutonium masses were poorly correlated with those in muscle and bone due to the presence of a small number of outliers (without the outliers, correlations improved to r = +0.66 and r = +0.51 for muscle and bone respectively). The activity concentrations in parasitic ticks were relatively high compared with those of their hosts Pseudomys hermannsburgensis (sandy inland mouse) and Ctenophorus cristatus (crested dragon lizard). Successful measurement of tick samples indicates a potential for use of parasites as general indicators of contamination within host organisms. The concentrations of actinides in found bones of Macropus rufus (red kangaroo) and O. cuniculus demonstrated potential for their use as indicators of the areal extent of

  19. Nanomaterials promise better bone repair

    Directory of Open Access Journals (Sweden)

    Qifei Wang

    2016-10-01

    Full Text Available Nanomaterials mimicking the nano-features of bones and offering unique smart functions are promising for better bone fracture repair. This review provides an overview of the current state-of-the-art research in developing and using nanomaterials for better bone fracture repair. This review begins with a brief introduction of bone fracture repair processes, then discusses the importance of vascularization, the role of growth factors in bone fracture repair, and the failure of bone fracture repair. Next, the review discusses the applications of nanomaterials for bone fracture repair, with a focus on the recent breakthroughs such as nanomaterials leading to precise immobilization of growth factors at the molecular level, promoting vascularization without the use of growth factors, and re-loading therapeutic agents after implantation. The review concludes with perspectives on challenges and future directions for developing nanomaterials for improved bone fracture repair.

  20. Imaging and management of complications of open surgical repair of abdominal aortic aneurysms

    Energy Technology Data Exchange (ETDEWEB)

    Nayeemuddin, M. [Department of Interventional Radiology, City General Hospital, University Hospital of North Staffordshire NHS Trust, Stoke-On-Trent (United Kingdom); Pherwani, A.D. [Department of Vascular Surgery, City General Hospital, University Hospital of North Staffordshire NHS Trust, Stoke-On-Trent (United Kingdom); Asquith, J.R., E-mail: john.asquith@uhns.nhs.uk [Department of Interventional Radiology, City General Hospital, University Hospital of North Staffordshire NHS Trust, Stoke-On-Trent (United Kingdom)

    2012-08-15

    Open repair is still considered the reference standard for long-term repair of abdominal aortic aneurysms (AAA). In contrast to endovascular aneurysm repair (EVAR), patients with open surgical repair of AAA are not routinely followed up with imaging. Although complications following EVAR are widely recognized and routinely identified on follow-up imaging, complications also do occur following open surgical repair. With frequent use of multi-slice computed tomography (CT) angiography (CTA) in vascular patients, there is now improved recognition of the potential complications following open surgical repair. Many of these complications are increasingly being managed using endovascular techniques. The aim of this review is to illustrate a variety of potential complications that may occur following open surgical repair and to demonstrate their management using both surgical and endovascular techniques.

  1. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of th...

  2. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Osorio, Ana; Milne, Roger L.; Kuchenbaecker, Karoline; Vaclova, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Diez, Orland; Ramon y Cajal, Teresa; Konstantopoulou, Irene; Martinez-Bouzas, Cristina; Conejero, Raquel Andres; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Beattie, Mary S.; Domchek, Susan M.; Nathanson, Katherine; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; John, Esther M.; Whittemore, Alice S.; Daly, Mary B.; Southey, Melissa; Hopper, John; Terry, Mary B.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas V. O.; Jonson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herraez, Belen; Moreno, Leticia Thais; Weitzel, Jeffrey N.; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K.; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Joerg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodriguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Rookus, Matti A.; van Os, Theo A. M.; van der Kolk, Lizet; de Lange, J. L.; Meijers-Heijboer, Hanne E. J.; van der Hout, A. H.; van Asperen, Christi J.; Gomez Garcia, Encarna B.; Hoogerbrugge, Nicoline; Collee, J. Margriet; van Deurzen, Carolien H. M.; van der Luijt, Rob B.; Devilee, Peter; Olah, Edith; Lazaro, Conxi; Teule, Alex; Menendez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Healey, Sue; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Benitez, Javier

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the c

  3. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Osorio, Ana; Milne, Roger L.; Kuchenbaecker, Karoline; Vaclova, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Diez, Orland; Ramon y Cajal, Teresa; Konstantopoulou, Irene; Martinez-Bouzas, Cristina; Conejero, Raquel Andres; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Beattie, Mary S.; Domchek, Susan M.; Nathanson, Katherine; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; John, Esther M.; Whittemore, Alice S.; Daly, Mary B.; Southey, Melissa; Hopper, John; Terry, Mary B.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas V. O.; Jonson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herraez, Belen; Moreno, Leticia Thais; Weitzel, Jeffrey N.; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K.; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Joerg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodriguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Rookus, Matti A.; van Os, Theo A. M.; van der Kolk, Lizet; de Lange, J. L.; Meijers-Heijboer, Hanne E. J.; van der Hout, A. H.; van Asperen, Christi J.; Gomez Garcia, Encarna B.; Hoogerbrugge, Nicoline; Collee, J. Margriet; van Deurzen, Carolien H. M.; van der Luijt, Rob B.; Devilee, Peter; Olah, Edith; Lazaro, Conxi; Teule, Alex; Menendez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Healey, Sue; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Benitez, Javier

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the c

  4. A Simple Laboratory Class Using a "Pseudomonas aeruginosa" Auxotroph to Illustrate UV-Mutagenic Killing, DNA Photorepair and Mutagenic DNA Repair

    Science.gov (United States)

    Sobrero, Patricio; Valverde, Claudio

    2013-01-01

    A simple and cheap laboratory class is proposed to illustrate the lethal effect of UV radiation on bacteria and the operation of different DNA repair mechanisms. The class is divided into two sessions, an initial 3-hour experimental session and a second 2-hour analytical session. The experimental session involves two separate experiments: one…

  5. 5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer

    Science.gov (United States)

    Preston, Mark A.; Wilson, Kathryn; Markt, Sarah C.; Ge, Rongbin; Morash, Christopher; Stampfer, Meir J.; Loda, Massimo F.; Giovannucci, Edward; Mucci, Lorelei A.; Olumi, Aria F.

    2014-01-01

    Importance 5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. Objective To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. Design, Setting, and Participants Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study. Exposure Use of 5ARIs between 1996–2010. Main Outcome Measures Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. Results During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease. Conclusions and

  6. Controversies in laparoscopic repair of incisional hernia

    Directory of Open Access Journals (Sweden)

    Sarela Abeezar

    2006-01-01

    Full Text Available Background: Incisional hernias can be a significant problem after open abdominal surgery. Laparoscopic incisional hernia repair (LIHR is conceptually appealing: a large, abdominal wall re-incision with potential wound-related ill effects is avoided and an intra-peritoneal onlay mesh is expected to provide security that is equivalent to open, retro-muscular mesh repair. As such, LIHR has gained substantial popularity despite sparse, randomised clinical data to compare with conventional, open repair. Aim: To enumerate and discuss important, controversial issues in patient-selection, technique and early post-operative care for LIHR. Materials and Methods: Pragmatic summary of comprehensive review of English language literature, discussion with experts and personal experience. Outcomes: Six important areas of some dispute were identified: 1. Size of abdominal-wall defect that is suitable for LIHR: Generally, defect-diameter > 10 cm is better served by open retromuscular repair with tension-free re-approximation of the edges of the defect. 2. Extent of adhesiolysis: Complete division of adhesions to the anterior abdominal wall may identify sub-clinical "Swiss-cheese" defects but incurs some risk of additional complications. 3. Intra-operative recognition of enterotomy: Possible options are either laparoscopic suture of bowel injury and simultaneous completion of LIHR, or staged LIHR or conversion to open suture-repair. 4. Choice of mesh: "Composite" meshes are regarded as the current standard of care but there is paucity of data regarding potential dangers of intra-peritoneal polypropylene mesh. 5. Technique of mesh-fixation: Trans-parietal sutures are more secure than tacks, with limited data to correlate with post-operative pain. 6. Alarm over post-operative pain: Unlike other advanced laparoscopic operations, the specificity of pain as a marker of intra-abdominal sepsis after LIHR remains unclear. Conclusion : Recognition of and attention to

  7. Biochip for the Detection of Bacillus anthracis Lethal Factor and Therapeutic Agents against Anthrax Toxins

    Directory of Open Access Journals (Sweden)

    Vitalii Silin

    2016-06-01

    Full Text Available Tethered lipid bilayer membranes (tBLMs have been used in many applications, including biosensing and membrane protein structure studies. This report describes a biosensor for anthrax toxins that was fabricated through the self-assembly of a tBLM with B. anthracis protective antigen ion channels that are both the recognition element and electrochemical transducer. We characterize the sensor and its properties with electrochemical impedance spectroscopy and surface plasmon resonance. The sensor shows a sensitivity similar to ELISA and can also be used to rapidly screen for molecules that bind to the toxins and potentially inhibit their lethal effects.

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

    Energy Technology Data Exchange (ETDEWEB)

    Maize, Kimberly M.; Kurbanov, Elbek K.; Johnson, Rodney L.; Amin, Elizabeth Ambrose; Finzel, Barry C. (UMM)

    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.

  9. Role of pseudorabies virus glycoprotein II in protection from lethal infection.

    Science.gov (United States)

    Nakamura, T; Ihara, T; Nunoya, T; Kuwahara, H; Ishihama, A; Ueda, S

    1993-07-01

    A monoclonal antibody (mAb), named 1.21, with complement-dependent neutralizing activity was produced against glycoprotein II (gII) of pseudorabies virus (PRV). By immunoaffinity chromatography using a mAB 1.21 column, gII was purified from Nonidet P40-lysates of PRV infected BHK21/13 cells. When mice and pigs were immunized with purified gII, complement-dependent virus-neutralizing antibodies were produced. The immunized animals survived potentially lethal challenge with PRV. These results indicate that an immunological response against gII plays an important role in the protection from PRV infection.

  10. The "Lethal Chamber": Further Evidence of the Euthanasia Option.

    Science.gov (United States)

    Elks, Martin A.

    1993-01-01

    Historical discussions of the euthanasia or "lethal chamber" option in relation to people with mental retardation are presented. The paper concludes that eugenic beliefs in the primacy of heredity over environment and the positive role of natural selection may have condoned the poor conditions characteristic of large, segregated institutions and…

  11. Evaluation of lethality estimates for combustion gases in military scenarios.

    Science.gov (United States)

    Smith, S M; Stuhmiller, J H; Januszkiewicz, A J

    1996-12-31

    To meet the military objective of determining criteria for incapacitation and lethality from toxic gas exposures, a series of small animal tests and data analyses were conducted. Carbon monoxide (CO), a narcotic gas and nitrogen dioxide (NO2), an irritant gas, along with carbon dioxide (CO2) were tested individually and in the following mixtures: (CO + CO2), (NO2 + CO2) and (NO2 + CO + CO2). A group of six animals was exposed to each of the gases and their combinations, lethality and biophysical data were collected. We conclude that our observations of lethality from single toxic gases can be correlated with a fractional effective dose (FED) description, in which external concentrations are corrected for minute volume changes. Multiple gas exposures clearly demonstrate synergistic effects because lethality rates greatly exceed those expected from statistically independent causes. Simple addition of the FED values, however, overstates the effect and implies a competition between the narcotic and irritant gas effects. The N-Gas model, while being an additive FED model, does not appear to be in a form that could guide the setting of military exposure standards.

  12. The Lethal "Femme Fatale" in the Noir Tradition.

    Science.gov (United States)

    Boozer, Jack

    2000-01-01

    Traces the lethal seductress through Hollywood's "noir" history from "Double Indemnity" (1944) to "The Last Seduction" (1996). Examines how this figure largely abjures traditional romance and passive domesticity, choosing instead to apply her sexuality to homicidal plots toward greed. Argues that her narrative positioning serves as a barometer of…

  13. Papaya Lethal Yellowing Virus (PLYV) Infects Vasconcellea cauliflora

    NARCIS (Netherlands)

    Amaral, P.P.R.; Resende, de R.O.; Souza, M.T.

    2006-01-01

    Papaya lethal yellowing virus (PLYV) é um dos três vírus descritos infectando mamoeiros (Carica papaya L.) no Brasil. Vasconcellea cauliflora (Jacq.) A. DC., antes denominada de Carica cauliflora (Jacq.), é uma reconhecida fonte de resistência natural ao Papaya ringspot virus (PRSV), causador da "Ma

  14. The Lethal "Femme Fatale" in the Noir Tradition.

    Science.gov (United States)

    Boozer, Jack

    2000-01-01

    Traces the lethal seductress through Hollywood's "noir" history from "Double Indemnity" (1944) to "The Last Seduction" (1996). Examines how this figure largely abjures traditional romance and passive domesticity, choosing instead to apply her sexuality to homicidal plots toward greed. Argues that her narrative…

  15. An overview of the future of non-lethal weapons.

    Science.gov (United States)

    Alexander, J B

    2001-01-01

    During the past decade, vast changes have occurred in the geopolitical landscape and the nature of the types of conflicts in which technologically developed countries have been involved. While the threat of conventional war remains, forces have been more frequently deployed in situations that require great restraint. Adversaries are often likely to be elusive and commingled with noncombatants. There has been some shift in public opinion away from tolerance of collateral casualties. Therefore there is a need to be able to apply force while limiting casualties. Non-lethal weapons provide part of the solution. Among the changes that will influence the future have been studies by the US and NATO concerning the use of non-lethal weapons, coincidental with increased funding for their development and testing. New concepts and policies have recently been formalized. Surprisingly, the most strident objections to the implementation of non-lethal weapons have come from organizations that are ostensibly designed to protect non-combatants. These arguments are specious and, while technically and academically challenging, actually serve to foster an environment that will result in the deaths of many more innocent civilians. They misconstrue technology with human intent. The reasons for use of force will not abate. Alternatives to bombs, missiles, tanks and artillery must therefore be found. Non-lethal weapons are not a panacea but do offer the best hope of minimizing casualties while allowing nations or alliances the means to use force in protection of national or regional interests.

  16. The Prevalence, Lethality and Intent of Suicide Attempts among Adolescents.

    Science.gov (United States)

    Andrews, Judy A.; Lewinsohn, Peter M.

    Although suicide is the second leading cause of death among adolescents in the United States, little is known about the prevalence or characteristics of suicide attempts among adolescents. Data from 1,710 adolescents attending 9 high schools in 5 communities were examined to determine the prevalence of suicide attempts and the lethality and intent…

  17. Conditional lethality strains for the biological control of Anastrepha species

    Science.gov (United States)

    Pro-apoptotic cell death genes are promising candidates for biologically-based autocidal control of pest insects as demonstrated by tetracycline (tet)-suppressible systems for conditional embryonic lethality in Drosophila melanogaster (Dm) and the medfly, Ceratitis capitata (Cc). However, for medfly...

  18. The "Lethal Chamber": Further Evidence of the Euthanasia Option.

    Science.gov (United States)

    Elks, Martin A.

    1993-01-01

    Historical discussions of the euthanasia or "lethal chamber" option in relation to people with mental retardation are presented. The paper concludes that eugenic beliefs in the primacy of heredity over environment and the positive role of natural selection may have condoned the poor conditions characteristic of large, segregated institutions and…

  19. Activated protein C ameliorates Bacillus anthracis lethal toxin-induced lethal pathogenesis in rats

    Directory of Open Access Journals (Sweden)

    Kau Jyh-Hwa

    2012-11-01

    Full Text Available Abstract Background Lethal toxin (LT is a major virulence factor of Bacillus anthracis. Sprague Dawley rats manifest pronounced lung edema and shock after LT treatments, resulting in high mortality. The heart failure that is induced by LT has been suggested to be a principal mechanism of lung edema and mortality in rodents. Since LT-induced death occurs more rapidly in rats than in mice, suggesting that other mechanisms in addition to the heart dysfunction may be contributed to the fast progression of LT-induced pathogenesis in rats. Coagulopathy may contribute to circulatory failure and lung injury. However, the effect of LT on coagulation-induced lung dysfunction is unclear. Methods To investigate the involvement of coagulopathy in LT-mediated pathogenesis, the mortality, lung histology and coagulant levels of LT-treated rats were examined. The effects of activated protein C (aPC on LT-mediated pathogenesis were also evaluated. Results Fibrin depositions were detected in the lungs of LT-treated rats, indicating that coagulation was activated. Increased levels of plasma D-dimer and thrombomodulin, and the ameliorative effect of aPC further suggested that the activation of coagulation-fibrinolysis pathways plays a role in LT-mediated pathogenesis in rats. Reduced mortality was associated with decreased plasma levels of D-dimer and thrombomodulin following aPC treatments in rats with LT-mediated pathogenesis. Conclusions These findings suggest that the activation of coagulation in lung tissue contributes to mortality in LT-mediated pathogenesis in rats. In addition, anticoagulant aPC may help to develop a feasible therapeutic strategy.

  20. DNA-repair measurements by use of the modified comet assay

    DEFF Research Database (Denmark)

    Godschalk, Roger W L; Ersson, Clara; Riso, Patrizia;

    2013-01-01

    The measurement of DNA-repair activity by extracts from cells or tissues by means of the single-cell gel electrophoresis (comet) assay has a high potential to become widely used in biomonitoring studies. We assessed the inter-laboratory variation in reported values of DNA-repair activity...... line as having the highest level of DNA-repair activity. The two laboratories that reported discordant results (with another cell line having the highest level of DNA-repair activity) were those that reported to have little experience with the modified comet assay to assess DNA repair. The laboratories...

  1. Laparoscopic Morgagni hernia repair: how I do it.

    Science.gov (United States)

    Park, Adrian; Doyle, Courtney

    2014-10-01

    Surgical repair of Morgagni hernias is recommended given their historically high risk of incarceration. Traditionally, such repair has been undertaken via laparotomy or thoracotomy or more recently, thoracoscopically or laparoscopically using mesh. Here, we describe a laparoscopic approach to the management of Morgagni hernias achieving a primary tissue repair without mesh implantation. This technique allows for the general benefits of minimally invasive surgery, such as less postoperative pain, reduced wound complications, decreased duration of the hospital stay, as well as offering an alternative to mesh implantation and its associated potential complications.

  2. Endovascular Repair of a Ruptured Descending Thoracic Aortic Aneurysm

    Science.gov (United States)

    DeFrain, Michael; Strickman, Neil E.; Ljubic, Branimir J.; Dougherty, Kathryn G.; Gregoric, Igor D.

    2006-01-01

    Endovascular aneurysm repair has considerable potential advantages over the surgical approach as a treatment for thoracic aortic rupture, in part because open surgical repair of ruptured thoracic aortic aneurysms is associated with high mortality and morbidity rates. We describe the successful endovascular deployment of stent-grafts to repair a contained rupture of a descending thoracic aortic aneurysm in an 86-year-old man whose comorbidities prohibited surgery. Two months after the procedure, magnetic resonance angiography showed a patent stent-graft, a patent left subclavian artery, and complete exclusion of the aneurysm. PMID:16878637

  3. Biology of biological meshes used in hernia repair.

    Science.gov (United States)

    Novitsky, Yuri W

    2013-10-01

    Successful repair of most hernias requires the use of a prosthetic implant for reinforcement of the defect. Because of the need for prosthetic implants to resist infections as well to support repairs in contaminated or potentially contaminated fields, biological meshes have been developed to take the place of nondegradable synthetic meshes in cases where mesh infection is of high concern. The ideal is a biological matrix that resists infection while providing durable reinforcement of a hernia repair. This article reviews the validity of assumptions that support the purported notion of the biological behavior of biological meshes.

  4. Annotating novel genes by integrating synthetic lethals and genomic information

    Directory of Open Access Journals (Sweden)

    Faty Mahamadou

    2008-01-01

    Full Text Available Abstract Background Large scale screening for synthetic lethality serves as a common tool in yeast genetics to systematically search for genes that play a role in specific biological processes. Often the amounts of data resulting from a single large scale screen far exceed the capacities of experimental characterization of every identified target. Thus, there is need for computational tools that select promising candidate genes in order to reduce the number of follow-up experiments to a manageable size. Results We analyze synthetic lethality data for arp1 and jnm1, two spindle migration genes, in order to identify novel members in this process. To this end, we use an unsupervised statistical method that integrates additional information from biological data sources, such as gene expression, phenotypic profiling, RNA degradation and sequence similarity. Different from existing methods that require large amounts of synthetic lethal data, our method merely relies on synthetic lethality information from two single screens. Using a Multivariate Gaussian Mixture Model, we determine the best subset of features that assign the target genes to two groups. The approach identifies a small group of genes as candidates involved in spindle migration. Experimental testing confirms the majority of our candidates and we present she1 (YBL031W as a novel gene involved in spindle migration. We applied the statistical methodology also to TOR2 signaling as another example. Conclusion We demonstrate the general use of Multivariate Gaussian Mixture Modeling for selecting candidate genes for experimental characterization from synthetic lethality data sets. For the given example, integration of different data sources contributes to the identification of genetic interaction partners of arp1 and jnm1 that play a role in the same biological process.

  5. Suppression of viral infectivity through lethal defection

    Science.gov (United States)

    Grande-Pérez, Ana; Lázaro, Ester; Lowenstein, Pedro; Domingo, Esteban; Manrubia, Susanna C.

    2005-01-01

    RNA viruses replicate with a very high error rate and give rise to heterogeneous, highly plastic populations able to adapt very rapidly to changing environments. Viral diseases are thus difficult to control because of the appearance of drug-resistant mutants, and it becomes essential to seek mechanisms able to force the extinction of the quasispecies before adaptation emerges. An alternative to the use of conventional drugs consists in increasing the replication error rate through the use of mutagens. Here, we report about persistent infections of lymphocytic choriomeningitis virus treated with fluorouracil, where a progressive debilitation of infectivity leading to eventual extinction occurs. The transition to extinction is accompanied by the production of large amounts of RNA, indicating that the replicative ability of the quasispecies is not strongly impaired by the mutagen. By means of experimental and theoretical approaches, we propose that a fraction of the RNA molecules synthesized can behave as a defective subpopulation able to drive the viable class extinct. Our results lead to the identification of two extinction pathways, one at high amounts of mutagen, where the quasispecies completely loses its ability to infect and replicate, and a second one, at lower amounts of mutagen, where replication continues while the infective class gets extinct because of the action of defectors. The results bear on a potential application of increased mutagenesis as an antiviral strategy in that low doses of a mutagenic agent may suffice to drive persistent virus to extinction. PMID:15767582

  6. The angiotensin-converting enzyme inhibitor captopril rescues mice from endotoxin-induced lethal hepatitis.

    Science.gov (United States)

    Ge, Pu; Jiang, Rong; Yao, Xin; Li, Jing; Dai, Jie; Zhang, Li; Ye, Bin

    2017-02-01

    The renin-angiotensin system is classically regarded as a crucial regulator of circulatory homeostasis, but recent studies also revealed its pro-inflammatory roles. The beneficial effects of the angiotensin-converting enzyme inhibitor (ACEI) in severe inflammatory injury in the lung and heart have been previously reported, but its potential effects on lethal hepatitis were unknown. In this study, a mouse model with LPS/d-galactosamine (GalN)-induced fulminant hepatitis were used to test the protective potential of captopril, a representative ACEI. The results indicated that treatment with captopril significantly decreased the plasma level of alanine aminotransferase and aspartate aminotransferase, alleviated the histopathological damage of the liver tissue and improve the survival rate of LPS/GalN-challenged mice. These effects were accompanied by reduced mRNA levels of TNF-α and IL-6 in the liver, and decreased protein level of TNF-α and IL-6 in the plasma. In addition, the activation of caspases 3, 8 and 9, and the presence of TUNEL-positive apoptotic cells, were also suppressed by captopril treatment. The above evidence suggested that the renin-angiotensin system might be involved in the development of LPS/GalN-induced fulminant hepatitis and ACEI might have potential value in lethal hepatitis.

  7. Antibodies against recombinant catalytic domain of lethal toxin of Clostridium sordellii neutralize lethal toxin toxicity in HeLa cells.

    Science.gov (United States)

    Arya, Preetika; Ponmariappan, S; Singh, Lokendra; Prasad, G B K S

    2013-02-01

    Lethal toxin of Clostridium sordellii (MLD 150 ng/kg) is one of the most potent Clostridial toxins and is responsible for most of the diseases including sudden death syndrome in cattle, sheep and toxic shock syndrome, necrotizing faciitis, neonatal omphalitis and gangrene in humans. Lethal toxin (TcsL) is a single chain protein of about 270 kDa. In the present study, 1.6 kb DNA fragment encoding for the catalytic domain of TcsL was PCR amplified, cloned in pQE30 UA vector and expressed in E. coli SG 13009. The expression of recombinant lethal toxin protein (rTcsL) was optimized and it was purified under native conditions using a single step Ni-NTA affinity chromatography. The purified recombinant protein was used for the production of polyclonal antibodies in mice and rabbit. The raised antibodies reacted specifically with the purified rTcsL and intact native lethal toxin on Western blot. The biological activity of the recombinant protein was tested in HeLa cells where it showed the cytotoxicity. Further, the polyclonal antibodies were used for in-vitro neutralization of purified rTcsL, acid precipitated C. sordellii and C. difficile native toxins in HeLa cells. Mice and rabbit anti-rTcsL sera effectively neutralized the cytotoxicity of rTcsL and C. sordellii native toxin but it did not neutralize the cytotoxicity of C. difficile toxin in HeLa cells.

  8. Broad spectrum antiviral activity of favipiravir (T-705: protection from highly lethal inhalational Rift Valley Fever.

    Directory of Open Access Journals (Sweden)

    Amy L Caroline

    2014-04-01

    Full Text Available BACKGROUND: Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705, which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV. RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route. METHODOLOGY/PRINCIPAL FINDINGS: Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92% survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease. CONCLUSIONS/SIGNIFICANCE: Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug.

  9. Photodynamic DNA damage induced by phycocyanin and its repair in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    M. Pádula

    1999-09-01

    Full Text Available In the present study, we analyzed DNA damage induced by phycocyanin (PHY in the presence of visible light (VL using a set of repair endonucleases purified from Escherichia coli. We demonstrated that the profile of DNA damage induced by PHY is clearly different from that induced by molecules that exert deleterious effects on DNA involving solely singlet oxygen as reactive species. Most of PHY-induced lesions are single strand breaks and, to a lesser extent, base oxidized sites, which are recognized by Nth, Nfo and Fpg enzymes. High pressure liquid chromatography coupled to electrochemical detection revealed that PHY photosensitization did not induce 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo at detectable levels. DNA repair after PHY photosensitization was also investigated. Plasmid DNA damaged by PHY photosensitization was used to transform a series of Saccharomyces cerevisiae DNA repair mutants. The results revealed that plasmid survival was greatly reduced in rad14 mutants, while the ogg1 mutation did not modify the plasmid survival when compared to that in the wild type. Furthermore, plasmid survival in the ogg1 rad14 double mutant was not different from that in the rad14 single mutant. The results reported here indicate that lethal lesions induced by PHY plus VL are repaired differently by prokaryotic and eukaryotic cells. Morever, nucleotide excision repair seems to play a major role in the recognition and repair of these lesions in Saccharomyces cerevisiae.

  10. Laparoscopic Repair of Morgagni Hernia

    Directory of Open Access Journals (Sweden)

    ilker murat arer

    2015-03-01

    Full Text Available Morgagni hernia is a congenital herniation of abdominal contents into the thoracic cavity through a retrosternal diaphragmatic defect and make up about 1 % - 5 % of all types of congenital diaphragmatic hernias. Surgical repair of Morgagni hernias is usually indicated when patients are symptomatic and have a high risk of strangulation or incarceration of the contained viscera. 71-year-old male patient admitted to emergency department with a 2-day history of abdominal pain, vomiting and obstipation. Laparoscopic repair for Morgagni hernia was performed. Laparoscopic repair for Morgagni hernia with mesh repair is secure, satisfactory and easily performed. [Cukurova Med J 2015; 40(Suppl 1: 71-74

  11. Combinatorial Reliability and Repair

    Science.gov (United States)

    1992-07-01

    Press, Oxford, 1987. [2] G. Gordon and L. Traldi, Generalized activities and the Tutte polynomial , Discrete Math. 85 (1990), 167-176. [3] A. B. Huseby, A...particular, Satyanarayana and Tindell introduced a notion of (K,j)-domination in their study of a K-terminal version of the chromatic polynomial [6], and it...G)) graphs. He also intends to look into the properties of the polynomial that gives the expected number of needed repairs of a K-terminal network

  12. Mammalian mismatch repair

    DEFF Research Database (Denmark)

    Pena Diaz, Javier; Jiricny, Josef

    2012-01-01

    A considerable surge of interest in the mismatch repair (MMR) system has been brought about by the discovery of a link between Lynch syndrome, an inherited predisposition to cancer of the colon and other organs, and malfunction of this key DNA metabolic pathway. This review focuses on recent...... advances in our understanding of the molecular mechanisms of canonical MMR, which improves replication fidelity by removing misincorporated nucleotides from the nascent DNA strand. We also discuss the involvement of MMR proteins in two other processes: trinucleotide repeat expansion and antibody maturation...

  13. Current options in local anesthesia for groin hernia repairs.

    Science.gov (United States)

    Kulacoglu, Hakan; Alptekin, Alp

    2011-01-01

    Inguinal hernia repair is one of the most common procedures in general surgery. All anesthetic methods can be used in inguinal hernia repairs. Local anesthesia for groin hernia repair had been introduced at the very beginning of the last century, and gained popularity following the success reports from the Shouldice Hospital, and the Lichtenstein Hernia Institute. Today, local anesthesia is routinely used in specialized hernia clinics, whereas its use is still not a common practice in general hospitals, in spite of its proven advantages and recommendations by current hernia repair guidelines. In this review, the technical options for local anaesthesia in groin hernia repairs, commonly used local anaesthetics and their doses, potential complications related to the technique are evaluated. A comparison of local, general and regional anesthesia methods is also presented. Local anaesthesia technique has a short learning curve requiring simple training. It is easy to learn and apply, and its use is in open anterior repairs a nice way for health care economics. Local anesthesia has been shown to have certain advantages over general and regional anesthesia in inguinal hernia repairs. It is more economic and requires a shorter time in the operating room and shorter stay in the institution. It causes less postoperative pain, requires less analgesic consumption; avoids nausea, vomiting, and urinary retention. Patients can mobilize and take oral liquids and solid foods much earlier. Most importantly, local anesthesia is the most suitable type of anesthesia in elder, fragile patients and patients with ASA II-IV scores.

  14. Biologics for tendon repair.

    Science.gov (United States)

    Docheva, Denitsa; Müller, Sebastian A; Majewski, Martin; Evans, Christopher H

    2015-04-01

    Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.

  15. Kvitebjoern gas pipeline repair - baptism of remote pipeline repair system

    Energy Technology Data Exchange (ETDEWEB)

    Gjertveit, Erling

    2010-07-01

    On the 1st of November 2007, severe anchor damage was discovered on the 30 inch Kvitebjoern gas export pipeline. The damage constituted a localised dent and a 17deg buckle, but no leakage. Statoil has invested in building an effective repair contingency structure for the large pipeline network on the Norwegian Continental shelf, with particular focus on the large gas export pipelines. The repair method for the Kvitebjoern pipeline was remotely operated using two Morgrip couplings and a spool. The installation used the purpose built Pipeline Repair System stored at Killingoey and couplings produced and tested back in 2005. This presentation will cover the initial damage investigations, the temporary operational phase, the repair preparations, the actual repair and lessons learned. (Author)

  16. Rescue of Lethal Hepatic Failure by Hepatized Lymph Nodes in Mice

    Science.gov (United States)

    Hoppo, Toshitaka; Komori, Junji; Manohar, Rohan; Stolz, Donna Beer; Lagasse, Eric

    2010-01-01

    BACKGROUND & AIMS Hepatocyte transplantation is a potential therapeutic approach for liver disease. However, most patients with chronic hepatic damage have cirrhosis and fibrosis, which limit the potential for cell-based therapy of the liver. The development of an ectopic liver as an additional site of hepatic function represents a new approach for patients with an end-stage liver disease. We investigated the development and function of liver tissue in lymph nodes in mice with liver failure. METHODS Hepatocytes were isolated from 8 to 12-week-old mice and transplanted by intraperitoneal injection into 8- to 12-week-old Fah-/- mice, a model of the human liver disease tyrosinemia type I. Survival was monitored and the locations and functions of the engrafted liver cells were determined. RESULTS Lymph nodes of Fah-/- mice were colonized by transplanted hepatocytes; Fah+ hepatocytes were detected adjacent to the CD45+ lymphoid cells of the lymphatic system. Ten weeks after transplantation, these mice had substantial improvements in serum levels of transaminases, bilirubin, and amino acids. Homeostatic expansion of donor hepatocytes in lymph nodes rescued the mice from lethal hepatic failure. CONCLUSIONS Functional ectopic liver tissue in lymph nodes rescues mice from lethal hepatic disease; lymph nodes might therefore be used as sites for hepatocyte transplantation. PMID:21070777

  17. Protection of Mice from Lethal Endotoxemia by Chimeric Human BPI-Fcγ1 Gene Delivery

    Institute of Scientific and Technical Information of China (English)

    Chen Li; Jing Li; Zhe Lv; Xinghua Guo; Qinghua Chen; Qingli Kong; Yunqing An

    2006-01-01

    To evaluate the potentiality of applying gene therapy to endotoxemia in high-risk patients, we investigated the effects of transferring an adeno-associated virus serotype 2 (AAV2)-mediated BPI-Fcγ1 gene on protecting mice from challenge of lethal endotoxin. The chimeric BPI-Fcγ1 gene consists of two parts, one encods functional N-terminus (1 to 199 amino acidic residues) of human BPI, which is a bactericidal/permeability-increasing protein,and the other encodes Fc segment of human immunoglobulin G1 (Fcγ1). Our results indicated that the target protein could be expressed and secreted into the serum of the gene-transferred mice. After lethal endotoxin challenge, the levels of endotoxin and TNF-α in the gene-transferred mice were decreased. The survival rate of the BPI-Fcγ1 gene-transferred mice was markedly increased. Our data suggest that AAV2-mediated chimeric BPI-Fcγ1 gene delivery can potentially be used clinically for the protection and treatment of endotoxemia and endotoxic shock in high-risk individuals.

  18. Antimicrobial, antityrosinase and brine shrimp lethality test of Bauhinia rufescens Lam (Fabaceae)

    Institute of Scientific and Technical Information of China (English)

    Aminu Muhammad; Hasnah Mohd Sirat

    2013-01-01

    Objective: To evaluate leaves and stem bark extracts of Bauhinia rufescens for antimicrobial activities, tyrosinase enzyme inhibition potentials and lethality to brine shrimp larvae (Artemiasalina ). Methods: The plant materials were extracted based on polarity gradient of petroleum ether, ethyl acetate and methanol. The extracts were investigated for their antimicrobial, antityrosinase and cytotoxicity potentials.Results:The antimicrobial results indicated that the extracts inhibited the microbial growth in the range of 6.00-12.57 mm (450-1 800 µg/mL) for bacterial strains and 7.33-14.03 mm (225-1 800 µg/mL) for fungal strains. While the tyrosinase enzyme inhibition assay of the extracts showed that both the petroleum ether leaves and stem bark extracts exhibited a moderate inhibition (39.60%and 39.89%) towards the action of mushroom tyrosinase enzyme on L-DOPA. In the brine shrimp lethality assay, ethyl acetate and methanol extracts of the leaves of the plant were found toxic to the Artemia salina with IC50 values of 0.059 mg/mL and 0.389 mg/mL. However, both the petroleum ether and ethyl acetate extracts of the stem bark were nontoxic to the larvae.Conclusions:The result of the present study suggest the presence of phytochemicals possessing antimicrobial and antityrosinase activity as well as cytotoxic agents.

  19. An improved brine shrimp larvae lethality microwell test method.

    Science.gov (United States)

    Zhang, Yi; Mu, Jun; Han, Jinyuan; Gu, Xiaojie

    2012-01-01

    This article described an improved brine shrimp larvae lethality microwell test method. A simply designed connecting vessel with alternative photoperiod was used to culture and collect high yield of active Artemia parthenogenetica nauplii for brine shrimp larvae lethality microwell test. Using this method, pure A. parthenogenetica nauplii suspension was easily cultured and harvested with high density about 100-150 larvae per milliliter and the natural mortality was reduced to near zero by elimination of unnecessary artificial disturbance. And its sensitivity was validated by determination of LC(50)-24 h of different reference toxicants including five antitumor agents, two pesticides, three organic pollutants, and four heavy metals salts, most of which exhibited LC(50)-24 h between 0.07 and 58.43 mg/L except for bleomycin and mitomycin C with LC(50)-24 h over 300 mg/L.

  20. Neonatal lethal dwarfism with distinct skeletal malformations - a separate entity?

    Energy Technology Data Exchange (ETDEWEB)

    Rosendahl, K.; Maurseth, K.; Olsen, Oe.E. [Dept. of Paediatric Radiology, Haukeland University Hospital, Bergen (Norway); Halvorsen, O.J. [Dept. of Pathology, Haukeland University Hospital, Bergen (Norway); Gjelland, K. [Dept. of Gynaecology, Haukeland University Hospital, Bergen (Norway); Engebretsen, L. [Dept. of Genetics, Haukeland University Hospital, Bergen (Norway)

    2001-09-01

    We describe a case of neonatal lethal dwarfism characterised by short trunk, short, stick-like tubular bones, deficient ossification of the axial skeleton and broad, sclerotic horizontal ribs. Two similar cases have previously been reported as examples of the Neu-Laxova syndrome. However, the radiological findings of the Neu-Laxova syndrome, as reported in 16 out of 40 documented cases, show a heterogeneous pattern of minor features, which differ distinctively from those found in the previous two cases and by us. A literature research did not reveal similar cases, and we therefore suggest that our case, together with the two previous cases, may represent a new distinctive form of neonatal lethal dwarfism. (orig.)

  1. Collateral Lethality: A new therapeutic strategy in oncology.

    Science.gov (United States)

    Muller, Florian L; Aquilanti, Elisa A; DePinho, Ronald A

    2015-11-01

    Genomic deletion of tumor suppressor genes (TSG) is a rite of passage for virtually all human cancers. The synthetic lethal paradigm has provided a framework for the development of molecular targeted therapeutics that are functionally linked to the loss of specific TSG functions. In the course of genomic events that delete TSGs, a large number of genes with no apparent direct role in tumor promotion also sustain deletion as a result of chromosomal proximity to the target TSG. In this perspective, we review the novel concept of "collateral lethality", which has served to identify cancer-specific therapeutic vulnerabilities resulting from co-deletion of passenger genes neighboring TSG. The large number of collaterally deleted genes, playing diverse functions in cell homeostasis, offers a rich repertoire of pharmacologically targetable vulnerabilities presenting novel opportunities for the development of personalized anti-neoplastic therapies.

  2. Mutagenesis-mediated virus extinction: Virus-dependent effect of viral load on sensitivity to lethal defection

    OpenAIRE

    Héctor Moreno; Héctor Tejero; Juan Carlos de la Torre; Esteban Domingo; Verónica Martín

    2012-01-01

    Background: Lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. Viral load and virus fitness are known to influence virus extinction. Here we examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis. Results: The effect of the mutagenic base analogue 5-fluorouracil (F...

  3. 28 CFR 552.25 - Use of chemical agents or non-lethal weapons.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Use of chemical agents or non-lethal weapons. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE... agents or non-lethal weapons. The Warden may authorize the use of chemical agents or non-lethal weapons...

  4. Meckel-Gruber syndrome: A rare and lethal anomaly

    OpenAIRE

    Kheir, Abdelmoneim E.M.; Imam, Abdelmutalab; Omer, Ilham M.; Hassan, Ibtsama M.A.; Elamin, Sara A.; Awadalla, Esra A.; Gadalla, Mohammed H.; Hamdoon, Tagwa A.

    2012-01-01

    Meckel-Gruber syndrome is a rare and lethal autosomal recessive disorder characterized by occipital encephalocele, postaxial polydactyly and bilateral dysplastic cystic kidneys. It can be associated with many other conditions. Antenatal ultrasound examination establishes the diagnosis by identifying at least two of the major features described. We describe a female baby who had the typical triad of Meckel-Gruber syndrome and died shortly after birth.

  5. Merging Hyperspectural Imagery and Multi Scale Modeling for Laser Lethality

    Science.gov (United States)

    2016-02-24

    field, to be submitted Combustion Theory and Modeling, 2016. Changes in research objectives (if any): Change in AFOSR Program Manager, if any...Extensions granted or milestones slipped, if any: AFOSR LRIR Number LRIR Title Reporting Period Laboratory Task Manager Program Officer Research Objectives ...AFRL-AFOSR-VA-TR-2016-0088 MERGING HYPERSPECTRAL IMAGERY AND MULTI -SCALE MODELING FOR LASER LETHALITY Leonid Zhigilei UNIVERSITY OF VIRGINIA Final

  6. [Lethal intravenous infusion of a wound antiseptic containing polyhexanide].

    Science.gov (United States)

    Wehner, Frank; Wehner, Heinz-Dieter; Schulz, Martin Manfred

    2009-01-01

    Polyhexamethylene biguanide (PHMB) is considered to be highly histocompatible and is one of the most frequently used wound antiseptics. Only one case of intoxication has been reported so far. The present case of a lethal intoxication is the first fatal incident described where causality is substantiated by a temporal coincidence between application and ascertainable organ damage. The laboratory-chemical and histological investigations verified the toxicity of this substance after intravenous application with the main findings being severe hepatic and pancreatic damage.

  7. Meckel-Gruber syndrome: A rare and lethal anomaly.

    Science.gov (United States)

    Kheir, Abdelmoneim E M; Imam, Abdelmutalab; Omer, Ilham M; Hassan, Ibtsama M A; Elamin, Sara A; Awadalla, Esra A; Gadalla, Mohammed H; Hamdoon, Tagwa A

    2012-01-01

    Meckel-Gruber syndrome is a rare and lethal autosomal recessive disorder characterized by occipital encephalocele, postaxial polydactyly and bilateral dysplastic cystic kidneys. It can be associated with many other conditions. Antenatal ultrasound examination establishes the diagnosis by identifying at least two of the major features described. We describe a female baby who had the typical triad of Meckel-Gruber syndrome and died shortly after birth.

  8. A lethal syndrome resembling branchio-oculo-facial syndrome.

    Science.gov (United States)

    Hing, A V; Torack, R; Dowton, S B

    1992-02-01

    Branchio-oculo-facial syndrome, a recently delineated autosomal dominant condition, is characterized by branchial cleft sinuses, ocular anomalies, and unusual facial appearance. A patient with branchial cleft fistulae, microphthalmia, nasomaxillary dysplasia, in addition to cardiac and CNS malformation (holoprosencephaly and meningo-encephalocele), is described. Although many features of this lethal malformation complex resemble those seen in the branchio-oculo-facial syndrome, the complex may represent a new multiple malformation syndrome.

  9. Handbook of adhesive bonded structural repair

    CERN Document Server

    Wegman, Raymond F

    1992-01-01

    Provides repair methods for adhesive bonded and composite structures; identifies suitable materials and equipment for repairs; describes damage evaluation criteria and techniques, and methods of inspection before and after repair.

  10. A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available BACKGROUND: A liver-derived protein, fetuin-A, was first purified from calf fetal serum in 1944, but its potential role in lethal systemic inflammation was previously unknown. This study aims to delineate the molecular mechanisms underlying the regulation of hepatic fetuin-A expression during lethal systemic inflammation (LSI, and investigated whether alterations of fetuin-A levels affect animal survival, and influence systemic accumulation of a late mediator, HMGB1. METHODS AND FINDINGS: LSI was induced by endotoxemia or cecal ligation and puncture (CLP in fetuin-A knock-out or wild-type mice, and animal survival rates were compared. Murine peritoneal macrophages were challenged with exogenous (endotoxin or endogenous (IFN-γ stimuli in the absence or presence of fetuin-A, and HMGB1 expression and release was assessed. Circulating fetuin-A levels were decreased in a time-dependent manner, starting between 26 h, reaching a nadir around 24-48 h, and returning towards base-line approximately 72 h post onset of endotoxemia or sepsis. These dynamic changes were mirrored by an early cytokine IFN-γ-mediated inhibition (up to 50-70% of hepatic fetuin-A expression. Disruption of fetuin-A expression rendered animals more susceptible to LSI, whereas supplementation of fetuin-A (20-100 mg/kg dose-dependently increased animal survival rates. The protection was associated with a significant reduction in systemic HMGB1 accumulation in vivo, and parallel inhibition of IFN-γ- or LPS-induced HMGB1 release in vitro. CONCLUSIONS: These experimental data suggest that fetuin-A is protective against lethal systemic inflammation partly by inhibiting active HMGB1 release.

  11. Clamp wins pipe repair prize

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2001-04-01

    This paper describes the permanent pipeline repair system, developed by Tekmar, which is powered by seawater hydraulics and is easily installed and tested by any workclass remotely operated vehicle (rov). Details are given of the two main components of the system, namely, the diverless high pressure split repair clamp and the rov-operated tool to install it.

  12. The journey of DNA repair

    OpenAIRE

    Saini, Natalie

    2015-01-01

    21 years ago, the DNA Repair Enzyme was declared “Molecule of the Year”. Today, we are celebrating another “year of repair”, with the 2015 Nobel Prize in Chemistry being awarded to Aziz Sancar, Tomas Lindahl and Paul Modrich for their collective work on the different DNA repair pathways.

  13. Nucleotide excision repair in yeast

    NARCIS (Netherlands)

    Eijk, Patrick van

    2012-01-01

    Nucleotide Excision Repair (NER) is a conserved DNA repair pathway capable of removing a broad spectrum of DNA damage. In human cells a defect in NER leads to the disorder Xeroderma pigmentosum (XP). The yeast Saccharomyces cerevisiae is an excellent model organism to study the mechanism of NER. The

  14. Mouse model of sublethal and lethal intraperitoneal glanders (Burkholderia mallei).

    Science.gov (United States)

    Fritz, D L; Vogel, P; Brown, D R; Deshazer, D; Waag, D M

    2000-11-01

    Sixty male BALB/c mice were inoculated intraperitoneally with either a sublethal or a lethal dose of Burkholderia mallei China 7 strain, then killed at multiple time points postinoculation. Histopathologic changes were qualitatively similar in both groups and consisted of pyogranulomatous inflammation. In sublethal study mice, changes were first seen at 6 hours in mediastinal lymph nodes, then in spleen, liver, peripheral lymph nodes, and bone marrow at day 3. These changes generally reached maximal incidence and severity by day 4 but decreased by comparison in all tissues except the liver. Changes were first seen in lethal study mice also at 6 hours in mediastinal lymph nodes and in spleens. At day 1, changes were present in liver, peripheral lymph nodes, and bone marrow. The incidence and severity of these changes were maximal at day 2. In contrast to sublethal study mice, the incidence and severity of the changes did not decrease through the remainder of the study. The most significant difference between the two groups was the rapid involvement of the spleen in the lethal study mice. Changes indicative of impaired vascular perfusion were more frequently seen in the sublethal study mice. Our findings indicate that mice are susceptible to B. mallei infection and may serve as an appropriate model for glanders infection in a resistant host such as human beings. Additionally, by immunoelectron microscopy, we showed the presence of type I O-antigenic polysaccharide (capsular) antigen surrounding B. mallei.

  15. Putative Enzymes of UV Photoproduct Repair

    Directory of Open Access Journals (Sweden)

    Cynthia J. Sakofsky

    2011-01-01

    Full Text Available In order to determine the biological relevance of two S. acidocaldarius proteins to the repair of UV photoproducts, the corresponding genes (Saci_1227 and Saci_1096 were disrupted, and the phenotypes of the resulting mutants were examined by various genetic assays. The disruption used integration by homologous recombination of a functional but heterologous pyrE gene, promoted by short sequences attached to both ends via PCR. The phenotypic analyses of the disruptants confirmed that ORF Saci_1227 encodes a DNA photolyase which functions in vivo, but they could not implicate ORF Saci_1096 in repair of UV- or other externally induced DNA damage despite its similarity to genes encoding UV damage endonucleases. The success of the gene-disruption strategy, which used 5′ extensions of PCR primers to target cassette integration, suggests potential advantages for routine construction of Sulfolobus strains.

  16. Emergent cardiopulmonary bypass during pectus excavatum repair

    Directory of Open Access Journals (Sweden)

    Ryan Craner

    2013-01-01

    Full Text Available Pectus excavatum is a chest wall deformity that produces significant cardiopulmonary disability and is typically seen in younger patients. Minimally invasive repair of pectus excavatum or Nuss procedure has become a widely accepted technique for adult and pediatric patients. Although it is carried out through a thoracoscopic approach, the procedure is associated with a number of potential intraoperative and post-operative complications. We present a case of cardiac perforation requiring emergent cardiopulmonary bypass in a 29-year-old male with Marfan syndrome and previous mitral valve repair undergoing a Nuss procedure for pectus excavatum. This case illustrates the importance of vigilance and preparation by the surgeons, anesthesia providers as well as the institution to be prepared with resources to handle the possible complications. This includes available cardiac surgical backup, perfusionist support and adequate blood product availability.

  17. Rethinking transcription coupled DNA repair.

    Science.gov (United States)

    Kamarthapu, Venu; Nudler, Evgeny

    2015-04-01

    Nucleotide excision repair (NER) is an evolutionarily conserved, multistep process that can detect a wide variety of DNA lesions. Transcription coupled repair (TCR) is a subpathway of NER that repairs the transcribed DNA strand faster than the rest of the genome. RNA polymerase (RNAP) stalled at DNA lesions mediates the recruitment of NER enzymes to the damage site. In this review we focus on a newly identified bacterial TCR pathway in which the NER enzyme UvrD, in conjunction with NusA, plays a major role in initiating the repair process. We discuss the tradeoff between the new and conventional models of TCR, how and when each pathway operates to repair DNA damage, and the necessity of pervasive transcription in maintaining genome integrity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. DNA base excision repair nanosystem engineering: model development.

    Science.gov (United States)

    Sokhansanj, B A

    2005-01-01

    DNA base damage results from a combination of endogenous sources, (normal metabolism, increased metabolism due to obesity, stress from diseases such as arthritis and diabetes, and ischemia) and the environment (ingested toxins, ionizing radiation, etc.). If unrepaired DNA base damage can lead to diminished cell function, and potentially diseases and eventually mutations that lead to cancer. Sophisticated DNA repair mechanisms have evolved in all living cells to preserve the integrity of inherited genetic information and transcriptional control. Understanding a system like DNA repair is greatly enhanced by using engineering methods, in particular modeling interactions and using predictive simulation to analyze the impact of perturbations. We describe the use of such a "nanosystem engineering" approach to analyze the DNA base excision repair pathway in human cells, and use simulation to predict the impact of varying enzyme concentration on DNA repair capacity.

  19. Reward optimization of a repairable system

    Energy Technology Data Exchange (ETDEWEB)

    Castro, I.T. [Departamento de Matematicas, Facultad de Veterinaria, Universidad de Extremadura, Avenida de la Universidad, s/n. 10071 Caceres (Spain)]. E-mail: inmatorres@unex.es; Perez-Ocon, R. [Departamento de Estadistica e Investigacion Operativa, Facultad de Ciencias, Universidad de Granada, Avenida de Severo Ochoa, s/n. 18071 Granada (Spain)]. E-mail: rperezo@ugr.es

    2006-03-15

    This paper analyzes a system subject to repairable and non-repairable failures. Non-repairable failures lead to replacement of the system. Repairable failures, first lead to repair but they lead to replacement after a fixed number of repairs. Operating and repair times follow phase type distributions (PH-distributions) and the pattern of the operating times is modelled by a geometric process. In this context, the problem is to find the optimal number of repairs, which maximizes the long-run average reward per unit time. To this end, the optimal number is determined and it is obtained by efficient numerical procedures.

  20. Wound repair in Pocillopora

    Science.gov (United States)

    Rodríguez-Villalobos, Jenny Carolina; Work, Thierry M.; Calderon-Aguileraa, Luis Eduardo

    2016-01-01

    Corals routinely lose tissue due to causes ranging from predation to disease. Tissue healing and regeneration are fundamental to the normal functioning of corals, yet we know little about this process. We described the microscopic morphology of wound repair in Pocillopora damicornis. Tissue was removed by airbrushing fragments from three healthy colonies, and these were monitored daily at the gross and microscopic level for 40 days. Grossly, corals healed by Day 30, but repigmentation was not evident at the end of the study (40 d). On histology, from Day 8 onwards, tissues at the lesion site were microscopically indistinguishable from adjacent normal tissues with evidence of zooxanthellae in gastrodermis. Inflammation was not evident. P. damicornis manifested a unique mode of regeneration involving projections of cell-covered mesoglea from the surface body wall that anastomosed to form gastrovascular canals.

  1. Groin hernia repair

    DEFF Research Database (Denmark)

    Kehlet, Henrik; Aasvang, Eske

    2005-01-01

    The choice of anesthesia for groin hernia repair is between general, regional (epidural or spinal), and local anesthesia. Existing data from large consecutive patient series and randomized studies have shown local anesthesia to be the method of choice because it can be performed by the surgeon......, does not necessarily require an attending anesthesiologist, translates into the shortest recovery (bypassing the postanesthesia care unit), has the lowest cost, and has the lowest postoperative morbidity regarding risk of urinary retention. Spinal anesthesia has no documented benefits for this small...... scientific data to support the choice of anesthesia, large epidemiologic and nationwide information from databases show an undesirable high (about 10-20%) use of spinal anesthesia and low (about 10%) use of local infiltration anesthesia. Surgeons and anesthesiologists should therefore adjust their anesthesia...

  2. Gonioscopically Guided Nonpenetrating Cyclodialysis Cleft Repair: A Novel Surgical Technique

    Science.gov (United States)

    Rodrigues, Ian AS; Shah, Brinda; Goyal, Saurabh

    2017-01-01

    ABSTRACT Aim We present a novel surgical technique for repair of persistent and symptomatic cyclodialysis clefts refractory to conservative or minimally invasive treatment. Background Numerous surgical techniques have been described to close cyclodialysis clefts. The current standard approach involves intraocular repair of cyclodialysis clefts underneath a full-thickness scleral flap. Technique Our technique employs intraoperative use of a direct gonioscope to guide a nonpenetrating surgical repair. Subsequently, a significantly less invasive, nonpenetrating technique utilizing a partial-thickness scleral flap can be performed that reduces potential risks associated with intraocular surgery. The direct gonioscope is also used for confirmation of adequate surgical closure of the cyclodialysis cleft prior to completion of surgery. This technique has been successfully carried out to repair traumatic chronic cyclodialysis clefts associated with hypotony in two patients. There were no significant adverse events as a result of using this technique. Conclusion The novel technique described increases the likelihood of successful and permanent repair of cyclodialysis clefts with resolution of symptoms associated with hypotony, through direct intraoperative visualization of the cleft. Clinical significance Gonioscopically guided nonpenetrating cyclodialysis cleft repair offers significant benefits over previously described techniques. Advantages of our technique include gonioscopic cleft visualization, enabling accurate localization of the area requiring repair, and subsequent confirmation of adequate closure of the cleft. Using a partial-thickness scleral flap is also less invasive and reduces risks associated with treatment of this potentially challenging complication of ocular trauma. How to cite this article Rodrigues IAS, Shah B, Goyal S, Lim S. Gonioscopically Guided Nonpenetrating Cyclodialysis Cleft Repair: A Novel Surgical Technique. J Curr Glaucoma Pract 2017

  3. Parametric studies on self-repairing approaches for resin infused composites subjected to low velocity impact

    Science.gov (United States)

    Motuku, M.; Vaidya, U. K.; Janowski, G. M.

    1999-10-01

    Low velocity impact response of glass reinforced polymer composites, which have the potential to self-repair both micro- and macro-damage, has been investigated. This class of material falls under the category of passive smart polymer composites. The self-repairing mechanism is achieved through the incorporation of hollow fibers in addition to the normal solid reinforcing fibers. The hollow fibers store the damage-repairing solution or chemicals that are released into the matrix or damaged zone upon fiber failure. Plain-weave S-2 glass fabric reinforcement, vinyl ester 411-C50 and EPON-862 epoxy resin systems were considered for this study. Different tubing materials were investigated for potential use as storage materials for the repairing chemicals instead of the actual hollow repair fibers and included borosilicate glass micro-capillary pipets, flint glass pasteur pipets, copper tubing and aluminum tubing. composite panels were fabricated by using a vacuum assisted resin transfer molding process. The present investigation addressed fabrication of self-repairing composite panels and some of the parameters that influence the response of self-repairing composites to impact loading. Specific issues addressed by this study include: the processing quality; the selection of storage material for the repairing solution; release and transportation of the repairing solution; the effect of the number, type and spatial distribution of the repairing tubes, specimen thickness, matrix material and impact energy level.

  4. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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 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.

  6. Reconstruction of Posterior Interosseous Nerve Injury Following Biceps Tendon Repair: Case Report and Cadaveric Study

    OpenAIRE

    Mokhtee, David B.; Brown, Justin M.; Mackinnon, Susan E.; Tung, Thomas H.

    2008-01-01

    Surgical repair of distal biceps tendon rupture is a technically challenging procedure that has the potential for devastating and permanently disabling complications. We report two cases of posterior interosseous nerve (PIN) injury following successful biceps tendon repair utilizing both the single-incision and two-incision approaches. We also describe our technique of posterior interosseous nerve repair using a medial antebrachial cutaneous nerve graft (MABC) and a new approach to the termin...

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

    Science.gov (United States)

    Gkazonis, Petros V; Dalkas, Georgios A; Chasapis, Christos T; Vlamis-Gardikas, Alexios; Bentrop, Detlef; Spyroulias, Georgios A

    2010-06-04

    Anthrax lethal toxin (LeTx) stands for the major virulence factor of the anthrax disease. It comprises a 90kDa highly specific metalloprotease, the anthrax lethal factor (LF). LF possesses a catalytic Zn(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 are essential to elucidate its enzymatic properties. Here we report the recombinant expression and purification of a C-terminal part of LF (LF(672-776)) that harbours the enzyme's core protease domain. The biophysical characterization and backbone assignments ((1)H, (13)C, (15)N) of the polypeptide revealed a stable, well folded structure even in the absence of Zn(2+), suitable for high resolution structural analysis by NMR.

  8. Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1

    Directory of Open Access Journals (Sweden)

    Matthew Locke

    2016-08-01

    Full Text Available Argininosuccinate synthase 1 (ASS1 is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers.

  9. Estimation of cytotoxic potency by brine shrimp lethality bioassay application of Clerodendrum infortunatum Linn.

    Directory of Open Access Journals (Sweden)

    Talukdar Muhammad Waliullah

    2015-08-01

    Full Text Available Objective: To learn a scientific and systematic knowledge of anticancer, antimicrobial and pharmacological activities of natural products and estimate cytotoxic potency by using ethanol and chloroform extracts of root, leaf and stem of Clerodendrum infortunatum (Verbenaceae due to its random use in customary and traditional medicine to cure common ailments such as intestinal disorder, diarrhea, tuberculosis and respiratory problems etc. Methods: The in vitro application was carried out with the bench-top bioassay method by using brine shrimp lethality bioassay. Results: All of the crude extracts were found to be lethal and effective. The LC50 value of ethyl alcohol fraction of root was 20.845 mg/L compared to the standard drug tetracycline of 14.675 mg/L to brine shrimp nauplii, indicating that the extracts were biologically active. Conclusions: The cytotoxic study of LC50 value showed that a good correlation with the antibiotic tetracycline. From the comparative correlation error bars and percentage, we understood that ethyl alcohol fraction of root extract was very effective. This study serves as a basis for further research to lead compounds to be isolated so that it may be as a template for the implications of these results for bioactivity and drug discovery potential of herbal products.

  10. Noninvasive risk stratification of lethal ventricular arrhythmias and sudden cardiac death after myocardial infarction

    Directory of Open Access Journals (Sweden)

    Kenji Yodogawa, MD

    2014-08-01

    Full Text Available Prediction of lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important and challenging problems after myocardial infarction (MI. Identification of MI patients who are prone to ventricular tachyarrhythmias allows for an indication of implantable cardioverter-defibrillator placement. To date, noninvasive techniques such as microvolt T-wave alternans (MTWA, signal-averaged electrocardiography (SAECG, heart rate variability (HRV, and heart rate turbulence (HRT have been developed for this purpose. MTWA is an indicator of repolarization abnormality and is currently the most promising risk-stratification tool for predicting malignant ventricular arrhythmias. Similarly, late potentials detected by SAECG are indices of depolarization abnormality and are useful in risk stratification. However, the role of SAECG is limited because of its low predictive accuracy. Abnormal HRV and HRT patterns reflect autonomic disturbances, which may increase the risk of lethal ventricular arrhythmias, but the existing evidence is insufficient. Further studies of noninvasive assessment may provide a new insight into risk stratification in post-MI patients.

  11. Molecular markers in prostate cancer.Part I:predicting lethality

    Institute of Scientific and Technical Information of China (English)

    Sachin Agrawal; William D.Dunsmuir

    2009-01-01

    Assessing the lethality of 'early,' potentially organ-confined prostate cancer (PCa) is one of the central controversies in moderu-day urological clinical practice.Such cases are often considered for radical 'curative' treatment,although active surveillance may be equally appropriate for many men.Moreover,the balance between judicious intervention and overtreatment can be difficult to judge.The patient's age,comorbidities,family history and philosophy of self-health care can be weighed against clinical features such as the palpability of disease,the number and percentage of biopsy cores involved with the disease,histological grade,presenting prostate-specific antigen (PSA) and possible previous PSA kinetics.For many years,scientists and physicians have sought additional molecular factors that may be predictive for disease stage,progression and lethality.Usually,claims for a 'new' unique marker fall short of true clinical value.More often than not,such molecular markers are useful only in multivariate models.This review summarizes relevant molecular markers and models reported up to and including 2008.

  12. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation.

    Science.gov (United States)

    Reno, Candace M; Daphna-Iken, Dorit; Chen, Y Stefanie; VanderWeele, Jennifer; Jethi, Krishan; Fisher, Simon J

    2013-10-01

    For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10-15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia-induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia-induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response.

  13. Variation in lethality and effects of two Australian chirodropid jellyfish venoms in fish.

    Science.gov (United States)

    Kintner, Anna H; Seymour, Jamie E; Edwards, Susan L

    2005-11-01

    The North Queensland chirodropid box jellyfish Chironex fleckeri and Chiropsalmus sp. share similar nematocyst composition and the same prey of Acetes australis shrimps in their early medusa stages; however, as C. fleckeri individuals reach larger size, the animals add fish to their diet and their complement of nematocyst types changes, allowing larger doses of venom to be delivered to prey. This study demonstrated that the venoms of the two species differ as well: despite similar effects previously documented in crustacean prey models, the two had widely different cardiac and lethal effects in fish, with C. fleckeri being substantially more potent in its ability to cause death. Comparisons between the venom delivery abilities of the two species showed that the change in nematocysts of C. fleckeri cannot alone account for its ontogenetic shift to prey fish; instead, its prey ecology clearly necessitates it having venom capable of acting efficiently to cause death in fish. Although this venom is almost certainly produced at greater metabolic cost to the animal than the less-lethal venom of Chiropsalmus sp., owing to its greater molecular protein complexity, it confers the advantage of increased caloric intake from fish prey, facilitating larger size and potentially greater reproductive output of C. fleckeri over Chiropsalmus sp.

  14. Estimation of cytotoxic potency by brine shrimp lethality bioassay application of Clerodendrum infortunatum Linn.

    Institute of Scientific and Technical Information of China (English)

    Talukdar Muhammad Waliullah; Akter MstYeasmin; Ashraful MdAlam; Wahedul Md Islam; Parvez Hassan

    2015-01-01

    Objective: To learn a scientific and systematic knowledge of anticancer, antimicrobial and pharmacological activities of natural products and estimate cytotoxic potency by using ethanol and chloroform extracts of root, leaf and stem of Clerodendrum infortunatum (Verbenaceae) due to its random use in customary and traditional medicine to cure common ailments such as intestinal disorder, diarrhea, tuberculosis and respiratory problems etc. Methods: The in vitro application was carried out with the bench-top bioassay method by using brine shrimp lethality bioassay. Results: All of the crude extracts were found to be lethal and effective. The LC50 value of ethyl alcohol fraction of root was 20.845 mg/L compared to the standard drug tetracycline of 14.675 mg/L to brine shrimp nauplii, indicating that the extracts were biologically active. Conclusions: The cytotoxic study of LC50 value showed that a good correlation with the antibiotic tetracycline. From the comparative correlation error bars and percentage, we understood that ethyl alcohol fraction of root extract was very effective. This study serves as a basis for further research to lead compounds to be isolated so that it may be as a template for the implications of these results for bioactivity and drug discovery potential of herbal products.

  15. In vitro lethal photosensitization of S. mutans using methylene blue and toluidine blue O as photosensitizers.

    Science.gov (United States)

    Araújo, Patrícia V; Teixeira, Karina I R; Lanza, Lincoln D; Cortes, Maria E; Poletto, Luiz T A

    2009-01-01

    The purpose of this in vitro study was to evaluate the antimicrobial effect of photodynamic therapy on Streptococcus mutans (A TCC 25175) suspensions, using a red laser for one minute in combination with toluidine blue O (TBO) or methylene blue (MB). Both photosensitizers were used in three concentrations (25, 10 and 5 mg/L). The activity ofphotosensitizers and laser irradiation were tested separately on the bacteria, as well as the irradiation of this light source in the presence of the TBO or MB. These groups were compared to a control group, in which the microorganism did not receive any treatment. The activity of both TBO and MB or laser irradiation, alone, were not able to reduce the number of S. mutans. In the groups of lethal photosensitization, a bacterial reduction of 70% for TBO and 73% for MB was observed when these photosensitizers were used at 25 mg/L and a reduction of 48% was observed for MB at 5mg/L. In other concentrations there were no significant differences in comparison to the control group. Both the TBO and the MB at 25 mg/L associated with a red laser had an excellent potential for use in PDT in lethal sensitization of S. mutans.

  16. Development of a non-lethal method for evaluating transcriptomic endpoints in Arctic grayling (Thymallus arcticus).

    Science.gov (United States)

    Veldhoen, Nik; Beckerton, Jean E; Mackenzie-Grieve, Jody; Stevenson, Mitchel R; Truelson, Robert L; Helbing, Caren C

    2014-07-01

    With increases in active mining and continued discharge associated with former mine operations, evaluating the health of watersheds in the Canadian Yukon Territory is warranted. Current environmental assessment approaches often employ guidelines established using sentinel species not relevant to Arctic monitoring programs. The present study focused on the successful development of a quantitative real-time polymerase chain reaction (qPCR) assay directed towards the indigenous Arctic grayling (Thymallus arcticus) and examines the feasibility of using non-lethal sampling from the caudal fin as a means for evaluation of mRNA abundance profiles reflective of environmental conditions. In a proof of concept study performed blind, qPCR results from animals in an area with elevated water concentrations of cadmium (Cd) and zinc (Zn) and higher body burdens of Cd, Zn, and lead (Pb) were compared to a reference location in the Yukon Territory. Lower condition factor and a higher abundance of hepatic and caudal fin gene transcripts encoding the metallothionein isoforms (mta/mtb), in addition to elevated heat shock protein 70 (hsp70) and catalase (cat) mRNAs in liver, were observed in fish from the test site. The strong positive correlation between metal body burden and caudal fin mta/mtb mRNA abundance demonstrates a high potential for use of the Arctic grayling assay in non-lethal environmental monitoring programs.

  17. How to repair an episiotomy.

    Science.gov (United States)

    Steen, Mary; Cummins, Bernie

    2016-02-17

    Rationale and key points Skilful repair of an episiotomy is an important aspect of maternal health care. It is essential that midwives and doctors have the knowledge and skills to undertake this procedure in a safe and effective manner. ▶ An episiotomy should be repaired promptly to reduce blood loss and prevent infection. ▶ Repair of an episiotomy is undertaken in three stages: repair of the vaginal mucosa, repair of the muscle layer and repair of the skin layer. ▶ Adequate pain relief should be provided before suturing. Reflective activity Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. Why a rectal examination is recommended before and following repair of an episiotomy. 2. What you would do to improve your suturing skills. 3. The factors that may prevent or delay an episiotomy from healing. Subscribers can upload their reflective accounts at rcni.com/portfolio .

  18. DNA repair in Chromobacterium violaceum.

    Science.gov (United States)

    Duarte, Fábio Teixeira; Carvalho, Fabíola Marques de; Bezerra e Silva, Uaska; Scortecci, Kátia Castanho; Blaha, Carlos Alfredo Galindo; Agnez-Lima, Lucymara Fassarella; Batistuzzo de Medeiros, Silvia Regina

    2004-03-31

    Chromobacterium violaceum is a Gram-negative beta-proteobacterium that inhabits a variety of ecosystems in tropical and subtropical regions, including the water and banks of the Negro River in the Brazilian Amazon. This bacterium has been the subject of extensive study over the last three decades, due to its biotechnological properties, including the characteristic violacein pigment, which has antimicrobial and anti-tumoral activities. C. violaceum promotes the solubilization of gold in a mercury-free process, and has been used in the synthesis of homopolyesters suitable for the production of biodegradable polymers. The complete genome sequence of this organism has been completed by the Brazilian National Genome Project Consortium. The aim of our group was to study the DNA repair genes in this organism, due to their importance in the maintenance of genomic integrity. We identified DNA repair genes involved in different pathways in C. violaceum through a similarity search against known sequences deposited in databases. The phylogenetic analyses were done using programs of the PHILYP package. This analysis revealed various metabolic pathways, including photoreactivation, base excision repair, nucleotide excision repair, mismatch repair, recombinational repair, and the SOS system. The similarity between the C. violaceum sequences and those of Neisserie miningitidis and Ralstonia solanacearum was greater than that between the C. violaceum and Escherichia coli sequences. The peculiarities found in the C. violaceum genome were the absence of LexA, some horizontal transfer events and a large number of repair genes involved with alkyl and oxidative DNA damage.

  19. Presence of a lethal protease in the extracellular products of Vibrio splendidus-Vibrio lentus related strains.

    Science.gov (United States)

    Farto, R; Armada, S P; Montes, M; Perez, M J; Nieto, T P

    2006-12-01

    The presence of a lethal extracellular 39-kDa protease, a virulence determinant of a Listonella pelagia strain which produces vibriosis in turbot, was determined in the extracellular products (ECP) of 33 Vibrionaceae strains. Both immunological and enzymatic techniques distinguished this specific protease from other Vibrionaceae proteins. It was detected in 15% (5/33) of the ECPs assayed belonging to strains of the Vibrio splendidus-V. lentus related group isolated in Galician aquaculture systems (NW Spain). As these strains were associated with diseased octopus and cultured turbot, were able to colonize the internal organs of fish and produced a lethal ECP for fish, they are a potential risk for the health of reared aquatic organisms.

  20. 40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

    Science.gov (United States)

    2010-07-01

    ... repair proficient and repair deficient bacteria: âBacterial DNA damage or repair tests.â 798.5500 Section... inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA damage or repair tests.” (a... killing or growth inhibition of repair deficient bacteria in a set of repair proficient and deficient...

  1. Bone repair and stem cells.

    Science.gov (United States)

    Ono, Noriaki; Kronenberg, Henry M

    2016-10-01

    Bones are an important component of vertebrates; they grow explosively in early life and maintain their strength throughout life. Bones also possess amazing capabilities to repair-the bone is like new without a scar after complete repair. In recent years, a substantial progress has been made in our understanding on mammalian bone stem cells. Mouse genetic models are powerful tools to understand the cell lineage, giving us better insights into stem cells that regulate bone growth, maintenance and repair. Recent findings about these stem cells raise new questions that require further investigations.

  2. Repairing and Upgrading Your PC

    CERN Document Server

    Thompson, Robert

    2009-01-01

    Repairing and Upgrading Your PC delivers start-to-finish instructions, simple enough for even the most inexperienced PC owner, for troubleshooting, repairing, and upgrading your computer. Written by hardware experts Robert Bruce Thompson and Barbara Fritchman Thompson, this book covers it all: how to troubleshoot a troublesome PC, how to identify which components make sense for an upgrade, and how to tear it all down and put it back together. This book shows how to repair and upgrade all of your PC's essential components.

  3. Laparoscopic repair of incisional hernia.

    Science.gov (United States)

    Lau, H; Lee, F; Patil, N G

    2001-09-01

    A 75-year-old man developed an incisional hernia over the upper abdomen following a wedge resection of a gastric stromal tumour in 1996. This is the first published report of a successful repair of an incisional hernia via a laparoscopic intraperitoneal on-lay technique using GORE-TEX DualMesh material in Hong Kong. Compared with conventional open repair of incisional hernia, long incisions and wound tension are avoided using the laparoscopic approach. This translates into a reduced risk of wound-related complications and facilitates recovery. In selected cases, minimally invasive surgery is a safe technique for the repair of incisional hernias.

  4. [Inguinal and femoral hernia repair].

    Science.gov (United States)

    Geissler, B; Anthuber, M

    2011-05-01

    With an incidence of 200,000 new cases per year in Germany, inguinal hernia has a significant socioeconomic impact. The 2009 guidelines from the European Hernia Society established treatment recommendations. Hernia repair is based on reinforcing the posterior wall of the inguinal canal by suture or mesh repair by an anterior or posterior approach. Lightweight mesh reduces recurrence rates and is the treatment of choice even in primary hernias. Laparoscopic hernia repair is associated with specific risks but is superior in postoperative pain and earlier return to work.

  5. Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain.

    Science.gov (United States)

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Crown, Devorah; Thai, April; Cregar-Hernandez, Lynne; McKasson, Linda; Sankaran, Banumathi; Lehrer, Axel; Wong, Teri; Johns, Lisa; Margosiak, Stephen A; Leppla, Stephen H; Johnson, Alan T

    2012-03-15

    Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.

  6. Large myelomeningocele repair

    Directory of Open Access Journals (Sweden)

    Farideh Nejat

    2011-01-01

    Full Text Available Background: Wound closure is accomplished in most cases of myelomeningocele (MMC by undermining of the skin edges surrounding the defect. However, large defects cannot be closed reliably by this simple technique. Due to the technical challenge associated with large MMC, surgeons have devised different methods for repairing large defects. In this paper, we report our experience of managing large defects, which we believe bears a direct relationship to decrease the incidence of wound complications. Materials and Methods: Forty children with large MMCs underwent surgical repair and represent our experience. We recommend using all hairy skin around the defect as a way to decrease the tension on the edges of the wound and the possible subsequent necrosis. It is our experience that vertical incision on one or two flanks parallel to the midline can decrease the tension of the wound. Moreover, ventriculo-peritoneal shunting for children who developed hydrocephalus was performed simultaneously, which constitutes another recommendation for preventing fluid collection and build up of pressure on the wound. Results: Patients in this study were in the age range of 2 days to 8 years. The most common location of MMC was in the thoracolumbar area. All but four patients had severe weakness in lower extremities. We used as much hairy skin around the MMC sac as possible in all cases. Vertical incisions on one or both flanks and simultaneous shunt procedure were performed in 36 patients. We treated children with large MMC defects with acceptable tension-free closure. Nonetheless, three patients developed superficial skin infection and partial wound dehiscence, and they were managed conservatively. Conclusions: We recommend using all hairy skin around the MMC defect for closure of large defects. In cases that were expected to be at a higher risk to develop dehiscence release incisions on one or two flanks towards the fascia were found to be useful. Simultaneous

  7. Complications and lethality rate in the surgery of cerebral aneurysms

    Directory of Open Access Journals (Sweden)

    Roganović Zoran

    2002-01-01

    Full Text Available Aim. To establish the risk factors for complications and fatal outcome after the operative occlusion of cerebral aneurysms. Methods. Retrospective study on 91 (lethality rate and on 72 operated patients (complications. For survived and dead patients, as well as for patients with and without complications, following parameters were compared: gender, age, clinical condition, preoperative interval, use of temporary clips, vasospasm, outcome, as well as localization, size and intraoperative rupture of the aneurysm. Results. Complications existed: in 54.5% of aneurysms of middle cerebral and 13.6% of aneurysms of internal carotid artery (p<0.01; in 18.2% of patients in the first and 45.8% of patients in the third clinical Hunt and Hess group (p<0.05; in 57.9% of patients with and 20.5% of patients without intraoperative rupture (p<0.01; in 50% of patients with and 18.7% of patients without vasospasm (p<0.05. Average aneurysmal size was 18 mm in group with complications and 10.8 mm in patients with no complications (p<0.05, while average preoperative intervals in these two groups were 20 and 8.7 days (p<0.05. Lethality rate was 25% for the third and 83.3% for the fourth and fifth clinical group (p<0.01, and the existence of complications significantly increased mortality (from 15.7% to 50%, p<0.01. Good outcome existed in 19.2% of operated patients with complications and in 78.3% of those without complications (p<0.01. Conclusions. Incidence of complications depended significantly on preoperative clinical condition, duration of preoperative interval, size, localization and intraoperative rupture of aneurysm. Complications significantly minimized the surgical treatment outcome and increased the lethality rate mortality.

  8. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  9. Mononuclear Cells and Vascular Repair in HHT

    Directory of Open Access Journals (Sweden)

    Calinda eDingenouts

    2015-03-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber disease is a rare genetic vascular disorder known for its endothelial dysplasia causing arteriovenous malformations and severe bleedings. HHT-1 and HHT-2 are the most prevalent variants and are caused by heterozygous mutations in endoglin and ALK1, respectively. An undervalued aspect of the disease is that HHT patients experience persistent inflammation. Although endothelial and mural cells have been the main research focus trying to unravel the mechanism behind the disease, wound healing is a process with a delicate balance between inflammatory and vascular cells. Inflammatory cells are part of the mononuclear cells (MNCs fraction, and can, next to eliciting an immune response, also have angiogenic potential. This biphasic effect of MNC can hold a promising mechanism to further elucidate treatment strategies for HHT patients. Before MNC are able to contribute to repair, they need to home to and retain in ischemic and damaged tissue. Directed migration (homing of mononuclear cells following tissue damage is regulated by the stromal cell derived factor 1 (SDF1. MNCs that express the C-X-C chemokine receptor 4 (CXCR4 migrate towards the tightly regulated gradient of SDF1. This directed migration of monocytes and lymphocytes can be inhibited by dipeptidyl peptidase 4 (DPP4. Interestingly, MNC of HHT patients express elevated levels of DPP4 and show impaired homing towards damaged tissue. Impaired homing capacity of the MNCs might therefore contribute to the impaired angiogenesis and tissue repair observed in HHT patients. This review summarizes recent studies regarding the role of MNCs in the etiology of HHT and vascular repair, and evaluates the efficacy of DPP4 inhibition in tissue integrity and repair.

  10. Lethal subarachnoid bleeding under immunosuppressive therapy due to mycotic arteritis

    Energy Technology Data Exchange (ETDEWEB)

    Weigel, S.; Kloska, S.; Freund, M. [Dept. of Clinical Radiology, Univ. Hospital of Muenster, Muenster (Germany); Kehl, H.G. [Dept. of Pediatric Cardiology, Univ. Hospital of Muenster, Muenster (Germany)

    2003-12-01

    A subarachnoid haemorrhage (SAH) occurred 67 days after cardiac transplantation in 10-year-old girl with consecutive immunocompromising therapy. Neither digital subtraction angiography (DSA) nor computed tomographic angiography showed signs of intracranial vascular malformations. One month before the lethal SAH occurred, she had developed arterial hypertension and attacks of severe headache with cerebrospinal fluid (CSF) pleocytosis while CT scans showed an infarct of the left thalamus. Pathologic findings established the rare diagnosis of SAH due to aspergillosis-related mycotic arteritis. Imaging characteristics are presented. (orig.)

  11. Perinatal lethal type II osteogenesis imperfecta: a case report.

    Science.gov (United States)

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure.

  12. Clinics in diagnostic imaging (112). Perinatal lethal hypophosphatasia (PLH).

    Science.gov (United States)

    Kritsaneepaiboon, S; Jaruratanasirikul, S; Dissaneevate, S

    2006-11-01

    A two-hour-old female infant presented with respiratory distress and short limbs. Neonatal radiographs showed micromelic dwarfism and generalised demineralisation, especially at the ribs, long bones of both forearms and both fibulae. The spine showed a flattened shape. All long bones showed metaphyseal irregularities and flaring. Normal serum calcium and elevated serum phosphorus were found, while serum alkaline phosphatase was markedly reduced. A diagnosis of perinatal lethal hypophosphatasia was made. The aetiology, clinical manifestations, radiographical findings, laboratory assays, prenatal diagnosis and treatment of hypophosphatasia are discussed.

  13. A Two-Unit Cold Standby Repairable System with One Replaceable Repair Facility and Delay Repair:Some Reliability Problems

    Institute of Scientific and Technical Information of China (English)

    WEI Ying-yuan; TANG Ying-hui

    2004-01-01

    This paper considers a two-unit same cold standby repairable system with a replaceable repair facility and delay repair .The failure time of unit is assumed to follow exponential distribution , and the repair time and delay time of failed unit are assumed to follow arbitrary distributions , whereas the failure and replacement time distributions of the repair facility are exponential and arbitrary . By using the Markov renewal process theory, some primary reliability quantities of the system are obtained.

  14. 40 CFR 63.1024 - Leak repair.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 10 2010-07-01 2010-07-01 false Leak repair. 63.1024 Section 63.1024... Standards for Equipment Leaks-Control Level 2 Standards § 63.1024 Leak repair. (a) Leak repair schedule. The owner or operator shall repair each leak detected as soon as practical, but not later than 15...

  15. 40 CFR 65.105 - Leak repair.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Leak repair. 65.105 Section 65.105... FEDERAL AIR RULE Equipment Leaks § 65.105 Leak repair. (a) Leak repair schedule. The owner or operator shall repair each leak detected as soon as practical but not later than 15 calendar days after it...

  16. 40 CFR 63.1005 - Leak repair.

    Science.gov (United States)

    2010-07-01

    ... successful repair of the leak. (3) Maximum instrument reading measured by Method 21 of 40 CFR part 60... 40 Protection of Environment 10 2010-07-01 2010-07-01 false Leak repair. 63.1005 Section 63.1005... Standards for Equipment Leaks-Control Level 1 § 63.1005 Leak repair. (a) Leak repair schedule. The owner...

  17. Protection of rabbits and immunodeficient mice against lethal poxvirus infections by human monoclonal antibodies.

    Directory of Open Access Journals (Sweden)

    Lindsay Crickard

    Full Text Available Smallpox (variola virus is a bioweapon concern. Monkeypox is a growing zoonotic poxvirus threat. These problems have resulted in extensive efforts to develop potential therapeutics that can prevent or treat potentially lethal poxvirus infections in humans. Monoclonal antibodies (mAbs against smallpox are a conservative approach to this problem, as the licensed human smallpox vaccine (vaccinia virus, VACV primarily works on the basis of protective antibody responses against smallpox. Fully human mAbs (hmAbs against vaccinia H3 (H3L and B5 (B5R, targeting both the mature virion (MV and extracellular enveloped virion (EV forms, have been developed as potential therapeutics for use in humans. Post-exposure prophylaxis was assessed in both murine and rabbit animal models. Therapeutic efficacy of the mAbs was assessed in three good laboratory practices (GLP studies examining severe combined immunodeficiency mice (SCID given a lethal VACV infection. Pre-exposure combination hmAb therapy provided significantly better protection against disease and death than either single hmAb or vaccinia immune globulin (VIG. Post-exposure combination mAb therapy provided significant protection against disease and death, and appeared to fully cure the VACV infection in ≥50% of SCID mice. Therapeutic efficacy was then assessed in two rabbit studies examining post-exposure hmAb prophylaxis against rabbitpox (RPXV. In the first study, rabbits were infected with RPVX and then provided hmAbs at 48 hrs post-infection, or 1 hr and 72 hrs post-infection. Rabbits in both groups receiving hmAbs were 100% protected from death. In the second rabbitpox study, 100% of animal treated with combination hmAb therapy and 100% of animals treated with anti-B5 hmAb were protected. These findings suggest that combination hmAb treatment may be effective at controlling smallpox disease in immunocompetent or immunodeficient humans.

  18. Exploiting Synthetic Lethal Relationships: Chemical Inhibition of Recombinational Repair as a Strategy to Selectively Target Tumor Cells

    Science.gov (United States)

    2011-03-01

    interaction) for each lead candidate compound will be described by conducting Michaelis - Menten kinetic assays to derive KM and kcat for ATP and dsDNA in the...radioactively (32P) at one 5’-end and the purified yeast Mus81-Mms4 protein, we showed in kinetic experiments that the fluorescence labels do not interfere...with endonuclease activity in comparison to several control substrates (8, 9). By determining the kinetic parameters, KM and kcat, we show that there

  19. Repair and actio spectrum of oxygen-independent lethality of near uv light on Haemophilus influenzae and lack of mutation

    Energy Technology Data Exchange (ETDEWEB)

    Cabrera-Juarez, E.; Setlow, J.K.

    1980-01-01

    Haemophilus influenzae has been inactivated anaerobically at 313, 334, 365, and 405 nm, and exhibits the greatest sensitivity at 334 nm. The rec1 and uvr1 mutants show the greatest increase in sensitivity over the wild-type at 313 nm, but differences could be seen also at the other wavelengths. Anaerobic irradiation is less effective for killing at all the wavelengths than irradiation under aerobic conditions, but the greatest difference was observed at 365 nm. No induced mutation was seen as a result of anaerobic irradiation at 334 nm, although purified transforming DNA can be mutated at this wavelength.

  20. Early days of DNA repair: discovery of nucleotide excision repair and homology-dependent recombinational repair.

    Science.gov (United States)

    Rupp, W Dean

    2013-12-13

    The discovery of nucleotide excision repair in 1964 showed that DNA could be repaired by a mechanism that removed the damaged section of a strand and replaced it accurately by using the remaining intact strand as the template. This result showed that DNA could be actively metabolized in a process that had no precedent. In 1968, experiments describing postreplication repair, a process dependent on homologous recombination, were reported. The authors of these papers were either at Yale University or had prior Yale connections. Here we recount some of the events leading to these discoveries and consider the impact on further research at Yale and elsewhere.

  1. Construction, repair and maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Hinger, R. [Terasen Pipelines, Calgary, AB (Canada); Wong, P. [KC Integrity Corp., Calgary, AB (Canada); Yeomans, M.; Glover, A. [TransCanada PipeLines Ltd., Calgary, AB (Canada)

    2003-07-01

    The presentations by Working Group 4 focused on construction, repair and maintenance of pipelines with particular reference to high-strength steels and their applications for natural gas transmission pipelines. Discussions focused on how technology can be used to provide cost-effective design and construction solutions for long distance pipelines in a manner that does not compromise safety and reliability. The role that carbon plays in increasing the toughness of steel was also discussed. A few fundamental changes in steel production technology and a reduction in carbon content can result in a simultaneous increase in strength and toughness of steels. The cost impact of this technology was summarized. It was concluded that high strength steels offer effective solutions to deliver cost-effective pipelines to transport natural gas from northern basins. This session also presented pipeline routes that transport diluted bitumens from the Athabasca Oil Sands Project and the Muskeg River Mine to upgrader facilities in Alberta. Construction issues included design conservatism, water course crossings, winter construction, winter ditching, and public consultation. Examples of high strength steel pipe applications were also included with reference to experience gained by TransCanada and Corridor Pipeline. tabs., figs.

  2. On Theft with Lethal Weapons in Criminal Law%论刑法中的携带凶器盗窃

    Institute of Scientific and Technical Information of China (English)

    安军

    2012-01-01

    我国刑法中携带凶器型盗窃的立法意图及模式为具体理解与适用提供了基准。作为规范构成要件要素的凶器,除了需要考察凶器的客观因素外,还必须考虑行为人的主观因素,即在具体的案件中应以客观的及主观的要素为根据综合判断。携带凶器的时间段应包括着手实行盗窃行为至盗窃罪构成要件完成(既遂)的全过程。在这一过程中,行为人认识到自己携带了凶器,认识到自己在盗窃他人财物,希望通过携带的凶器排除或阻止他人的反抗,以便非法占有他人财物。与普通盗窃相比,携带凶器型盗窃除了属于行为犯外,更具有抽象危险犯的特征,二者并行不悖。%In Chinese criminal law,the legislative intent and model of theft with lethal weapons provides a benchmark for specific understanding and application.As normative elements of constitutive requirements of lethal weapons,the behavior of subjective factors should also be considered in addition to the objective factors of the weapon;in other words,the judgment should be based on objective and subjective elements in specific cases.The period of carrying lethal weapons should be from the start of acting to execute theft to complete offense of theft.The subject recognized carrying lethal weapons and his stealing behaviors,wished to exclude or block resistance and occupy property of others by carrying lethal weapons in this process.Compared with ordinary theft,theft with lethal weapons has more features of abstract potential damage offense in addition to belonging to behavioral offense,two of which are not contradictary to each other.

  3. Umbilical and epigastric hernia repair.

    Science.gov (United States)

    Muschaweck, Ulrike

    2003-10-01

    The repair of umbilical and epigastric hernias still represents a challenge to surgeons. Although a common and relatively simple procedure, there is no exact protocol today on how the repair should be done. The Mayo technique and its alterations could not stand the test of time: a recurrence rate of 20% and higher is not acceptable for any surgical procedure. Although there is no consensus opinion, one thing is clear: the importance of an anatomic repair without tension and without an artificial enlargement of the defect. In 1987 Lichtenstein reported on 6321 cases of herniorraphy with a tension free repair, and in 1994 Stuart reemphasized that special importance in his editorial in the Lancet. A newer study from Brancato and coworkers in Italy also states the advantage of a tension-free prosthetic repair in 16 patients with epigastric hernia. We have gone even further and recommend a tailored-to-the-patient repair using a customized polypropylene mesh and a one-layer running suture. The advantages should be obvious: no artificial creation of an even bigger than original defect, a completely tension-free repair, and little to no recurrence of the hernia. Our results clearly prove that assumption. Moreover, the procedure is extremely safe and complications are very rare and minor. We conclude that using a mesh plug in a customized tension-free repair of umbilical and epigastric hernia shows many advantages over the commonly used methods. And we finally conclude with the words of Albert Einstein: "The only source of knowledge is experience."

  4. Repair Types, Procedures - Part 1

    Science.gov (United States)

    2010-05-01

    New Jersey, USA. Repair Types, Procedures – Part I RTO-EN-AVT-156 9 - 19 [5] Drieker R, Botello C, MacBeth S, and Grody J, “Aircraft Battle... MacBeth S, and Grody J, “Aircraft Battle Damage Assessment and Repair (ABDAR), Vol. III: Field Test Report,” AFRL-HE-WP-TR-2002-0039, July 2000. [8

  5. Hand function after nerve repair.

    OpenAIRE

    Lundborg, Göran; Rosén, Birgitta

    2007-01-01

    Treatment of injuries to major nerve trunks in the hand and upper extremity remains a major and challenging reconstructive problem. Such injuries may cause long-lasting disabilities in terms of lost fine sensory and motor functions. Nowadays there is no surgical repair technique that can ensure recovery of tactile discrimination in the hand of an adult patient following nerve repair while very young individuals usually regain a complete recovery of functional sensibility. Post-traumatic nerve...

  6. Cobbler's technique for Iridodialysis repair

    Directory of Open Access Journals (Sweden)

    Surinder Singh Pandav

    2016-01-01

    Full Text Available We describe a novel “Cobbler's technique” for iridodialysis repair in the right eye of a patient aged 18 years, with a traumatic iridodialysis secondary to open globe injury with an iron rod. Our technique is simple with easy surgical maneuvers, that is, effective for repairing iridodialysis. The “Cobbler's technique” allows a maximally functional and cosmetic result for iridodialysis.

  7. Rehabilitation after Rotator Cuff Repair.

    Science.gov (United States)

    Nikolaidou, Ourania; Migkou, Stefania; Karampalis, Christos

    2017-01-01

    Rotator cuff tears are a very common condition that is often incapacitating. Whether non-surgical or surgical, successful management of rotator cuff disease is dependent on appropriate rehabilitation. If conservative management is insufficient, surgical repair is often indicated. Postsurgical outcomes for patients having had rotator cuff repair can be quite good. A successful outcome is much dependent on surgical technique as it is on rehabilitation. Numerous rehabilitation protocols for the management of rotator cuff disease are based primarily on clinical experience and expert opinion. This article describes the different rehabilitation protocols that aim to protect the repair in the immediate postoperative period, minimize postoperative stiffness and muscle atrophy. A review of currently available literature on rehabilitation after arthroscopic rotator cuff tear repair was performed to illustrate the available evidence behind various postoperative treatment modalities. There were no statistically significant differences between a conservative and an accelerated rehabilitation protocol . Early passive range of motion (ROM) following arthroscopic cuff repair is thought to decrease postoperative stiffness and improve functionality. However, early aggressive rehabilitation may compromise repair integrity. The currently available literature did not identify any significant differences in functional outcomes and relative risks of re-tears between delayed and early motion in patients undergoing arthroscopic rotator cuff repairs. A gentle rehabilitation protocol with limits in range of motion and exercise times after arthroscopic rotator cuff repair would be better for tendon healing without taking any substantial risks. A close communication between the surgeon, the patient and the physical therapy team is important and should continue throughout the whole recovery process.

  8. Repairing Learned Knowledge Using Experience

    Science.gov (United States)

    1990-05-01

    It necessar and Identify by’ 6109h nii be) learning precedent-based learning knowledge repair explanation-based learning near - miss groups 20. ABSTRACT...can a program use explanations to repair a recollection, preventing further misapplication? Near - Miss Groups Isolate Suspicious Relations If a metal...pail differs from a porcelain cup only in the position of handle attachment, then we would say that the pail is a near miss . Unfortunately, there are

  9. Aircraft Metal Skin Repair and Honeycomb Structure Repair; Sheet Metal Work 3: 9857.02.

    Science.gov (United States)

    Dade County Public Schools, Miami, FL.

    The course helps students determine types of repairs, compute repair sizes, and complete the repair through surface protection. Course content includes goals, specific objectives, protection of metals, repairs to metal skin, and honeycomb structure repair. A bibliography and post-test are appended. A prerequisite for this course is mastery of the…

  10. Regulation of Ceramide Synthase-Mediated Crypt Epithelium Apoptosis by DNA Damage Repair Enzymes

    Science.gov (United States)

    Rotolo, Jimmy A.; Mesicek, Judith; Maj, Jerzy; Truman, Jean-Philip; Haimovitz-Friedman, Adriana; Kolesnick, Richard; Fuks, Zvi

    2015-01-01

    Acute endothelial cell apoptosis and microvascular compromise couple GI tract irradiation to reproductive death of intestinal crypt stem cell clonogens (SCCs) following high-dose radiation. Genetic or pharmacologic inhibition of endothelial apoptosis prevents intestinal damage, but as the radiation dose is escalated, SCCs become directly susceptible to an alternate cell death mechanism, mediated via ceramide synthase (CS)-stimulated de novo synthesis of the pro-apoptotic sphingolipid ceramide, and p53-independent apoptosis of crypt SCCs. We previously reported that ATM deficiency resets the primary radiation lethal pathway, allowing CS-mediated apoptosis at the low-dose range of radiation. The mechanism for this event, termed target reordering, remains unknown. Here we show that inactivation of DNA damage repair pathways signal CS-mediated apoptosis in crypt SCCs, presumably via persistent unrepaired DNA double strand breaks (DSBs). Genetic loss-of-function of sensors and transducers of DNA DSB repair confers the CS-mediated lethal pathway in intestines of sv129/B6Mre11ATLD1/ATLD1 and C57BL/6Prkdc/SCID (SCID) mice exposed to low-dose radiation. In contrast, CS-mediated SCC lethality was mitigated in irradiated gain-of-function Rad50S/S mice, and epistasis studies order Rad50 upstream of Mre11. These studies suggest unrepaired DNA DSBs as causative in target re-ordering in intestinal SCCs. As such, we provide an in vivo model of DNA damage repair that is standardized, can be exploited to understand allele-specific regulation in intact tissue, and is pharmacologically tractable. PMID:20086180

  11. The role of protein interactions in mediating essentiality and synthetic lethality.

    Science.gov (United States)

    Talavera, David; Robertson, David L; Lovell, Simon C

    2013-01-01

    Genes are characterized as essential if their knockout is associated with a lethal phenotype, and these "essential genes" play a central role in biological function. In addition, some genes are only essential when deleted in pairs, a phenomenon known as synthetic lethality. Here we consider genes displaying synthetic lethality as "essential pairs" of genes, and analyze the properties of yeast essential genes and synthetic lethal pairs together. As gene duplication initially produces an identical pair or sets of genes, it is often invoked as an explanation for synthetic lethality. However, we find that duplication explains only a minority of cases of synthetic lethality. Similarly, disruption of metabolic pathways leads to relatively few examples of synthetic lethality. By contrast, the vast majority of synthetic lethal gene pairs code for proteins with related functions that share interaction partners. We also find that essential genes and synthetic lethal pairs cluster in the protein-protein interaction network. These results suggest that synthetic lethality is strongly dependent on the formation of protein-protein interactions. Compensation by duplicates does not usually occur mainly because the genes involved are recent duplicates, but is more commonly due to functional similarity that permits preservation of essential protein complexes. This unified view, combining genes that are individually essential with those that form essential pairs, suggests that essentiality is a feature of physical interactions between proteins protein-protein interactions, rather than being inherent in gene and protein products themselves.

  12. The role of protein interactions in mediating essentiality and synthetic lethality.

    Directory of Open Access Journals (Sweden)

    David Talavera

    Full Text Available Genes are characterized as essential if their knockout is associated with a lethal phenotype, and these "essential genes" play a central role in biological function. In addition, some genes are only essential when deleted in pairs, a phenomenon known as synthetic lethality. Here we consider genes displaying synthetic lethality as "essential pairs" of genes, and analyze the properties of yeast essential genes and synthetic lethal pairs together. As gene duplication initially produces an identical pair or sets of genes, it is often invoked as an explanation for synthetic lethality. However, we find that duplication explains only a minority of cases of synthetic lethality. Similarly, disruption of metabolic pathways leads to relatively few examples of synthetic lethality. By contrast, the vast majority of synthetic lethal gene pairs code for proteins with related functions that share interaction partners. We also find that essential genes and synthetic lethal pairs cluster in the protein-protein interaction network. These results suggest that synthetic lethality is strongly dependent on the formation of protein-protein interactions. Compensation by duplicates does not usually occur mainly because the genes involved are recent duplicates, but is more commonly due to functional similarity that permits preservation of essential protein complexes. This unified view, combining genes that are individually essential with those that form essential pairs, suggests that essentiality is a feature of physical interactions between proteins protein-protein interactions, rather than being inherent in gene and protein products themselves.

  13. Base excision repair in sugarcane

    Directory of Open Access Journals (Sweden)

    Agnez-Lima Lucymara F.

    2001-01-01

    Full Text Available DNA damage can be induced by a large number of physical and chemical agents from the environment as well as compounds produced by cellular metabolism. This type of damage can interfere with cellular processes such as replication and transcription, resulting in cell death and/or mutations. The low frequency of mutagenesis in cells is due to the presence of enzymatic pathways which repair damaged DNA. Several DNA repair genes (mainly from bacteria, yeasts and mammals have been cloned and their products characterized. The high conservation, especially in eukaryotes, of the majority of genes related to DNA repair argues for their importance in the maintenance of life on earth. In plants, our understanding of DNA repair pathways is still very poor, the first plant repair genes having only been cloned in 1997 and the mechanisms of their products have not yet been characterized. The objective of our data mining work was to identify genes related to the base excision repair (BER pathway, which are present in the database of the Sugarcane Expressed Sequence Tag (SUCEST Project. This search was performed by tblastn program. We identified sugarcane clusters homologous to the majority of BER proteins used in the analysis and a high degree of conservation was observed. The best results were obtained with BER proteins from Arabidopsis thaliana. For some sugarcane BER genes, the presence of more than one form of mRNA is possible, as shown by the occurrence of more than one homologous EST cluster.

  14. Scarf Repair of Composite Laminates

    Directory of Open Access Journals (Sweden)

    Xie Zonghong

    2016-01-01

    Full Text Available The use of composite materials, such as carbon-fiber reinforced plastic (CFRP composites, aero-structures has led to an increased need of advanced assembly joining and repair technologies. Adhesive bonded repairs as an alternative to recover full or part of initial strength were investigated. Tests were conducted with the objective of evaluating the effectiveness of techniques used for repairing damage fiber reinforced laminated composites. Failure loads and failure modes were generated and compared with the following parameters: scarf angles, roughness of grind tool and number of external plies. Results showed that scarf angle was the critical parameter and the largest tensile strength was observed with the smallest scarf angle. Besides, the use of external plies at the outer surface could not increase the repairs efficiency for large scarf angle. Preparing the repair surfaces by sanding them with a sander ranging from 60 to 100 grit number had significant effect on the failure load. These results allowed the proposal of design principles for repairing CFRP structures.

  15. Lethal and sub-lethal effects of elevated CO2 concentrations on marine benthic invertebrates and fish.

    Science.gov (United States)

    Lee, Changkeun; Hong, Seongjin; Kwon, Bong-Oh; Lee, Jung-Ho; Ryu, Jongseong; Park, Young-Gyu; Kang, Seong-Gil; Khim, Jong Seong

    2016-08-01

    Concern about leakage of carbon dioxide (CO2) from deep-sea storage in geological reservoirs is increasing because of its possible adverse effects on marine organisms locally or at nearby coastal areas both in sediment and water column. In the present study, we examined how elevated CO2 affects various intertidal epibenthic (benthic copepod), intertidal endobenthic (Manila clam and Venus clam), sub-tidal benthic (brittle starfish), and free-living (marine medaka) organisms in areas expected to be impacted by leakage. Acute lethal and sub-lethal effects were detected in the adult stage of all test organisms exposed to varying concentrations of CO2, due to the associated decline in pH (8.3 to 5.2) during 96-h exposure. However, intertidal organisms (such as benthic copepods and clams) showed remarkable resistance to elevated CO2, with the Venus clam being the most tolerant (LpH50 = 5.45). Sub-tidal species (such as brittle starfish [LpH50 = 6.16] and marine medaka [LpH50 = 5.91]) were more sensitive to elevated CO2 compared to intertidal species, possibly because they have fewer defensive capabilities. Of note, the exposure duration might regulate the degree of acute sub-lethal effects, as evidenced by the Venus clam, which showed a time-dependent effect to elevated CO2. Finally, copper was chosen as a model toxic element to find out the synergistic or antagonistic effects between ocean acidification and metal pollution. Combination of CO2 and Cu exposure enhances the adverse effects to organisms, generally supporting a synergistic effect scenario. Overall, the significant variation in the degree to which CO2 adversely affected organisms (viz., working range and strength) was clearly observed, supporting the general concept of species-dependent effects of elevated CO2.

  16. Aging and DNA repair capability. [Review

    Energy Technology Data Exchange (ETDEWEB)

    Tice, R R

    1977-01-01

    A review of the literature on DNA repair processes in relation to aging is presented under the following headings: DNA repair processes; age-related occurrence of unrepaired DNA lesions; DNA repair capability as a function of age; tissue-specific DNA repair capability; acceleration of the aging process by exposure to DNA damaging agents; human genetic syndromes; and longevity and DNA repair processes. (HLW)

  17. Effectiveness of lethal, directed wolf-depredation control in Minnesota

    Science.gov (United States)

    Harper, E.K.; Paul, W.J.; Mech, L.D.; Weisberg, S.

    2008-01-01

    Wolf (Canis lupus) depredations on livestock in Minnesota, USA, are an economic problem for many livestock producers, and depredating wolves are lethally controlled. We sought to determine the effectiveness of lethal control through the analysis of data from 923 government-verified wolf depredations from 1979 to 1998. We analyzed the data by 1) assessing the correlations between the number of wolves killed in response to depredations with number of depredations the following year at state and local levels, and 2) the time to the next depredation. No analysis indicated that trapping wolves substantially reduced the following year's depredations at state or local levels. However, more specific analyses indicated that in certain situations, killing wolves was more effective than no action (i.e., not trapping). For example, trapping and killing adult males decreased the re-depredation risk. At sheep farms, killing wolves was generally effective. Attempting to trap, regardless of the results, seemed more effective at reducing depredations than not trapping, suggesting that mere human activity near depredation sites might deter future depredations.

  18. Suppressive effects of anthrax lethal toxin on megakaryopoiesis.

    Directory of Open Access Journals (Sweden)

    Po-Kong Chen

    Full Text Available Anthrax lethal toxin (LT is a major virulence factor of Bacillus anthracis. LT challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. LT inhibits cellular mitogen-activated protein kinases (MAPKs, which are vital pathways responsible for cell survival, differentiation, and maturation. One of the MAPKs, the MEK1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. This study evaluates the hypothesis that LT may suppress the progenitor cells of platelets, thereby inducing thrombocytopenic responses. Using cord blood-derived CD34(+ cells and mouse bone marrow mononuclear cells to perform in vitro differentiation, this work shows that LT suppresses megakaryopoiesis by reducing the survival of megakaryocytes. Thrombopoietin treatments can reduce thrombocytopenia, megakaryocytic suppression, and the quick onset of lethality in LT-challenged mice. These results suggest that megakaryocytic suppression is one of the mechanisms by which LT induces thrombocytopenia. These findings may provide new insights for developing feasible approaches against anthrax.

  19. Engineered female-specific lethality for control of pest Lepidoptera.

    Science.gov (United States)

    Jin, Li; Walker, Adam S; Fu, Guoliang; Harvey-Samuel, Timothy; Dafa'alla, Tarig; Miles, Andrea; Marubbi, Thea; Granville, Deborah; Humphrey-Jones, Nerys; O'Connell, Sinead; Morrison, Neil I; Alphey, Luke

    2013-03-15

    The sterile insect technique (SIT) is a pest control strategy involving the mass release of radiation-sterilized insects, which reduce the target population through nonviable matings. In Lepidoptera, SIT could be more broadly applicable if the deleterious effects of sterilization by irradiation could be avoided. Moreover, male-only release can improve the efficacy of SIT. Adequate methods of male-only production in Lepidoptera are currently lacking, in contrast to some Diptera. We describe a synthetic genetic system that allows male-only moth production for SIT and also replaces radiation sterilization with inherited female-specific lethality. We sequenced and characterized the doublesex (dsx) gene from the pink bollworm (Pectinophora gossypiella). Sex-alternate splicing from dsx was used to develop a conditional lethal genetic sexing system in two pest moths: the diamondback moth (Plutella xylostella) and pink bollworm. This system shows promise for enhancing existing pink bollworm SIT, as well as broadening SIT-type control to diamondback moth and other Lepidoptera.

  20. Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir.

    Science.gov (United States)

    de Ávila, Ana I; Gallego, Isabel; Soria, Maria Eugenia; Gregori, Josep; Quer, Josep; Esteban, Juan Ignacio; Rice, Charles M; Domingo, Esteban; Perales, Celia

    2016-01-01

    Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagen. Here we show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during its replication in human hepatoma cells. T-705 leads to an excess of G → A and C → U transitions in the mutant spectrum of preextinction HCV populations. Infectivity decreased significantly in the presence of concentrations of T-705 which are 2- to 8-fold lower than its cytotoxic concentration 50 (CC50). Passaging the virus five times in the presence of 400 μM T-705 resulted in virus extinction. Since T-705 has undergone advanced clinical trials for approval for human use, the results open a new approach based on lethal mutagenesis to treat hepatitis C virus infections. If proven effective for HCV in vivo, this new anti-HCV agent may be useful in patient groups that fail current therapeutic regimens.

  1. Killing Range: Explaining Lethality Variance within a Terrorist Organization.

    Science.gov (United States)

    Asal, Victor; Gill, Paul; Rethemeyer, R Karl; Horgan, John

    2015-04-01

    This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level.

  2. An outbreak of lethal adenovirus infection among different otariid species.

    Science.gov (United States)

    Inoshima, Yasuo; Murakami, Tomoaki; Ishiguro, Naotaka; Hasegawa, Kazuhiro; Kasamatsu, Masahiko

    2013-08-30

    An outbreak of fatal fulminant hepatitis at a Japanese aquarium involved 3 otariids: a California sea lion (Zalophus californianus), a South African fur seal (Arctocephalus pusillus) and a South American sea lion (Otaria flavescens). In a span of about a week in February 2012, 3 otariids showed diarrhea and were acutely low-spirited; subsequently, all three animals died within a period of 3 days. Markedly increased aspartate amino transferase and alanine amino transferase activities were observed. Necrotic hepatitis and eosinophilic intranuclear inclusion bodies in liver hepatocytes and intestinal epithelial cells were observed in the South American sea lion on histological examination. Otarine adenovirus DNA was detected from the livers of all three animals by polymerase chain reaction and determination of the sequences showed that all were identical. These results suggest that a single otarine adenovirus strain may have been the etiological agent of this outbreak of fatal fulminant hepatitis among the different otariid species, and it may be a lethal threat to wild and captive otariids. This is the first evidence of an outbreak of lethal adenovirus infection among different otariid species.

  3. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes.

    Science.gov (United States)

    Thompson, Benjamin C; Surjana, Devita; Halliday, Gary M; Damian, Diona L

    2014-07-01

    Cutaneous melanoma is a significant cause of morbidity and mortality. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. Here, we report the effect of nicotinamide on DNA damage and repair in primary human melanocytes. Nicotinamide significantly enhanced the repair of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine) and cyclobutane pyrimidine dimers induced by UV exposure. It also enhanced the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine induced by the culture conditions in unirradiated melanocytes. A significant increase in the percentage of melanocytes undergoing unscheduled but not scheduled DNA synthesis was observed, confirming that nicotinamide enhances DNA repair in human melanocytes. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma.

  4. The Fanconi anaemia components UBE2T and FANCM are functionally linked to nucleotide excision repair.

    Directory of Open Access Journals (Sweden)

    Ian R Kelsall

    Full Text Available The many proteins that function in the Fanconi anaemia (FA monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes--UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair.

  5. On the role of baculovirus photolyases in DNA repair upon UV damage of occlusion bodies

    NARCIS (Netherlands)

    Biernat, M.A.; Caballero, P.; Vlak, J.M.; Oers, van M.M.

    2013-01-01

    The use of baculoviruses in insect biocontrol is hampered by their sensitivity to ultraviolet (UV) light. This irradiation induces cyclobutane pyrimidine dimers (CPDs) in DNA. CPD-photolyases repair CPDs using visible light. Plusiine baculoviruses encode photolyases, which could potentially repair

  6. Cartilage repair by mesenchymal stem cells: Clinical trial update and perspectives

    Directory of Open Access Journals (Sweden)

    Wayne Yuk-wai Lee

    2017-04-01

    The translational potential of this article: This review summarises recent MSC-related clinical research that focuses on cartilage repair. We also propose a novel possible translational direction for hyaline cartilage formation and a new paradigm making use of extra-cellular signalling and epigenetic regulation in the application of MSCs for cartilage repair.

  7. Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.

    Directory of Open Access Journals (Sweden)

    Gabriela A Ferreyra

    Full Text Available BACKGROUND: Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB challenge was investigated in six tissues. RESULTS: The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC, spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature. CONCLUSION: Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.

  8. Advanced Strategies for Articular Cartilage Defect Repair

    Directory of Open Access Journals (Sweden)

    Fergal J. O'Brien

    2013-02-01

    Full Text Available Articular cartilage is a unique tissue owing to its ability to withstand repetitive compressive stress throughout an individual’s lifetime. However, its major limitation is the inability to heal even the most minor injuries. There still remains an inherent lack of strategies that stimulate hyaline-like articular cartilage growth with appropriate functional properties. Recent scientific advances in tissue engineering have made significant steps towards development of constructs for articular cartilage repair. In particular, research has shown the potential of biomaterial physico-chemical properties significantly influencing the proliferation, differentiation and matrix deposition by progenitor cells. Accordingly, this highlights the potential of using such properties to direct the lineage towards which such cells follow. Moreover, the use of soluble growth factors to enhance the bioactivity and regenerative capacity of biomaterials has recently been adopted by researchers in the field of tissue engineering. In addition, gene therapy is a growing area that has found noteworthy use in tissue engineering partly due to the potential to overcome some drawbacks associated with current growth factor delivery systems. In this context, such advanced strategies in biomaterial science, cell-based and growth factor-based therapies that have been employed in the restoration and repair of damaged articular cartilage will be the focus of this review article.

  9. In vitro binding kinetics of DNA double strand break repair proteins Ku70/80 and DNA-PKcs quantified by fluorescence correlation spectroscopy and fluorescence cross-correlation spectroscopy

    Science.gov (United States)

    Abdisalaam, Salim; Chen, David J.; Alexandrakis, George

    2012-02-01

    DNA double-strand breaks (DSBs) are one of the most lethal types of DNA damage that occurs in eukaryotic cells. There are two distinct pathways of repairing DSBs, homologous recombination (HR) and non-homologous end joining (NHEJ). In the NHEJ repairing pathway, DSB recognition and repair initiation is directed by the interaction of DNAbinding subunit Ku70/80 heterodimer with the DNA-PK protein catalytic subunit (DNA-PKcs). Mutations in these proteins result in repair stalling and eventual DNA misrepair that may lead to genomic instability. Studying the binding kinetics of these repair proteins is therefore important for understanding the conditions under which DSB repair stalls. Currently open questions are, what is the minimum DNA length that this complex needs to get a foothold onto a DSB and how tightly does DNA-PKcs bind onto the DNA-Ku70/80 complex. Fluorescence Correlation Spectroscopy (FCS) and Fluorescence Cross-Correlation Spectroscopy (FCCS) techniques have the potential to give information about the binding kinetics of DNA-protein and protein-protein interactions at the single-molecule level. In this work, FCS/FCCS measurements were performed to explore the minimum DNA base-pair (bp) length that Ku70/80 needed as a foothold to bind effectively onto the tips of different lengths of double-stranded DNA (dsDNA) fragments that mimic DSBs. 25 bp, 33 bp and 50 bp of dsDNA were used for these experiments and binding was studied as a function of salt concentration in solution. It was found that the 25 bp binding was weak even at physiological salt concentrations while the dissociation constant (Kd) remained constant for 33 and 50 bp dsDNA strand lengths. These studies indicated that the minimum binding length for the Ku70/8 is in the vicinity of 25 bp. The specificity of binding of Ku70/80 was proven by competitive binding FCCS experiments between Cy5-labeled DNA, GFP-Ku70/80 and titrations of unlabeled Ku70/80. Finally, using FCCS it was possible to estimate

  10. Analysis of DNA double-strand break repair pathways in mice

    Energy Technology Data Exchange (ETDEWEB)

    Brugmans, Linda [Department of Cell Biology and Genetics, Erasmus MC, Dr. Molewaterplein 50, PO Box 1738, Rotterdam 3015GE (Netherlands); Kanaar, Roland [Department of Cell Biology and Genetics, Erasmus MC, Dr. Molewaterplein 50, PO Box 1738, Rotterdam 3015GE (Netherlands); Department of Radiation Oncology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam (Netherlands); Essers, Jeroen [Department of Cell Biology and Genetics, Erasmus MC, Dr. Molewaterplein 50, PO Box 1738, Rotterdam 3015GE (Netherlands) and Department of Radiation Oncology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam (Netherlands)]. E-mail: j.essers@erasmusmc.nl

    2007-01-03

    During the last years significant new insights have been gained into the mechanism and biological relevance of DNA double-strand break (DSB) repair in relation to genome stability. DSBs are a highly toxic DNA lesion, because they can lead to chromosome fragmentation, loss and translocations, eventually resulting in cancer. DSBs can be induced by cellular processes such as V(D)J recombination or DNA replication. They can also be introduced by exogenous agents DNA damaging agents such as ionizing radiation or mitomycin C. During evolution several pathways have evolved for the repair of these DSBs. The most important DSB repair mechanisms in mammalian cells are nonhomologous end-joining and homologous recombination. By using an undamaged repair template, homologous recombination ensures accurate DSB repair, whereas the untemplated nonhomologous end-joining pathway does not. Although both pathways are active in mammals, the relative contribution of the two repair pathways to genome stability differs in the different cell types. Given the potential differences in repair fidelity, it is of interest to determine the relative contribution of homologous recombination and nonhomologous end-joining to DSB repair. In this review, we focus on the biological relevance of DSB repair in mammalian cells and the potential overlap between nonhomologous end-joining and homologous recombination in different tissues.

  11. 2'-Phosphate cyclase activity of RtcA: a potential rationale for the operon organization of RtcA with an RNA repair ligase RtcB in Escherichia coli and other bacterial taxa.

    Science.gov (United States)

    Das, Ushati; Shuman, Stewart

    2013-10-01

    RNA terminal phosphate cyclase catalyzes the ATP-dependent conversion of a 3'-phosphate RNA end to a 2',3'-cyclic phosphate via covalent enzyme-(histidinyl-Nε)-AMP and RNA(3')pp(5')A intermediates. Here, we report that Escherichia coli RtcA (and its human homolog Rtc1) are capable of cyclizing a 2'-phosphate RNA end in high yield. The rate of 2'-phosphate cyclization by RtcA is five orders of magnitude slower than 3'-phosphate cyclization, notwithstanding that RtcA binds with similar affinity to RNA3'p and RNA2'p substrates. These findings expand the functional repertoire of RNA cyclase and suggest that phosphate geometry during adenylate transfer to RNA is a major factor in the kinetics of cyclization. RtcA is coregulated in an operon with an RNA ligase, RtcB, that splices RNA 5'-OH ends to either 3'-phosphate or 2',3'-cyclic phosphate ends. Our results suggest that RtcA might serve an end healing function in an RNA repair pathway, by converting RNA 2'-phosphates, which cannot be spliced by RtcB, to 2',3'-cyclic phosphates that can be sealed. The rtcBA operon is controlled by the σ(54) coactivator RtcR encoded by an adjacent gene. This operon arrangement is conserved in diverse bacterial taxa, many of which have also incorporated the RNA-binding protein Ro (which is implicated in RNA quality control under stress conditions) as a coregulated component of the operon.

  12. Insoluble glycogen, a metabolizable internal adsorbent, decreases the lethality of endotoxin shock in rats

    Directory of Open Access Journals (Sweden)

    S. Sipka

    1997-01-01

    Full Text Available Insoluble glycogen is an enzymatically modified form of naturally occurring soluble glycogen with a great adsorbing capacity. It can be metabolized by phagocytes to glucose. In this study we used insoluble glycogen intravenously in the experimental endotoxin shock of rats. Wistar male rats were sensitized to endotoxin by Pb acetate. The survival of rats were compared in groups of animals endotoxin shock treated and non-treated with insoluble glycogen. Furthermore, we have determined in vitro the binding capacity of insoluble glycogen for endotoxin, tumour necrosis factor alpha, interleukin-1 and secretable phospholipase A2. Use of 10 mg/kg dose of insoluble glycogen could completely prevent the lethality of shock induced by LD50 quantity of endotoxin in rats. All animals treated survived. Insoluble glycogen is a form of ‘metabolizable internal adsorbents’. It can potentially be used for treatment of septic shock.

  13. Flavanones and Chromones from Salicornia herbacea Mitigate Septic Lethality via Restoration of Vascular Barrier Integrity.

    Science.gov (United States)

    Tuan, Nguyen Quoc; Lee, Wonhwa; Oh, Joonseok; Kulkarni, Roshan Rajan; Gény, Charlotte; Jung, Byeongjin; Kang, Hyejin; Bae, Jong-Sup; Na, MinKyun

    2015-11-25

    Salicornia herbacea is an annual halophytic glasswort that has been employed as a culinary vegetable, salad, and traditional medicinal resource. Chemical investigation of the aerial parts of S. herbacea led to the isolation of two new (1, 2) and known (3) flavanones as well as a new nature-derived (4) and two known chromone derivatives (5, 6). These purified compounds were evaluated for their suppressive potentials against the release of high-mobility group box 1 protein (HMGB1), which has captured attention as a viable target for alleviating serious septic manifestations or septicemia. The phenolic compounds improved the survival rates of cecal ligation and puncture operation (CLP) in murine models, simulating severe septic shock and its related complications, to 40-60%. These results collectively validate that flavanone- and chromone-based secondary metabolites may serve as prospective prodrugs or food additives that may be commercialized for the control of septic complications and lethality.

  14. Myxoma virus expressing interleukin-15 fails to cause lethal myxomatosis in European rabbits.

    Science.gov (United States)

    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.

  15. Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits▿

    Science.gov (United States)

    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

  16. Lethal and sub-lethal chronic effects of the herbicide diuron on seagrass.

    Science.gov (United States)

    Negri, Andrew P; Flores, Florita; Mercurio, Phil; Mueller, Jochen F; Collier, Catherine J

    2015-08-01

    Photosystem II herbicides from agricultural sources have been detected throughout nearshore tropical habitats including seagrass meadows. While PSII herbicides have been shown to inhibit growth in microalgae at low concentrations, the potential impacts of chronic low concentration exposures to seagrass health and growth have not been investigated. Here we exposed two tropical seagrass species Halodule uninervis and Zostera muelleri to elevated diuron concentrations (from 0.3 to 7.2μgl(-1)) over a 79-day period followed by a 2-week recovery period in uncontaminated seawater. PAM fluorometry demonstrated rapid effect of diuron on photosystem II (PSII) in both seagrass species at 0.3μgl(-1). This effect included significant inhibition of photosynthetic efficiency (ΔF/Fm') and inactivation of PSII (Fv/Fm) over the 11 week exposure period. Significant mortality and reductions in growth was only observed at the highest exposure concentration of 7.2μgl(-1) diuron. However, biochemical indicators demonstrated that the health of seagrass after this prolonged exposure was significantly compromised at lower concentrations. For example, the drop in C:N ratios (0.6μgl(-1)) and reduced δ(13)C (1.7μgl(-1)) in seagrass leaves indicated reduced C-assimilation from photosynthesis. Critically, the energetic reserves of the plants (as measured by starch content in the root-rhizome complex) were approximately halved following diuron exposure at and above 1.7μgl(-1). During the 2-week recovery period, the photosynthetic capacity of the seagrass improved with only plants from the highest diuron treatment still exhibiting chronic damage to PSII. This study shows that, although seagrass may survive prolonged herbicide exposures, concentrations ≥0.6μgl(-1) diuron equivalents cause measureable impacts on energetic status that may leave the plants vulnerable to other simultaneous stressors. For example, tropical seagrasses have been heavily impacted by reduced light from coastal

  17. ntibacterial and brine shrimp lethality effect of marine actinobacterium Streptomyces sp. CAS72 against human pathogenic bacteria

    Directory of Open Access Journals (Sweden)

    Palaniappan Sivasankar

    2013-08-01

    Full Text Available Objective: To investigate the in vitro antibacterial activity against human pathogenic bacteria and brine shrimp lethality bioassay of the marine actinobacterium. Methods: Forty six marine actinobacterial strains were isolated from sediment samples of Uppanar estuary, Cuddalore, India. Preliminary screening was done by cross-streak method and the potential strain was identified by morphological, chemotaxonomical and molecular methods. Fermentation was done and the metabolite was obtained by liquid-liquid extraction using ethyl acetate and purified by silica gel (100-200 mesh column chromatography. The purified metabolite was tested for antibacterial activity, minimal inhibitory concentration and brine shrimp lethality bioassay. Results: Among the forty six strains, CAS72 was found effective against human pathogenic bacteria. The strain CAS72 was identified as Streptomyces sp. The purified metabolite exhibited a significant in vitro antibacterial activity. The MIC value was also determined against human pathogenic bacteria and a strong cytotoxic activity in brine shrimp lethality assay was observed and the LC 50 value was 23.5 µg/mL. Conclusions: The present investigation reveals that the marine actinobacteria are well obtainable in Uppanar estuary environment and it can provide a definite source for novel bioactive metabolites.

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

    Science.gov (United States)

    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.

  19. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.

    Science.gov (United States)

    Channappanavar, Rudragouda; Fehr, Anthony R; Vijay, Rahul; Mack, Matthias; Zhao, Jincun; Meyerholz, David K; Perlman, Stanley

    2016-02-10

    Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Bacillus anthracis lethal toxin disrupts TCR signaling in CD1d-restricted NKT cells leading to functional anergy.

    Directory of Open Access Journals (Sweden)

    Sunil K Joshi

    2009-09-01

    Full Text Available Exogenous CD1d-binding glycolipid (alpha-Galactosylceramide, alpha-GC stimulates TCR signaling and activation of type-1 natural killer-like T (NKT cells. Activated NKT cells play a central role in the regulation of adaptive and protective immune responses against pathogens and tumors. In the present study, we tested the effect of Bacillus anthracis lethal toxin (LT on NKT cells both in vivo and in vitro. LT is a binary toxin known to suppress host immune responses during anthrax disease and intoxicates cells by protective antigen (PA-mediated intracellular delivery of lethal factor (LF, a potent metalloprotease. We observed that NKT cells expressed anthrax toxin receptors (CMG-2 and TEM-8 and bound more PA than other immune cell types. A sub-lethal dose of LT administered in vivo in C57BL/6 mice decreased expression of the activation receptor NKG2D by NKT cells but not by NK cells. The in vivo administration of LT led to decreased TCR-induced cytokine secretion but did not affect TCR expression. Further analysis revealed LT-dependent inhibition of TCR-stimulated MAP kinase signaling in NKT cells attributable to LT cleavage of the MAP kinase kinase MEK-2. We propose that Bacillus anthracis-derived LT causes a novel form of functional anergy in NKT cells and therefore has potential for contributing to immune evasion by the pathogen.

  1. Animal Models of Emerging Tick-Borne Phleboviruses: Determining Target Cells in a Lethal Model of SFTSV Infection

    Science.gov (United States)

    Matsuno, Keita; Orba, Yasuko; Maede-White, Kimberly; Scott, Dana; Feldmann, Friederike; Liang, Mifang; Ebihara, Hideki

    2017-01-01

    The pathogenesis of clinical manifestations caused by newly emerging tick-borne phleboviruses [i.e., Severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV)], such as severe thrombocytopenia and lymphocytopenia, are not yet fully understood. In the present study, to establish an animal model mimicking the profile of fatal human cases, we examined the susceptibilities of adult mice from 12 strains, aged mice from two strains, and cynomolgus macaques to SFTSV and/or HRTV infections. However, none of these immunocompetent animals developed lethal diseases after infection with SFTSV or HRTV. Thus, we tested a lethal animal model of SFTSV infection using interferon-α/β receptor knock-out (IFNAR-/-) mice to identify the target cell(s) of virus infection, as well as lesions that are potentially associated with hematological changes. IbaI-positive macrophages and Pax5-positive immature B cells overlapped with SFTSV-positive cells in the spleen and lymph nodes of IFNAR-/- mice, and IbaI-SFTSV-double positive cells were also observed in the liver and kidney, thereby suggesting crucial roles for macrophages in the pathogenesis of SFTSV infection in mice. In the mandibular lymph nodes and spleens of infected mice, we observed extensive necrosis comprising B220-positive B cells, which may be associated with severe lymphocytopenia. The results of this study suggest a resemblance between the IFNAR-/- mouse model and lethal infections in humans, as well as roles for multiple cells during pathogenesis in mice. PMID:28194148

  2. Sciatic nerve repair using adhesive bonding and a modiifed conduit

    Institute of Scientific and Technical Information of China (English)

    Xiangdang Liang; Hongfei Cai; Yongyu Hao; Geng Sun; Yaoyao Song; Wen Chen

    2014-01-01

    When repairing nerves with adhesives, most researchers place glue directly on the nerve stumps, but this method does not ifx the nerve ends well and allows glue to easily invade the nerve ends. In this study, we established a rat model of completely transected sciatic nerve injury and re-paired it using a modiifed 1 cm-length conduit with inner diameter of 1.5 mm. Each end of the cylindrical conduit contains a short linear channel, while the enclosed central tube protects the nerve ends well. Nerves were repaired with 2-octyl-cyanoacrylate and suture, which complement the function of the modiifed conduit. The results demonstrated that for the same conduit, the av-erage operation time using the adhesive method was much shorter than with the suture method. No signiifcant differences were found between the two groups in sciatic function index, motor evoked potential latency, motor evoked potential amplitude, muscular recovery rate, number of medullated nerve fibers, axon diameter, or medullary sheath thickness. Thus, the adhesive method for repairing nerves using a modiifed conduit is feasible and effective, and reduces the operation time while providing an equivalent repair effect.

  3. Highly predictive support vector machine (SVM) models for anthrax toxin lethal factor (LF) inhibitors.

    Science.gov (United States)

    Zhang, Xia; Amin, Elizabeth Ambrose

    2016-01-01

    Anthrax is a highly lethal, acute infectious disease caused by the rod-shaped, Gram-positive bacterium Bacillus anthracis. The anthrax toxin lethal factor (LF), a zinc metalloprotease secreted by the bacilli, plays a key role in anthrax pathogenesis and is chiefly responsible for anthrax-related toxemia and host death, partly via inactivation of mitogen-activated protein kinase kinase (MAPKK) enzymes and consequent disruption of key cellular signaling pathways. Antibiotics such as fluoroquinolones are capable of clearing the bacilli but have no effect on LF-mediated toxemia; LF itself therefore remains the preferred target for toxin inactivation. However, currently no LF inhibitor is available on the market as a therapeutic, partly due to the insufficiency of existing LF inhibitor scaffolds in terms of efficacy, selectivity, and toxicity. In the current work, we present novel support vector machine (SVM) models with high prediction accuracy that are designed to rapidly identify potential novel, structurally diverse LF inhibitor chemical matter from compound libraries. These SVM models were trained and validated using 508 compounds with published LF biological activity data and 847 inactive compounds deposited in the Pub Chem BioAssay database. One model, M1, demonstrated particularly favorable selectivity toward highly active compounds by correctly predicting 39 (95.12%) out of 41 nanomolar-level LF inhibitors, 46 (93.88%) out of 49 inactives, and 844 (99.65%) out of 847 Pub Chem inactives in external, unbiased test sets. These models are expected to facilitate the prediction of LF inhibitory activity for existing molecules, as well as identification of novel potential LF inhibitors from large datasets.

  4. An Antivector Vaccine Protects against a Lethal Vector-Borne Pathogen.

    Directory of Open Access Journals (Sweden)

    2006-04-01

    Full Text Available Vaccines that target blood-feeding disease vectors, such as mosquitoes and ticks, have the potential to protect against the many diseases caused by vector-borne pathogens. We tested the ability of an anti-tick vaccine derived from a tick cement protein (64TRP of Rhipicephalus appendiculatus to protect mice against tick-borne encephalitis virus (TBEV transmitted by infected Ixodes ricinus ticks. The vaccine has a "dual action" in immunized animals: when infested with ticks, the inflammatory and immune responses first disrupt the skin feeding site, resulting in impaired blood feeding, and then specific anti-64TRP antibodies cross-react with midgut antigenic epitopes, causing rupture of the tick midgut and death of engorged ticks. Three parameters were measured: "transmission," number of uninfected nymphal ticks that became infected when cofeeding with an infected adult female tick; "support," number of mice supporting virus transmission from the infected tick to cofeeding uninfected nymphs; and "survival," number of mice that survived infection by tick bite and subsequent challenge by intraperitoneal inoculation of a lethal dose of TBEV. We show that one dose of the 64TRP vaccine protects mice against lethal challenge by infected ticks; control animals developed a fatal viral encephalitis. The protective effect of the 64TRP vaccine was comparable to that of a single dose of a commercial TBEV vaccine, while the transmission-blocking effect of 64TRP was better than that of the antiviral vaccine in reducing the number of animals supporting virus transmission. By contrast, the commercial antitick vaccine (TickGARD that targets only the tick's midgut showed transmission-blocking activity but was not protective. The 64TRP vaccine demonstrates the potential to control vector-borne disease by interfering with pathogen transmission, apparently by mediating a local cutaneous inflammatory immune response at the tick-feeding site.

  5. An antivector vaccine protects against a lethal vector-borne pathogen.

    Directory of Open Access Journals (Sweden)

    Milan Labuda

    2006-04-01

    Full Text Available Vaccines that target blood-feeding disease vectors, such as mosquitoes and ticks, have the potential to protect against the many diseases caused by vector-borne pathogens. We tested the ability of an anti-tick vaccine derived from a tick cement protein (64TRP of Rhipicephalus appendiculatus to protect mice against tick-borne encephalitis virus (TBEV transmitted by infected Ixodes ricinus ticks. The vaccine has a "dual action" in immunized animals: when infested with ticks, the inflammatory and immune responses first disrupt the skin feeding site, resulting in impaired blood feeding, and then specific anti-64TRP antibodies cross-react with midgut antigenic epitopes, causing rupture of the tick midgut and death of engorged ticks. Three parameters were measured: "transmission," number of uninfected nymphal ticks that became infected when cofeeding with an infected adult female tick; "support," number of mice supporting virus transmission from the infected tick to cofeeding uninfected nymphs; and "survival," number of mice that survived infection by tick bite and subsequent challenge by intraperitoneal inoculation of a lethal dose of TBEV. We show that one dose of the 64TRP vaccine protects mice against lethal challenge by infected ticks; control animals developed a fatal viral encephalitis. The protective effect of the 64TRP vaccine was comparable to that of a single dose of a commercial TBEV vaccine, while the transmission-blocking effect of 64TRP was better than that of the antiviral vaccine in reducing the number of animals supporting virus transmission. By contrast, the commercial antitick vaccine (TickGARD that targets only the tick's midgut showed transmission-blocking activity but was not protective. The 64TRP vaccine demonstrates the potential to control vector-borne disease by interfering with pathogen transmission, apparently by mediating a local cutaneous inflammatory immune response at the tick-feeding site.

  6. Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Azorsa David O

    2009-06-01

    Full Text Available Abstract Background Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement. Methods In order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine. Results Results from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1. Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine. Conclusion These findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer

  7. 49 CFR 1242.42 - Administration, repair and maintenance, machinery repair, equipment damaged, dismantling retired...

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Administration, repair and maintenance, machinery repair, equipment damaged, dismantling retired property, fringe benefits, other casualties and insurance... maintenance, machinery repair, equipment damaged, dismantling retired property, fringe benefits,...

  8. Lethal and sub-lethal chronic effects of the herbicide diuron on seagrass

    Energy Technology Data Exchange (ETDEWEB)

    Negri, Andrew P., E-mail: a.negri@aims.gov.au [Australian Institute of Marine Science, Townsville, Queensland 4810 (Australia); Flores, Florita [Australian Institute of Marine Science, Townsville, Queensland 4810 (Australia); Mercurio, Phil [Australian Institute of Marine Science, Townsville, Queensland 4810 (Australia); University of Queensland and National Research Centre for Environmental Toxicology, Coopers Plains, Queensland 4108 (Australia); Mueller, Jochen F. [University of Queensland and National Research Centre for Environmental Toxicology, Coopers Plains, Queensland 4108 (Australia); Collier, Catherine J. [Centre for Tropical Water & Aquatic Ecosystem Research (TropWATER), James Cook University, Cairns, Queensland 4870 (Australia)

    2015-08-15

    Highlights: • We performed chronic exposures of two seagrass species to the herbicide diuron. • Diuron affected photosystem II (PSII) at 0.3 μg l{sup −1} and growth at 7.2 μg l{sup −1}. • Biomarkers indicated that carbon-assimilation from photosynthesis dropped following 0.6 μg l{sup −1} diuron exposure. • Energetic reserves in the seagrass were halved at 1.7 μg l{sup −1} after 11 weeks. • Chronic exposure to diuron is likely to enhance the impacts of low light stress during flood plumes - Abstract: Photosystem II herbicides from agricultural sources have been detected throughout nearshore tropical habitats including seagrass meadows. While PSII herbicides have been shown to inhibit growth in microalgae at low concentrations, the potential impacts of chronic low concentration exposures to seagrass health and growth have not been investigated. Here we exposed two tropical seagrass species Halodule uninervis and Zostera muelleri to elevated diuron concentrations (from 0.3 to 7.2 μg l{sup −1}) over a 79-day period followed by a 2-week recovery period in uncontaminated seawater. PAM fluorometry demonstrated rapid effect of diuron on photosystem II (PSII) in both seagrass species at 0.3 μg l{sup −1}. This effect included significant inhibition of photosynthetic efficiency (ΔF/F{sub m}′) and inactivation of PSII (F{sub v}/F{sub m}) over the 11 week exposure period. Significant mortality and reductions in growth was only observed at the highest exposure concentration of 7.2 μg l{sup −1} diuron. However, biochemical indicators demonstrated that the health of seagrass after this prolonged exposure was significantly compromised at lower concentrations. For example, the drop in C:N ratios (0.6 μg l{sup −1}) and reduced δ{sup 13}C (1.7 μg l{sup −1}) in seagrass leaves indicated reduced C-assimilation from photosynthesis. Critically, the energetic reserves of the plants (as measured by starch content in the root-rhizome complex) were

  9. Antibiotic persistence: the role of spontaneous DNA repair response.

    Science.gov (United States)

    Debbia, E A; Roveta, S; Schito, A M; Gualco, L; Marchese, A

    2001-01-01

    Persisters are a small proportion of a bacterial population that exists in a physiological state permitting survival despite the lethal activity of antibiotics. To explain this phenomenon, it has been suggested that persisters are bacteria repairing spontaneous errors of DNA synthesis. To verify this assumption, Escherichia coli AB1157 and its lexA3 derivative were exposed to a dose 6x MIC of various antibiotics representative of different molecular mechanisms of action (ampicillin, ceftriaxone, meropenem, amikacin, ciprofloxacin). Bacterial cell counts, after 24 hr of exposure to the antimicrobials, revealed a reduction of about 90% of viable organisms in the lexA3 strains in comparison to the lexA+. In several cases, the number of colony-forming units decreased below the limit of assay. This behavior was noted with all antibiotics used, alone or in combination (amikacin plus ceftriaxone and amikacin plus ciprofloxacin). The same experiments were repeated using E. coli AB1157 cultured in the presence of mitomycin C (0.25x MIC), and the number of survivors exceeded by about 90% the values found in the nonexposed control. In contrast, in the sulA background, mitomycin C reacted synergically with all the antibiotics tested causing a strong reduction of the survivors in comparison with the control. The addition of chloramphenicol (0.125x MIC), on the contrary, caused a reduction of the number of survivors of about 90%. These findings indicate that, when DNA repair is active (a mechanism known to block cell division), the number of survivors is greater than that observed with lexA3. Thus, in addition to other possible explanations, persisters might be a fraction of bacteria that during antibiotic treatment are not growing because they are repairing spontaneous errors of DNA synthesis.

  10. Lethality and histopathological alterations caused by Phoneutria nigriventer spider venom from Argentina: Neutralization of lethality by experimental and therapeutic antivenoms.

    Science.gov (United States)

    de Roodt, Adolfo Rafael; Lago, Néstor Rubén; Lanari, Laura Cecilia; Laskowicz, Rodrigo Daniel; Costa de Oliveira, Vanessa; Neder de Román, Estela; de Titto, Ernesto Horacio; Damin, Carlos Fabián

    2017-01-01

    Although the spiders of the genus Phoneutria cause envenomation and their presence has been described in several provinces of the north of Argentina, they are not as common as other spiders of sanitary importance. In the present work, we studied the toxicity of samples of venom of Phoneutria spiders from the provinces of Misiones (where severe envenomation and deaths by Phoneutria have been recorded) and Jujuy (where no deaths have been recorded and severe envenomations are not frequent). To this end, we assessed the lethal potency in mice and guinea pigs and the histopathological alterations caused by both venoms, as well as the neutralization by the commonly used therapeutic antivenom produced by the Butantan Institute in Brazil and by an experimental antivenom developed with venom of P. nigriventer from Misiones. There were no differences in the lethality of the venoms of spiders from both regions. Post mortem examination showed that the heart and lungs were the most affected organs, while important pulmonary edema was seen macroscopically. Histological analysis showed edema, atelectasis, emphysema and cardiac lesion in both experimental models. The antivenoms assayed showed good neutralization of the venoms in the two experimental models. Despite the different geographic origins, the venoms showed similar toxicity and both the experimental antivenom and therapeutic antivenmos were able to neutralize the venoms of Argentinean P. nigriventer.

  11. A Methodology to Assess Lethality and Collateral Damage for Nonfragmenting Precision-Guided Weapons

    Science.gov (United States)

    2008-12-01

    date, guidelines to determine lethality, based on mannequin test data, have not been articulated for nonfragmenting warheads such as FLM. Medical and...the impact on lethality. To date, guidelines to determine lethality, based on mannequin data have not been articulated for nonfragmenting warheads such...circumference of the cylinder at midheight represent the pressure felt on the chest, right side, left side, and back of a human thorax . Each measurement is

  12. EFIKASI INSEKTISIDA BERBAHAN AKTIF CYPERMETHRIN DENGAN METODE LETHAL OVITRAP TERHADAP Aedes aegypti DI LABORATORIUM

    OpenAIRE

    Zumrotus Sholichah; Tri Ramadhani; Adil Ustiawan

    2012-01-01

    Various vector control efforts have been done but dengue hemorrhagic fever still tends to increase. Lethal Ovitrap (LO) was modification from ovitrap where in lethal ovitrap installed ovistrip contain insecticide. The aim of this research was to determine efficacy Cypermethrin and determine the residual effect with lethal ovitrap method on Ae. aegypti at laboratory. This research was laboratory experiment with postest only control group design. Research was done in August-December 2009 at Lok...

  13. DNA Ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair

    Science.gov (United States)

    Gao, Yankun; Katyal, Sachin; Lee, Youngsoo; Zhao, Jingfeng; Rehg, Jerold E.; Russell, Helen R.; McKinnon, Peter J.

    2011-01-01

    DNA replication and repair in mammalian cells involves three distinct DNA ligases; ligase I (Lig1), ligase III (Lig3) and ligase IV (Lig4)1. Lig3 is considered a key ligase during base excision repair because its stability depends upon its nuclear binding partner Xrcc1, a critical factor for this DNA repair pathway2,3. Lig3 is also present in the mitochondria where its role in mitochondrial DNA (mtDNA) maintenance is independent of Xrcc14. However, the biological role of Lig3 is unclear as inactivation of murine Lig3 results in early embryonic lethality5. Here we report that Lig3 is essential for mtDNA integrity but dispensable for nuclear DNA repair. Inactivation of Lig3 in the mouse nervous system resulted in mtDNA loss leading to profound mitochondrial dysfunction, disruption of cellular homeostasis and incapacitating ataxia. Similarly, inactivation of Lig3 in cardiac muscle resulted in mitochondrial dysfunction and defective heart pump function leading to heart failure. However, Lig3 inactivation did not result in nuclear DNA repair deficiency, indicating essential DNA repair functions of Xrcc1 can occur in the absence of Lig3. Instead, we found that Lig1 was critical for DNA repair, but in a cooperative manner with Lig3. Additionally, Lig3 deficiency did not recapitulate the hallmark features of neural Xrcc1 inactivation such as DNA damage-induced cerebellar interneuron loss6, further underscoring functional separation of these DNA repair factors. Therefore, our data reveal that the critical biological role of Lig3 is to maintain mtDNA integrity and not Xrcc1-dependent DNA repair. PMID:21390131

  14. Defective kernel mutants of maize. I. Genetic and lethality studies.

    Science.gov (United States)

    Neuffer, M G; Sheridan, W F

    1980-08-01

    A planting of 3,919 M(1) kernels from normal ears crossed by EMS-treated pollen produced 3,461 M(1) plants and 3,172 selfed ears. These plants yielded 2,477 (72%) total heritable changes; the selfed ears yielded 2,457 (78%) recessive mutants, including 855 (27%) recessive kernel mutants and 8 (0.23%) viable dominant mutants. The ratio of recessive to dominant mutants was 201:1. The average mutation frequency for four known loci was three per 3,172 genomes analyzed. The estimated total number of loci mutated was 535 and the estimated number of kernel mutant loci mutated was 285. Among the 855 kernel mutants, 432 had a nonviable embryo, and 59 germinated but had a lethal seedling. A sample of 194 of the latter two types was tested for heritability, lethality, chromosome arm location and endosperm-embryo interaction between mutant and nonmutant tissues in special hyper-hypoploid combinations produced by manipulation of B-A translocations. The selected 194 mutants were characterized and catalogued according to endosperm phenotype and investigated to determine their effects on the morphology and development of the associated embryo. The possibility of rescuing some of the lethal mutants by covering the mutant embryo with a normal endosperm was investigated. Ninety of these 194 mutants were located on 17 of the 18 chromosome arms tested. Nineteen of the located mutants were examined to determine the effect of having a normal embryo in the same kernel with a mutant endosperm, and vice versa, as compared to the expression observed in kernels with both embryo and endosperm in a mutant condition. In the first situation, for three of the 19 mutants, the mutant endosperm was less extreme (the embryo helped); for seven cases, the mutant endosperm was more extreme (the embryo hindered); and for nine cases, there was no change. In the reverse situation, for four cases the normal endosperm helped the mutant embryo; for 14 cases there was no change and one case was inconclusive.

  15. Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

    Science.gov (United States)

    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.

  16. Studying survivors of near-lethal suicide attempts as a proxy for completed suicide in prisons.

    Science.gov (United States)

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

    2012-07-10

    Suicides in prisons are common. There is a pressing need to understand more about the causes and prevention of prisoner suicides. A particularly informative approach is through studying survivors of near-lethal suicide attempts. However, the extent to which this approach is a good proxy for completed suicide requires verification. In this article we aimed to assess (1) the extent to which male and female prisoners who made near-lethal suicide attempts in prison are similar to prisoners who die by suicide; (2) the suicidal intent of those making near-lethal suicide attempts; and (3) the applicability of the Suicide Intent Scale in prisons. Survivors of near-lethal suicide attempts and prisoners who died by suicide were compared on sociodemographic and criminological characteristics. The suicidal intent of prisoners engaging in near-lethal self-harm was assessed using Beck's Suicide Intent Scale. There were no significant differences when the sociodemographic and criminological profiles of prisoners who made near-lethal suicide attempts and those who died by suicide were compared, except that male prisoners who made near-lethal suicide attempts were somewhat younger. Most prisoners carrying out near-lethal acts had high suicidal intent. However, some questions in the Suicide Intent Scale were inappropriate for assessing intent in prisoners. Prisoners who survive near-lethal self-harm would appear to be a valid proxy for those who die by suicide in prison. The Suicide Intent Scale requires some modifications for use in prisons.

  17. Repair pathways evident in human liver organ slices

    NARCIS (Netherlands)

    Vickers, Alison E. M.; Fisher, Robyn; Olinga, Peter; Dial, Sharon

    2011-01-01

    The extension of human liver slice culture viability for several days broadens the potential of this ex vivo model for characterizing pathways of organ injury and repair, and allows for the multiple dosing of compounds. Extended viability is demonstrated by continued synthesis of GSH and ATP, and ma

  18. Evaluation of Lethal Giant Larvae as a Schistosomiasis Vaccine Candidate

    Science.gov (United States)

    Cao, Yufan; Qiao, Hongbin; Shi, Yanli; Han, Yu; Liu, Jinming; Li, Hao; Lu, Ke; Lin, Jiaojiao

    2016-01-01

    Schistosomiasis is a neglected tropical disease of humans, and it is considered to be the second most devastating parasitic disease after malaria. Eggs produced by normally developed female worms are important in the transmission of the parasite, and they responsible for the pathogenesis of schistosomiasis. The tumor suppressor gene lethal giant larvae (lgl) has an essential function in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. In our earlier study, downregulation of the lgl gene induced a significant reduction in the egg hatching rate of Schistosoma japonicum (Sj) eggs. In this study, the Sjlgl gene was used as a vaccine candidate against schistosomiasis, and vaccination achieved and maintained a stable reduction of the egg hatching rate, which is consistent with previous studies, in addition to reducing the worm burden and liver egg burden in some trials. PMID:27957496

  19. Radiosensitivity Parameters For Lethal Mutagenesis In Caenorhabditis Elegans

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, F.A.; Wilson, J.W.; Katz, R.

    1994-01-01

    For the first time track structure theory has been applied to radiobiological effects in a living organism. Data for lethal mutagenesis in Caenorhabditis elegans, obtained after irradiation with nine different types of ions of atomic number 1-57 and gamma rays have yielded radiosensitivity parameters (E{sub 0}, sigma{sub 0}, Kappa, m = 68 Gy, 2.5 x 10(exp {minus}9) cm (exp 2), 750, 2) comparable with those found for the transformation of C3HT10 1/2 cells (180 Gy, 1.15 x 10(exp {minus}10) cm(exp 2), 750, 2) but remote from those (E{sub 0} and sigma{sub 0} = approx. 2 Gy, approx. 5 x 10(exp {minus}7) cm(exp 2)) for mammalian cell survival.

  20. Evaluation of Lethal Giant Larvae as a Schistosomiasis Vaccine Candidate

    Directory of Open Access Journals (Sweden)

    Yufan Cao

    2016-01-01

    Full Text Available Schistosomiasis is a neglected tropical disease of humans, and it is considered to be the second most devastating parasitic disease after malaria. Eggs produced by normally developed female worms are important in the transmission of the parasite, and they responsible for the pathogenesis of schistosomiasis. The tumor suppressor gene lethal giant larvae (lgl has an essential function in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. In our earlier study, downregulation of the lgl gene induced a significant reduction in the egg hatching rate of Schistosoma japonicum (Sj eggs. In this study, the Sjlgl gene was used as a vaccine candidate against schistosomiasis, and vaccination achieved and maintained a stable reduction of the egg hatching rate, which is consistent with previous studies, in addition to reducing the worm burden and liver egg burden in some trials.