Structural and biochemical characterization of the cell fate determining nucleotidyltransferase fold protein MAB21L1.

Science.gov (United States)

de Oliveira Mann, Carina C; Kiefersauer, Reiner; Witte, Gregor; Hopfner, Karl-Peter

2016-06-08

The exceptionally conserved metazoan MAB21 proteins are implicated in cell fate decisions and share considerable sequence homology with the cyclic GMP-AMP synthase. cGAS is the major innate immune sensor for cytosolic DNA and produces the second messenger 2'-5', 3'-5' cyclic GMP-AMP. Little is known about the structure and biochemical function of other proteins of the cGAS-MAB21 subfamily, such as MAB21L1, MAB21L2 and MAB21L3. We have determined the crystal structure of human full-length MAB21L1. Our analysis reveals high structural conservation between MAB21L1 and cGAS but also uncovers important differences. Although monomeric in solution, MAB21L1 forms a highly symmetric double-pentameric oligomer in the crystal, raising the possibility that oligomerization could be a feature of MAB21L1. In the crystal, MAB21L1 is in an inactive conformation requiring a conformational change - similar to cGAS - to develop any nucleotidyltransferase activity. Co-crystallization with NTP identified a putative ligand binding site of MAB21 proteins that corresponds to the DNA binding site of cGAS. Finally, we offer a structure-based explanation for the effects of MAB21L2 mutations in patients with eye malformations. The underlying residues participate in fold-stabilizing interaction networks and mutations destabilize the protein. In summary, we provide a first structural framework for MAB21 proteins.

Multicapillary SDS-gel electrophoresis for the analysis of fluorescently labeled mAb preparations: a high throughput quality control process for the production of QuantiPlasma and PlasmaScan mAb libraries.

Science.gov (United States)

Székely, Andrea; Szekrényes, Akos; Kerékgyártó, Márta; Balogh, Attila; Kádas, János; Lázár, József; Guttman, András; Kurucz, István; Takács, László

2014-08-01

Molecular heterogeneity of mAb preparations is the result of various co- and post-translational modifications and to contaminants related to the production process. Changes in molecular composition results in alterations of functional performance, therefore quality control and validation of therapeutic or diagnostic protein products is essential. A special case is the consistent production of mAb libraries (QuantiPlasma™ and PlasmaScan™) for proteome profiling, quality control of which represents a challenge because of high number of mAbs (>1000). Here, we devise a generally applicable multicapillary SDS-gel electrophoresis process for the analysis of fluorescently labeled mAb preparations for the high throughput quality control of mAbs of the QuantiPlasma™ and PlasmaScan™ libraries. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The UC Davis/NIH NeuroMab Facility

Data.gov (United States)

Federal Laboratory Consortium — The mission of the UC Davis/NIH NeuroMab facility is to generate and distribute high quality, validated mouse monoclonal antibodies against molecular targets found...

Neutron Reflection Study of Surface Adsorption of Fc, Fab, and the Whole mAb.

Science.gov (United States)

Li, Zongyi; Li, Ruiheng; Smith, Charles; Pan, Fang; Campana, Mario; Webster, John R P; van der Walle, Christopher F; Uddin, Shahid; Bishop, Steve M; Narwal, Rojaramani; Warwicker, Jim; Lu, Jian Ren

2017-07-12

Characterizing the influence of fragment crystallization (Fc) and antigen-binding fragment (Fab) on monoclonal antibody (mAb) adsorption at the air/water interface is an important step to understanding liquid mAb drug product stability during manufacture, shipping, and storage. Here, neutron reflection is used to study the air/water adsorption of a mAb and its Fc and Fab fragments. By varying the isotopic contrast, the adsorbed amount, thickness, orientation, and immersion of the adsorbed layers could be determined unambiguously. While Fc adsorption reached saturation within the hour, its surface adsorbed amount showed little variation with bulk concentration. In contrast, Fab adsorption was slower and the adsorbed amount was concentration dependent. The much higher Fc adsorption, as compared to Fab, was linked to its lower surface charge. Time and concentration dependence of mAb adsorption was dominated by Fab behavior, although both Fab and Fc behaviors contributed to the amount of mAb adsorbed. Changing the pH from 5.5 to 8.8 did not much perturb the adsorbed amount of Fc, Fab, or mAb. However, a small decrease in adsorption was observed for the Fc over pH 8-8.8 and vice versa for the Fab and mAb, consistent with a dominant Fab behavior. As bulk concentration increased from 5 to 50 ppm, the thicknesses of the Fc layers were almost constant at 40 Å, while Fab and mAb layers increased from 45 to 50 Å. These results imply that the adsorbed mAb, Fc, and Fab all retained their globular structures and were oriented with their short axial lengths perpendicular to the interface.

Analysis of Japanese Municipalities With Geopark, MAB, and GIAHS Certification

Directory of Open Access Journals (Sweden)

Ryo Kohsaka

2015-11-01

Full Text Available We analyzed the discussions of Japanese municipalities in their process for obtaining certifications for the Geoparks by the United Nations Educational, Scientific and Cultural Organization (UNESCO, the Man and the Biosphere Programme (MAB by the UNESCO, and the Globally Important Agricultural Heritage systems (GIAHS by the Food and Agriculture Organization (FAO of the United Nations. The official records at the municipality diet were analyzed in a quantitative manner from 2011 to 2013. As the first step, we analyzed the eight municipalities of Noto and Sado for the GIAHS, the cities Itoigawa and Hakusan for the Geopark, and Katsuyama Yamanouchi village from Nagano for the MAB. As individual examples, we analyzed City of Suzu with GIAHS, Itoigawa (Geopark, and Yamanouchi town (MAB with the text-mining approach. For the GIAHS, it was clear that the larger municipalities with city status tended to discuss certification issues more frequently than the smaller towns and villages. Terms such as conservation and certification tended to be used with GIAHS at the Suzu City. The term brand was used with GIAHS and MAB but not for the Geopark. The findings using quantitative methods are at initial stage for analysis of municipality strategies and require further future research.

Immunoreactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Primary Lymphoid Tumors and Lymph Node Metastasis

Science.gov (United States)

Blanco, Rancés; Blanco, Damián; Quintana, Yisel; Escobar, Xiomara; Rengifo, Charles E.; Osorio, Marta; Gutiérrez, Zailí; Lamadrid, Janet; Cedeño, Mercedes; Frómeta, Milagros; Carr, Adriana; Rengifo, Enrique

2013-01-01

The reactivity of the 14F7 Mab, a highly specific IgG1 against N-glycolyl GM3 ganglioside (NeuGcGM3) in normal tissues, lymphomas, lymph node metastasis, and other metastatic sites was assessed by immunohistochemistry. In addition, the effect of chemical fixation on the 14F7 Mab staining using monolayers of P3X63Ag.653 cells was also evaluated. Moreover, the ability of 14F7 to bind NeuGcGM3 ganglioside inducing complement-independent cytotoxicity by a flow cytometry-based assay was measured. The 14F7 Mab was reactive in unfixed, 4% paraformaldehyde, 4% formaldehyde, and acetone fixed cells. Postfixation with acetone did not alter the localization of NeuGcGM3, while the staining with 14F7 Mab was significantly eliminated in both cells fixed and postfixed with methanol but only partially reduced with ethanol. The staining with 14F7 Mab was evidenced in the 89.2%, 89.4%, and 88.9% of lymphomas, lymph node metastasis, and other metastatic sites, respectively, but not in normal tissues. The treatment with 14F7 Mab affected both morphology and membrane integrity of P3X63Ag.653 cells. This cytotoxic activity was dose-dependent and ranged from 24.0 to 84.7% (10–1000 μg/mL) as compared to the negative control. Our data could support the possible use of NeuGcGM3 as target for both active and passive immunotherapy against malignancies expressing this molecule. PMID:24381785

ChLpMab-23: Cancer-Specific Human-Mouse Chimeric Anti-Podoplanin Antibody Exhibits Antitumor Activity via Antibody-Dependent Cellular Cytotoxicity.

Science.gov (United States)

Kaneko, Mika K; Nakamura, Takuro; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Yamada, Shinji; Yanaka, Miyuki; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Ogasawara, Satoshi; Kato, Yukinari

2017-06-01

Podoplanin is expressed in many cancers, including oral cancers and brain tumors. The interaction between podoplanin and its receptor C-type lectin-like receptor 2 (CLEC-2) has been reported to be involved in cancer metastasis and tumor malignancy. We previously established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-23 (IgG 1 , kappa), one of the mouse anti-podoplanin mAbs, was shown to be a CasMab. However, we have not shown the usefulness of LpMab-23 for antibody therapy against podoplanin-expressing cancers. In this study, we first determined the minimum epitope of LpMab-23 and revealed that Gly54-Leu64 peptide, especially Gly54, Thr55, Ser56, Glu57, Asp58, Arg59, Tyr60, and Leu64 of podoplanin, is a critical epitope of LpMab-23. We further produced human-mouse chimeric LpMab-23 (chLpMab-23) and investigated whether chLpMab-23 exerts antibody-dependent cellular cytotoxicity (ADCC) and antitumor activity. In flow cytometry, chLpMab-23 showed high sensitivity against a podoplanin-expressing glioblastoma cell line, LN319, and an oral cancer cell line, HSC-2. chLpMab-23 also showed ADCC activity against podoplanin-expressing CHO cells (CHO/podoplanin). In xenograft models with HSC-2 and CHO/podoplanin, chLpMab-23 exerts antitumor activity using human natural killer cells, indicating that chLpMab-23 could be useful for antibody therapy against podoplanin-expressing cancers.

Controlling the Glycosylation Profile in mAbs Using Time-Dependent Media Supplementation

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Devesh Radhakrishnan

2017-12-01

Full Text Available In order to meet desired drug product quality targets, the glycosylation profile of biotherapeutics such as monoclonal antibodies (mAbs must be maintained consistently during manufacturing. Achieving consistent glycan distribution profiles requires identifying factors that influence glycosylation, and manipulating them appropriately via well-designed control strategies. Now, the cell culture media supplement, MnCl2, is known to alter the glycosylation profile in mAbs generally, but its effect, particularly when introduced at different stages during cell growth, has yet to be investigated and quantified. In this study, we evaluate the effect of time-dependent addition of MnCl2 on the glycan profile quantitatively, using factorial design experiments. Our results show that MnCl2 addition during the lag and exponential phases affects the glycan profile significantly more than stationary phase supplementation does. Also, using a novel computational technique, we identify various combinations of glycan species that are affected by this dynamic media supplementation scheme, and quantify the effects mathematically. Our experiments demonstrate the importance of taking into consideration the time of addition of these trace supplements, not just their concentrations, and our computational analysis provides insight into what supplements to add, when, and how much, in order to induce desired changes.

Monoclonal Antibody L1Mab-13 Detected Human PD-L1 in Lung Cancers.

Science.gov (United States)

Yamada, Shinji; Itai, Shunsuke; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Suzuki, Hiroyoshi; Kaneko, Mika K; Kato, Yukinari

2018-04-01

Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells. It is also expressed in several tumor cells such as melanoma and lung cancer cells. A strong correlation has been reported between human PD-L1 (hPD-L1) expression in tumor cells and negative prognosis in cancer patients. Here, a novel anti-hPD-L1 monoclonal antibody (mAb) L 1 Mab-13 (IgG 1 , kappa) was produced using a cell-based immunization and screening (CBIS) method. We investigated hPD-L1 expression in lung cancer using flow cytometry, Western blot, and immunohistochemical analyses. L 1 Mab-13 specifically reacted hPD-L1 of hPD-L1-overexpressed Chinese hamster ovary (CHO)-K1 cells and endogenous hPD-L1 of KMST-6 (human fibroblast) in flow cytometry and Western blot. Furthermore, L 1 Mab-13 reacted with lung cancer cell lines (EBC-1, Lu65, and Lu99) in flow cytometry and stained lung cancer tissues in a membrane-staining pattern in immunohistochemical analysis. These results indicate that a novel anti-hPD-L1 mAb, L 1 Mab-13, is very useful for detecting hPD-L1 of lung cancers in flow cytometry, Western blot, and immunohistochemical analyses.

Dynamics of immature mAb glycoform secretion during CHO cell culture

DEFF Research Database (Denmark)

Jimenez del Val, Ioscani; Fan, Yuzhou; Weilguny, Dietmar

2016-01-01

Ensuring consistent glycosylation-associated quality of therapeutic monoclonal antibodies (mAbs) has become a priority in pharmaceutical bioprocessing given that the distribution and composition of the carbohydrates (glycans) bound to these molecules determines their therapeutic efficacy and immu......Ensuring consistent glycosylation-associated quality of therapeutic monoclonal antibodies (mAbs) has become a priority in pharmaceutical bioprocessing given that the distribution and composition of the carbohydrates (glycans) bound to these molecules determines their therapeutic efficacy...

Development of at-line assay to monitor charge variants of MAbs during production.

Science.gov (United States)

St Amand, M M; Ogunnaike, B A; Robinson, A S

2014-01-01

One major challenge currently facing the biopharmaceutical industry is to understand how MAb microheterogeneity affects therapeutic efficacy, potency, immunogenicity, and clearance. MAb micro-heterogeneity can result from post-translational modifications such as sialylation, galactosylation, C-terminal lysine cleavage, glycine amidation, and tryptophan oxidation, each of which can generate MAb charge variants; such heterogeneity can affect pharmacokinetics (PK) considerably. Implementation of appropriate on-line quality control strategies may help to regulate bioprocesses, thus enabling more homogenous material with desired post-translational modifications and PK behavior. However, one major restriction to implementation of quality control strategies is the availability of techniques for obtaining on-line or at-line measurements of these attributes. In this work, we describe the development of an at-line assay to separate MAb charge variants in near real-time, which could ultimately be used to implement on-line quality control strategies for MAb production. The assay consists of a 2D-HPLC method with sequential in-line Protein A and WCX-10 HPLC column steps. To perform the 2D-HPLC assay at-line, the two columns steps were integrated into a single method using a novel system configuration that allowed parallel flow over column 1 or column 2 or sequential flow from column 1 to column 2. A bioreactor system was also developed such that media samples could be removed automatically from bioreactor vessels during production and delivered to the 2D-HPLC for analysis. With this at-line HPLC assay, we have demonstrated that MAb microheterogeneity occurs throughout the cell cycle whether the host cell line is grown under different or the same nominal culture conditions. © 2013 American Institute of Chemical Engineers.

Development of an Anti-HER2 Monoclonal Antibody H2Mab-139 Against Colon Cancer.

Science.gov (United States)

Kaneko, Mika K; Yamada, Shinji; Itai, Shunsuke; Kato, Yukinari

2018-02-01

Human epidermal growth factor receptor 2 (HER2) expression has been reported in several cancers, such as breast, gastric, lung, pancreatic, and colorectal cancers. HER2 is overexpressed in those cancers and is associated with poor clinical outcomes. Trastuzumab, a humanized anti-HER2 antibody, provides significant survival benefits for patients with HER2-overexpressing breast cancers and gastric cancers. In this study, we developed a novel anti-HER2 monoclonal antibody (mAb), H 2 Mab-139 (IgG 1 , kappa) and investigated it against colon cancers using flow cytometry, western blot, and immunohistochemical analyses. Flow cytometry analysis revealed that H 2 Mab-139 reacted with colon cancer cell lines, such as Caco-2, HCT-116, HCT-15, HT-29, LS 174T, COLO 201, COLO 205, HCT-8, SW1116, and DLD-1. Although H 2 Mab-139 strongly reacted with LN229/HER2 cells on the western blot, we did not observe a specific signal for HER2 in colon cancer cell lines. Immunohistochemical analyses revealed sensitive and specific reactions of H 2 Mab-139 against colon cancers, indicating that H 2 Mab-139 is useful in detecting HER2 overexpression in colon cancers using flow cytometry and immunohistochemical analyses.

H2Mab-77 is a Sensitive and Specific Anti-HER2 Monoclonal Antibody Against Breast Cancer.

Science.gov (United States)

Itai, Shunsuke; Fujii, Yuki; Kaneko, Mika K; Yamada, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Saidoh, Noriko; Chang, Yao-Wen; Handa, Saori; Takahashi, Maki; Suzuki, Hiroyoshi; Harada, Hiroyuki; Kato, Yukinari

2017-08-01

Human epidermal growth factor receptor 2 (HER2) plays a critical role in the progression of breast cancers, and HER2 overexpression is associated with poor clinical outcomes. Trastuzumab is an anti-HER2 humanized antibody that leads to significant survival benefits in patients with HER2-positive metastatic breast cancers. In this study, we developed novel anti-HER2 monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. Initially, we expressed the full length or ectodomain of HER2 in LN229 glioblastoma cells and then immunized mice with ectodomain of HER2 or LN229/HER2, and performed the first screening by enzyme-linked immunosorbent assays using ectodomain of HER2. Subsequently, we selected mAbs according to their efficacy in flow cytometry (second screening), Western blot (third screening), and immunohistochemical analyses (fourth screening). Among 100 mAb clones, only three mAbs reacted with HER2 in Western blot, and clone H 2 Mab-77 (IgG 1 , kappa) was selected. Finally, immunohistochemical analyses with H 2 Mab-77 showed sensitive and specific reactions against breast cancer cells, warranting the use of H 2 Mab-77 to detect HER2 in pathological analyses of breast cancers.

Germline-specific MATH-BTB substrate adaptor MAB1 regulates spindle length and nuclei identity in maize.

Science.gov (United States)

Juranič, Martina; Srilunchang, Kanok-orn; Krohn, Nádia Graciele; Leljak-Levanic, Dunja; Sprunck, Stefanie; Dresselhaus, Thomas

2012-12-01

Germline and early embryo development constitute ideal model systems to study the establishment of polarity, cell identity, and asymmetric cell divisions (ACDs) in plants. We describe here the function of the MATH-BTB domain protein MAB1 that is exclusively expressed in the germ lineages and the zygote of maize (Zea mays). mab1 (RNA interference [RNAi]) mutant plants display chromosome segregation defects and short spindles during meiosis that cause insufficient separation and migration of nuclei. After the meiosis-to-mitosis transition, two attached nuclei of similar identity are formed in mab1 (RNAi) mutants leading to an arrest of further germline development. Transient expression studies of MAB1 in tobacco (Nicotiana tabacum) Bright Yellow-2 cells revealed a cell cycle-dependent nuclear localization pattern but no direct colocalization with the spindle apparatus. MAB1 is able to form homodimers and interacts with the E3 ubiquitin ligase component Cullin 3a (CUL3a) in the cytoplasm, likely as a substrate-specific adapter protein. The microtubule-severing subunit p60 of katanin was identified as a candidate substrate for MAB1, suggesting that MAB1 resembles the animal key ACD regulator Maternal Effect Lethal 26 (MEL-26). In summary, our findings provide further evidence for the importance of posttranslational regulation for asymmetric divisions and germline progression in plants and identified an unstable key protein that seems to be involved in regulating the stability of a spindle apparatus regulator(s).

Antiglycopeptide Mouse Monoclonal Antibody LpMab-21 Exerts Antitumor Activity Against Human Podoplanin Through Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

Science.gov (United States)

Kato, Yukinari; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Uchida, Hiroaki; Tahara, Hideaki; Yamada, Shinji; Yanaka, Miyuki; Nakamura, Takuro; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Honma, Ryusuke; Takagi, Michiaki; Ogasawara, Satoshi; Murata, Takeshi; Kaneko, Mika K

2017-02-01

The interaction between podoplanin (PDPN) and C-type lectin-like receptor 2 (CLEC-2) is involved in tumor malignancy. We have established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-21, one of the mouse antipodoplanin mAbs, is of the IgG 2a subclass, and its minimum epitope was determined to be Thr76-Arg79 of the human podoplanin. Importantly, sialic acid is linked to Thr76; therefore, LpMab-21 is an antiglycopeptide mAb (GpMab). In this study, we investigated whether LpMab-21 shows antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against human podoplanin-expressing cancer cell lines in vitro and also studied its antitumor activities using a xenograft model. LpMab-21 showed high ADCC and CDC activities against not only podoplanin-expressing Chinese hamster ovary cells but also LN319 glioblastoma cells and PC-10 lung cancer cells, both of which endogenously express podoplanin. Furthermore, LpMab-21 decreased tumor growth in vivo, indicating that LpMab-21 could be useful for antibody therapy against human podoplanin-expressing cancers.

SPECT scintigraphy with HDP and Mab BW 250/183 of loosened hip endoprothesis

Energy Technology Data Exchange (ETDEWEB)

Predic, P [Hospital Celje, Celje (Sierra Leone); Gregoric, E [Hospital Izola, Izola (Sierra Leone); Dodig, D [Clinical Hospital Centre, Zagreb (Croatia). Dept. of Nuclear Medicine and Radiation Protection

1994-10-01

Main problem of the loosened hip endoprothesis is in distinguishing between the aseptic and septic loosening of endoprothesis. The study involved 27 pts with a loosened hip; 15 pts with aseptic and 12 pts with septic loosening. The patients were injected 550-770 MBq Tc-99m-HDP and underwent SPECT scintigraphy of the hips to repeat then the examination with only 370 MBq Tc-99m-Mab Bw 230/183. HDP application evidenced positive accumulation at the endoprothesis in all patients with a loosened hip while Mab Bw 250/183 only in the patients with septic loosening. Conclusion: SPECT scintigraphy of hip endoprothesis with HDP and Mab BW 250/183 allows differential diagnosing between septic and aseptic hip loosening and hereby a correct therapeutical approach. (author).

Morbidity and mortality following induced abortion in Nnewi, Nigeria.

Science.gov (United States)

Ikechebelu, J I; Okoli, C C

2003-07-01

We present a study of the maternal morbidity and mortality among 76 patients treated at the Nnamdi Azikiwe University Teaching Hospital, Nnewi for complications of induced abortion from January 1996 to December 2000. The total number of maternal admissions over this period was 5750, and illegal induced abortion was responsible for 1.3% of the admissions, with a mortality rate of 5.3% (n = 4) for induced abortion. This accounted for 21.1% of the total maternal deaths (n = 19) for the period. The mean age of the women was 20.6 years (range 15-34 years), 94.7% (n = 72) were unmarried, 93.5% (n = 71) were nulliparous and 76.5% (n = 58) were unemployed, 67.1% (n = 51) had had a mid-trimester termination at > 13 weeks gestational age. It is significant that 55.3% of the patients were teenagers and 45.1% of the mid-trimester abortions occurred in this group. Genital sepsis, haemorrhage, pelvic infection with peritonitis and abscess formation, uterine perforation, and gut injury were the major complications encountered. This study demonstrates that induced abortion is still a major cause of maternal mortality in Nigeria. Integrated family health education, planned parenthood and contraceptive education, a mass literacy campaign and improvement of the existing national health services are recommended in order to ameliorate the problems of illegally induced abortion in Nigeria.

Disease-induced mortality in density-dependent discrete-time S-I-S epidemic models.

Science.gov (United States)

Franke, John E; Yakubu, Abdul-Aziz

2008-12-01

The dynamics of simple discrete-time epidemic models without disease-induced mortality are typically characterized by global transcritical bifurcation. We prove that in corresponding models with disease-induced mortality a tiny number of infectious individuals can drive an otherwise persistent population to extinction. Our model with disease-induced mortality supports multiple attractors. In addition, we use a Ricker recruitment function in an SIS model and obtained a three component discrete Hopf (Neimark-Sacker) cycle attractor coexisting with a fixed point attractor. The basin boundaries of the coexisting attractors are fractal in nature, and the example exhibits sensitive dependence of the long-term disease dynamics on initial conditions. Furthermore, we show that in contrast to corresponding models without disease-induced mortality, the disease-free state dynamics do not drive the disease dynamics.

Germline-Specific MATH-BTB Substrate Adaptor MAB1 Regulates Spindle Length and Nuclei Identity in Maize[W

Science.gov (United States)

Juranić, Martina; Srilunchang, Kanok-orn; Krohn, Nádia Graciele; Leljak-Levanić, Dunja; Sprunck, Stefanie; Dresselhaus, Thomas

2012-01-01

Germline and early embryo development constitute ideal model systems to study the establishment of polarity, cell identity, and asymmetric cell divisions (ACDs) in plants. We describe here the function of the MATH-BTB domain protein MAB1 that is exclusively expressed in the germ lineages and the zygote of maize (Zea mays). mab1 (RNA interference [RNAi]) mutant plants display chromosome segregation defects and short spindles during meiosis that cause insufficient separation and migration of nuclei. After the meiosis-to-mitosis transition, two attached nuclei of similar identity are formed in mab1 (RNAi) mutants leading to an arrest of further germline development. Transient expression studies of MAB1 in tobacco (Nicotiana tabacum) Bright Yellow-2 cells revealed a cell cycle–dependent nuclear localization pattern but no direct colocalization with the spindle apparatus. MAB1 is able to form homodimers and interacts with the E3 ubiquitin ligase component Cullin 3a (CUL3a) in the cytoplasm, likely as a substrate-specific adapter protein. The microtubule-severing subunit p60 of katanin was identified as a candidate substrate for MAB1, suggesting that MAB1 resembles the animal key ACD regulator Maternal Effect Lethal 26 (MEL-26). In summary, our findings provide further evidence for the importance of posttranslational regulation for asymmetric divisions and germline progression in plants and identified an unstable key protein that seems to be involved in regulating the stability of a spindle apparatus regulator(s). PMID:23250449

A multi-species synthesis of physiological mechanisms in drought-induced tree mortality

Energy Technology Data Exchange (ETDEWEB)

Adams, Henry D.; Zeppel, Melanie J. B.; Anderegg, William R. L.; Hartmann, Henrik; Landhäusser, Simon M.; Tissue, David T.; Huxman, Travis E.; Hudson, Patrick J.; Franz, Trenton E.; Allen, Craig D.; Anderegg, Leander D. L.; Barron-Gafford, Greg A.; Beerling, David J.; Breshears, David D.; Brodribb, Timothy J.; Bugmann, Harald; Cobb, Richard C.; Collins, Adam D.; Dickman, L. Turin; Duan, Honglang; Ewers, Brent E.; Galiano, Lucía; Galvez, David A.; Garcia-Forner, Núria; Gaylord, Monica L.; Germino, Matthew J.; Gessler, Arthur; Hacke, Uwe G.; Hakamada, Rodrigo; Hector, Andy; Jenkins, Michael W.; Kane, Jeffrey M.; Kolb, Thomas E.; Law, Darin J.; Lewis, James D.; Limousin, Jean-Marc; Love, David M.; Macalady, Alison K.; Martínez-Vilalta, Jordi; Mencuccini, Maurizio; Mitchell, Patrick J.; Muss, Jordan D.; O’Brien, Michael J.; O’Grady, Anthony P.; Pangle, Robert E.; Pinkard, Elizabeth A.; Piper, Frida I.; Plaut, Jennifer A.; Pockman, William T.; Quirk, Joe; Reinhardt, Keith; Ripullone, Francesco; Ryan, Michael G.; Sala, Anna; Sevanto, Sanna; Sperry, John S.; Vargas, Rodrigo; Vennetier, Michel; Way, Danielle A.; Xu, Chonggang; Yepez, Enrico A.; McDowell, Nate G.

2017-08-07

Widespread tree mortality associated with drought has been observed on all forested continents, and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere-atmosphere interactions of carbon, water, and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analyzed across species and biomes using a standardized physiological framework. Here we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought-induced mortality. All species assessed had 60% or greater loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrates at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in hydraulic deterioration. The consistent Our finding that across species of hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function.

A multi-species synthesis of physiological mechanisms in drought-induced tree mortality.

Science.gov (United States)

Adams, Henry D; Zeppel, Melanie J B; Anderegg, William R L; Hartmann, Henrik; Landhäusser, Simon M; Tissue, David T; Huxman, Travis E; Hudson, Patrick J; Franz, Trenton E; Allen, Craig D; Anderegg, Leander D L; Barron-Gafford, Greg A; Beerling, David J; Breshears, David D; Brodribb, Timothy J; Bugmann, Harald; Cobb, Richard C; Collins, Adam D; Dickman, L Turin; Duan, Honglang; Ewers, Brent E; Galiano, Lucía; Galvez, David A; Garcia-Forner, Núria; Gaylord, Monica L; Germino, Matthew J; Gessler, Arthur; Hacke, Uwe G; Hakamada, Rodrigo; Hector, Andy; Jenkins, Michael W; Kane, Jeffrey M; Kolb, Thomas E; Law, Darin J; Lewis, James D; Limousin, Jean-Marc; Love, David M; Macalady, Alison K; Martínez-Vilalta, Jordi; Mencuccini, Maurizio; Mitchell, Patrick J; Muss, Jordan D; O'Brien, Michael J; O'Grady, Anthony P; Pangle, Robert E; Pinkard, Elizabeth A; Piper, Frida I; Plaut, Jennifer A; Pockman, William T; Quirk, Joe; Reinhardt, Keith; Ripullone, Francesco; Ryan, Michael G; Sala, Anna; Sevanto, Sanna; Sperry, John S; Vargas, Rodrigo; Vennetier, Michel; Way, Danielle A; Xu, Chonggang; Yepez, Enrico A; McDowell, Nate G

2017-09-01

Widespread tree mortality associated with drought has been observed on all forested continents and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere-atmosphere interactions of carbon, water and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analysed across species and biomes using a standardized physiological framework. Here, we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought-induced mortality. All species assessed had 60% or higher loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrate reserves at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in reducing hydraulic function. Our finding that hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function.

A multi-species synthesis of physiological mechanisms in drought-induced tree mortality

Science.gov (United States)

Adams, Henry D.; Zeppel, Melanie; Anderegg, William R.L.; Hartmann, Henrik; Landhäusser, Simon M.; Tissue, David T.; Huxman, Travis E.; Hudson, Patrick J.; Franz, Trenton E.; Allen, Craig D.; Anderegg, Leander D. L.; Barron-Gafford, Greg A.; Beerling, David; Breshears, David D.; Brodribb, Timothy J.; Bugmann, Harald; Cobb, Richard C.; Collins, Adam D.; Dickman, L. Turin; Duan, Honglang; Ewers, Brent E.; Galiano, Lucia; Galvez, David A.; Garcia-Forner, Núria; Gaylord, Monica L.; Germino, Matthew J.; Gessler, Arthur; Hacke, Uwe G.; Hakamada, Rodrigo; Hector, Andy; Jenkins, Michael W.; Kane, Jeffrey M.; Kolb, Thomas E.; Law, Darin J.; Lewis, James D.; Limousin, Jean-Marc; Love, David; Macalady, Alison K.; Martinez-Vilalta, Jordi; Mencuccini, Maurizio; Mitchell, Patrick J.; Muss, Jordan D.; O'Brien, Michael J.; O'Grady, Anthony P.; Pangle, Robert E.; Pinkard, Elizabeth A.; Piper, Frida I.; Plaut, Jennifer; Pockman, William T.; Quirk, Joe; Reinhardt, Keith; Ripullone, Francesco; Ryan, Michael G.; Sala, Anna; Sevanto, Sanna; Sperry, John S.; Vargas, Rodrigo; Vennetier, Michel; Way, Danielle A.; Wu, Chonggang; Yepez, Enrico A.; McDowell, Nate G.

2017-01-01

Widespread tree mortality associated with drought has been observed on all forested continents and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere–atmosphere interactions of carbon, water and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analysed across species and biomes using a standardized physiological framework. Here, we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought-induced mortality. All species assessed had 60% or higher loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrate reserves at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in reducing hydraulic function. Our finding that hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function.

Conservation Compromises: The MAB and the Legacy of the International Biological Program, 1964-1974.

Science.gov (United States)

Schleper, Simone

2017-02-01

This article looks at the International Biological Program (IBP) as the predecessor of UNESCO's well-known and highly successful Man and the Biosphere Programme (MAB). It argues that international conservation efforts of the 1970s, such as the MAB, must in fact be understood as a compound of two opposing attempts to reform international conservation in the 1960s. The scientific framework of the MAB has its origins in disputes between high-level conservationists affiliated with the International Union for the Conservation of Nature and Natural Resources (IUCN) about what the IBP meant for the future of conservation. Their respective visions entailed different ecological philosophies as much as diverging sets of political ideologies regarding the global implementation of conservation. Within the IBP's Conservation Section, one group propagated a universal systems approach to conservation with a centralized, technocratic management of nature and society by an elite group of independent scientific experts. Within IUCN, a second group based their notion of environmental expert roles on a more descriptive and local ecology of resource mapping as practiced by UNESCO. When the IBP came to an end in 1974, both groups' ecological philosophies played into the scientific framework underlying the MAB's World Network or Biosphere Reserves. The article argues that it is impossible to understand the course of conservation within the MAB without studying the dynamics and discourses between the two underlying expert groups and their respective visions for reforming conservation.

Immunohistochemical Analysis Using Antipodocalyxin Monoclonal Antibody PcMab-47 Demonstrates Podocalyxin Expression in Oral Squamous Cell Carcinomas.

Science.gov (United States)

Itai, Shunsuke; Yamada, Shinji; Kaneko, Mika K; Harada, Hiroyuki; Kato, Yukinari

2017-10-01

Podocalyxin is a CD34-related type I transmembrane protein that is highly glycosylated with N-glycan, O-glycan, and keratan sulfate. Podocalyxin was originally found in the podocytes of rat kidney and is reportedly expressed in many types of tumors, including brain tumors, colorectal cancers, and breast cancers. Overexpression of podocalyxin is an independent predictor of progression, metastasis, and poor outcome. We recently immunized mice with recombinant human podocalyxin, which was produced using LN229 glioblastoma cells, and produced a novel antipodocalyxin monoclonal antibody (mAb), PcMab-47, which reacts with endogenous podocalyxin-expressing cancer cell lines and normal cell lines independent of glycosylation in Western blot, flow cytometry, and immunohistochemical analyses. In this study, we performed immunohistochemical analysis against oral cancers using PcMab-47. PcMab-47-stained oral squamous cell carcinoma cells in a cytoplasmic pattern and detected 26/38 (68.4%) of oral squamous cell carcinoma cells on tissue microarrays. These results indicate that PcMab-47 is useful in detecting podocalyxin of oral cancers for immunohistochemical analysis.

Hydraulic Function in Australian Tree Species during Drought-Induced Mortality

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Tissue, D.; Maier, C.; Creek, D.; Choat, B.

2016-12-01

Drought induced tree mortality and decline are key issues facing forest ecology and management. Here, we primarily investigated the hydraulic limitations underpinning drought-induced mortality in three Australian tree species. Using field-based large rainout shelters, three angiosperm species (Casuarina cunninghamiana, Eucalyptus sideroxylon, Eucalyptus tereticornis) were subjected to two successive drought and recovery cycles, prior to a subsequent long and extreme drought to mortality; total duration of experiment was 2.5 years. Leaf gas exchange, leaf and stem hydraulics, and carbon reserves were monitored during the experiment. Trees died as a result of failure in the hydraulic transport system, primarily related to water stress induced embolism. Stomatal closure occurred prior to the induction of significant embolism in the stem xylem of all species. Nonetheless, trees suffered a rapid decline in xylem water potential and increase in embolism during the severe drought treatment. Trees died at water potentials causing greater than 90% loss of hydraulic conductivity in the stem, providing support for the theory that lethal water potential is correlated with complete loss of hydraulic function in the stem xylem of angiosperms.

The UNC-4 homeobox protein represses mab-9 expression in DA motor neurons in Caenorhabditis elegans

DEFF Research Database (Denmark)

Jafari, Gholamali; Appleford, Peter J; Seago, Julian

2011-01-01

, an RNAi screen designed to identify upstream transcriptional regulators of mab-9 showed that silencing of unc-4 (encoding a paired-class homeodomain protein) increases mab-9::gfp expression in the nervous system, specifically in posterior DA motor neurons. Over-expression of unc-4 from a heat...

Identification and quantification of predominant metabolites of synthetic cannabinoid MAB-CHMINACA in an authentic human urine specimen.

Science.gov (United States)

Hasegawa, Koutaro; Minakata, Kayoko; Gonmori, Kunio; Nozawa, Hideki; Yamagishi, Itaru; Watanabe, Kanako; Suzuki, Osamu

2018-02-01

An autopsy case in which the cause of death was judged as drug poisoning by two synthetic cannabinoids, including MAB-CHMINACA, was investigated. Although unchanged MAB-CHMINACA could be detected from solid tissues, blood and stomach contents in the case, the compound could not be detected from a urine specimen. We obtained six kinds of reference standards of MAB-CHMINACA metabolites from a commercial source. The MAB-CHMINACA metabolites from the urine specimen of the abuser were extracted using a QuEChERS method including dispersive solid-phase extraction, and analyzed by liquid chromatography-tandem mass spectrometry with or without hydrolysis with β-glucuronidase. Among the six MAB-CHMINACA metabolites tested, two predominant metabolites could be identified and quantified in the urine specimen of the deceased. After hydrolysis with β-glucuronidase, an increase of the two metabolites was not observed. The metabolites detected were a 4-monohydroxycyclohexylmethyl metabolite M1 (N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-((4-hydroxycyclohexyl)methyl)-1H-indazole-3-carboxamide) and a dihydroxyl (4-hydroxycyclohexylmethyl and tert-butylhydroxyl) metabolite M11 (N-(1-amino-4-hydroxy-3,3-dimethyl-1-oxobutan-2-yl)-1-((4-hydroxycyclohexyl)methyl)-1H-indazole-3-carboxamide). Their concentrations were 2.17 ± 0.15 and 10.2 ± 0.3 ng/mL (n = 3, each) for M1 and M11, respectively. Although there is one previous in vitro study showing the estimation of metabolism of MAB-CHMINACA using human hepatocytes, this is the first report dealing with in vivo identification and quantification of MAB-CHMINACA metabolites in an authentic human urine specimen. Copyright © 2017 John Wiley & Sons, Ltd.

Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells.

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Klitgaard, Josephine L; Koefoed, Klaus; Geisler, Christian; Gadeberg, Ole V; Frank, David A; Petersen, Jørgen; Jurlander, Jesper; Pedersen, Mikkel W

2013-10-01

The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of mAbs against human CD5 was generated and tested for ability to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) both as single mAbs and combinations of two mAbs against non-overlapping epitopes on human CD5. The results demonstrated that combinations of two mAbs significantly increased the level of CDC compared to the single mAbs, while no enhancement of ADCC was seen with anti-CD5 mAb combinations. High levels of CDC and ADCC correlated with low levels of Ab-induced CD5 internalization and degradation. Importantly, an anti-CD5 mAb combination enhanced CDC of CLL cells when combined with the anti-CD20 mAbs rituximab and ofatumumab as well as with the anti-CD52 mAb alemtuzumab. These results suggest that an anti-CD5 mAb combination inducing CDC and ADCC may be effective alone, in combination with mAbs against other targets or combined with chemotherapy for CLL and other CD5-expressing haematological or lymphoid malignancies. © 2013 John Wiley & Sons Ltd.

Insect-induced tree mortality of boreal forests in eastern Canada under a changing climate.

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Zhang, Xiongqing; Lei, Yuancai; Ma, Zhihai; Kneeshaw, Dan; Peng, Changhui

2014-06-01

Forest insects are major disturbances that induce tree mortality in eastern coniferous (or fir-spruce) forests in eastern North America. The spruce budworm (SBW) (Choristoneura fumiferana [Clemens]) is the most devastating insect causing tree mortality. However, the relative importance of insect-caused mortality versus tree mortality caused by other agents and how this relationship will change with climate change is not known. Based on permanent sample plots across eastern Canada, we combined a logistic model with a negative model to estimate tree mortality. The results showed that tree mortality increased mainly due to forest insects. The mean difference in annual tree mortality between plots disturbed by insects and those without insect disturbance was 0.0680 per year (P eastern Canada but that tree mortality induced by insect outbreaks will decrease in eastern Canada under warming climate.

Detection of high PD-L1 expression in oral cancers by a novel monoclonal antibody L1Mab-4.

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Yamada, Shinji; Itai, Shunsuke; Kaneko, Mika K; Kato, Yukinari

2018-03-01

Programmed cell death-ligand 1 (PD-L1), which is a ligand of programmed cell death-1 (PD-1), is a type I transmembrane glycoprotein that is expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells. There is a strong correlation between human PD-L1 (hPD-L1) expression on tumor cells and negative prognosis in cancer patients. In this study, we produced a novel anti-hPD-L1 monoclonal antibody (mAb), L 1 Mab-4 (IgG 2b , kappa), using cell-based immunization and screening (CBIS) method and investigated hPD-L1 expression in oral cancers. L 1 Mab-4 reacted with oral cancer cell lines (Ca9-22, HO-1-u-1, SAS, HSC-2, HSC-3, and HSC-4) in flow cytometry and stained oral cancers in a membrane-staining pattern. L 1 Mab-4 stained 106/150 (70.7%) of oral squamous cell carcinomas, indicating the very high sensitivity of L 1 Mab-4. These results indicate that L 1 Mab-4 could be useful for investigating the function of hPD-L1 in oral cancers.

Inhibition of Helicobacter pylori CagA-Induced Pathogenesis by Methylantcinate B from Antrodia camphorata

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Chun-Jung Lin

2013-01-01

Full Text Available The bacterial pathogen Helicobacter pylori (Hp is the leading risk factor for the development of gastric cancer. Hp virulence factor, cytotoxin-associated gene A (CagA interacted with cholesterol-enriched microdomains and leads to induction of inflammation in gastric epithelial cells (AGS. In this study, we identified a triterpenoid methylantcinate B (MAB from the medicinal mushroom Antrodia camphoratawhich inhibited the translocation and phosphorylation of CagA and caused a reduction in hummingbird phenotype in HP-infected AGS cells. Additionally, MAB suppressed the Hp-induced inflammatory response by attenuation of NF-κB activation, translocation of p65 NF-κB, and phosphorylation of IκB-α, indicating that MAB modulates CagA-mediated signaling pathway. Additionally, MAB also suppressed the IL-8 luciferase activity and its secretion in HP-infected AGS cells. On the other hand, molecular structure simulations revealed that MAB interacts with CagA similarly to that of cholesterol. Moreover, binding of cholesterol to the immobilized CagA was inhibited by increased levels of MAB. Our results demonstrate that MAB is the first natural triterpenoid which competes with cholesterol bound to CagA leading to attenuation of Hp-induced pathogenesis of epithelial cells. Thus, this study indicates that MAB may have a scope to develop as a therapeutic candidate against Hp CagA-induced inflammation.

Detection of high PD-L1 expression in oral cancers by a novel monoclonal antibody L1Mab-4

Directory of Open Access Journals (Sweden)

Shinji Yamada

2018-03-01

Full Text Available Programmed cell death-ligand 1 (PD-L1, which is a ligand of programmed cell death-1 (PD-1, is a type I transmembrane glycoprotein that is expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells. There is a strong correlation between human PD-L1 (hPD-L1 expression on tumor cells and negative prognosis in cancer patients. In this study, we produced a novel anti-hPD-L1 monoclonal antibody (mAb, L1Mab-4 (IgG2b, kappa, using cell-based immunization and screening (CBIS method and investigated hPD-L1 expression in oral cancers. L1Mab-4 reacted with oral cancer cell lines (Ca9-22, HO-1-u-1, SAS, HSC-2, HSC-3, and HSC-4 in flow cytometry and stained oral cancers in a membrane-staining pattern. L1Mab-4 stained 106/150 (70.7% of oral squamous cell carcinomas, indicating the very high sensitivity of L1Mab-4. These results indicate that L1Mab-4 could be useful for investigating the function of hPD-L1 in oral cancers. Keywords: Programmed cell death-ligand 1, Monoclonal antibody, Oral cancer

Establishment of H2Mab-119, an Anti-Human Epidermal Growth Factor Receptor 2 Monoclonal Antibody, Against Pancreatic Cancer.

Science.gov (United States)

Yamada, Shinji; Itai, Shunsuke; Nakamura, Takuro; Chang, Yao-Wen; Harada, Hiroyuki; Suzuki, Hiroyoshi; Kaneko, Mika K; Kato, Yukinari

2017-12-01

Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast cancer and is associated with poor clinical outcomes. In addition, HER2 expression has been reported in other cancers, such as gastric, colorectal, lung, and pancreatic cancers. An anti-HER2 humanized antibody, trastuzumab, leads to significant survival benefits in patients with HER2-overexpressing breast cancers and gastric cancers. Herein, we established a novel anti-HER2 monoclonal antibody (mAb), H 2 Mab-119 (IgG 1 , kappa), and characterized its efficacy against pancreatic cancers using flow cytometry, Western blot, and immunohistochemical analyses. H 2 Mab-119 reacted with pancreatic cancer cell lines, such as KLM-1, Capan-2, and MIA PaCa-2, but did not react with PANC-1 in flow cytometry analysis. Western blot analysis also revealed a moderate signal for KLM-1 and a weak signal for MIA PaCa-2, although H 2 Mab-119 reacted strongly with LN229/HER2 cells. Finally, immunohistochemical analyses with H 2 Mab-119 revealed sensitive and specific reactions against breast and colon cancers but did not react with pancreatic cancers, indicating that H 2 Mab-119 is useful for detecting HER2 overexpression in pancreatic cancers using flow cytometry and Western blot analyses.

Frequency of maternal mortality and morbidity in pregnancy-induced hypertension

International Nuclear Information System (INIS)

Riaz, S.; Jabeen, A.

2011-01-01

Background: Pregnancy-induced hypertension (PIH) is defines as hypertension in pregnancy, and is sustained blood pressure >140 mm Hg systolic or 90 mm Hg diastolic. Objective of this study was to see the maternal outcome in terms of morbidity and mortality in PIH. Methods: This descriptive study was conducted in Obstetrics and Gynaecology Unit of Fauji Foundation Hospital, Rawalpindi from January to December 2010. Both booked and un-booked cases were selected after fulfilling inclusion criteria. A detailed history and clinical examination was recorded and relevant investigations were performed. Patients were monitored for rise in blood pressure, development of complications related to hypertensions in pregnancy as well as maternal and perinatal outcome. Results: During this period, 100 patients were admitted with pregnancy-induced hypertension. Majority were un-booked. Primigravida were 60 (60%), and were in age group 21-30 year, remaining were above 30 year. Four patients had placental abruption, 2 pulmonary oedema, 5 HELLP syndrome, 2 severe renal impairment, 20 elevated liver enzyme, 23 uncontrolled blood pressure, 20 server preeclampsia, 10 thrombocytopenia, 3 eclampsia, 10 had impaired coagulation profile, and 1 had maternal death. Conclusion: Pregnancy induced hypertension is a major cause of maternal mortality and morbidity. In Pakistan, its incidence and related mortality are high due to lack of adequate antenatal care. (author)

Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality

Science.gov (United States)

Buchanan, Gordon F; Murray, Nicholas M; Hajek, Michael A; Richerson, George B

2014-01-01

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of SUDEP, and serotonin (5-HT) system dysfunction may be involved. Here we examined the effect of 5-HT neurone elimination or 5-HT reduction on seizure risk and seizure-induced mortality. Adult Lmx1bf/f/p mice, which lack >99% of 5-HT neurones in the CNS, and littermate controls (Lmx1bf/f) were subjected to acute seizure induction by maximal electroshock (MES) or pilocarpine, variably including electroencephalography, electrocardiography, plethysmography, mechanical ventilation or pharmacological therapy. Lmx1bf/f/p mice had a lower seizure threshold and increased seizure-induced mortality. Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by mechanical ventilation during the seizure or 5-HT2A receptor agonist pretreatment. The selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1bf/f but not of Lmx1bf/f/p mice. In C57BL/6N mice, reduction of 5-HT synthesis with para-chlorophenylalanine increased MES-induced seizure severity but not mortality. We conclude that 5-HT neurones raise seizure threshold and decrease seizure-related mortality. Death ensued from respiratory failure, followed by terminal asystole. Given that SUDEP often occurs in association with generalised seizures, some mechanisms causing death in our model might be shared with those leading to SUDEP. This model may help determine the relationship between seizures, 5-HT system dysfunction, breathing and death, which may lead to novel ways to prevent SUDEP. PMID:25107926

Physico-chemical Stability of MabThera Drug-product Solution for Subcutaneous Injection under in-use Conditions with Different Administration Materials.

Science.gov (United States)

Mueller, Claudia; Dietel, Elke; Heynen, Severin R; Nalenz, Heiko; Goldbach, Pierre; Mahler, Hanns-Christian; Schmidt, Johannes; Grauschopf, Ulla; Schoenhamnmer, Karin

2015-01-01

MabThera is an essential component of the standard-of-care regimens in the treatment of non-Hodgkin lymphoma and Chronic Lymphatic Leukemia. MabThera for subcutaneous injection is a novel line extension that has been approved by the European Medicines Agency for the treatment of patients with follicular lymphoma and diffuse large B-cell lymphoma. This study aimed to evaluate in-use stability data of MabThera subcutaneous drug-product solution in single-use syringes for subcutaneous administration according to the European Medicines Agency guideline. The drug-product solution was exposed to material contact surfaces of five different administration setups commonly used in subcutaneous drug delivery. MabThera subcutaneous was transferred under aseptic conditions into polypropylene and polycarbonate syringes and stored for 1, 2, and 4 weeks at 2°C to 8°C followed by 24 hours at 30°C. After storage, subcutaneous administration was simulated and MabThera subcutaneous drug-product solution quality attributes were evaluated by using compendial physico-chemical tests, as well as suitable and validated molecule- and formulation-specific analytical methods. MabThera subcutaneous vials were treated and analyzed in parallel. The physico-chemical results of MabThera subcutaneous in the different setups were comparable to the control for all timepoints. No change in drug-product quality after storage and simulated administration was found compared to the control. However, since single-dose products do not contain preservatives, microbial contamination and growth needs to be avoided and product sterility needs to be ensured. The results showed that MabThera subcutaneous remains compatible and stable, from a physico-chemical perspective, for up to 4 weeks at 2°C to 8°C followed by 24 hours at 30°C with the contact materials tested in this study. In order to avoid and minimize microbial growth, MabThera subcutaneous should be used immediately after removal from the original

Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus.

Science.gov (United States)

Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo; Dutta, Kaushik; Nosanchuk, Joshua D; Fries, Bettina C

2017-08-18

Staphylococcus aureus is a leading infectious cause of life-threatening disease in humans, yet there is currently no vaccine to combat this bacterium. The pathogenesis of S. aureus is mediated by a diverse array of protein toxins including a large family of secreted pyrogenic superantigens. Neutralization of superantigens, including SEB and TSST-1, has proven to be protective in several animal models of toxic shock and sepsis. We demonstrate, for the first time, that a far more prevalent staphylococcal superantigen, SEK, can also induce lethal shock in mice. Additionally, we describe monoclonal antibodies (mAbs) that inhibit SEK-induced mitogenicity as well as protect against SEK-induced lethality, and enhance survival from S. aureus septicemia in murine models. MAb-4G3 (IgG2b), mAb-5G2 (IgG1), and mAb-9H2 (IgG1), all inhibit SEK-induced proliferation and cytokine production of human immune cells. We then demonstrate that passive immunization with a combination of mAb-4G3 and mAb-5G4, 2 mAbs that do not compete for epitope(s) on SEK, significantly enhance survival in a murine model of SEK-induced toxic shock (p = 0.006). In the setting of sepsis, passive immunization with this combination of mAbs also significantly enhances survival in mice after challenge with CA-MRSA strain USA300 (p = 0.03). Furthermore, septic mice that received mAb treatment in conjunction with vancomycin exhibit less morbidity than mice treated with vancomycin alone. Taken together, these findings suggest that the contribution of SEK to S. aureus pathogenesis may be greater than previously appreciated, and that adjunctive therapy with passive immunotherapy against SEs may be beneficial.

Plant Water Content is the Best Predictor of Drought-induced Mortality

Science.gov (United States)

Sapes, G.; Roskilly, B.; Dobrowski, S.; Sala, A.

2017-12-01

Predicting drought-induced forest mortality remains extremely challenging. Recent research has shown that both plant hydraulics and stored non-structural carbohydrates (NSC) interact during drought-induced mortality. The strong interaction between these two variables and the fact that they are both difficult to measure render drought-induced plant mortality extremely difficult to monitor and predict. A variable that is easier to measure and that integrates hydraulic transport and carbohydrate dynamics may, therefore, improve our ability to monitor and predict mortality. Here, we tested whether plant water content is such an integrator variable and, therefore, a better predictor of mortality under drought. We subjected 250 two-year-old ponderosa pine seedlings to drought until they died in a greenhouse experiment. Periodically during the dry down, we measured percent loss of hydraulic conductivity (PLC), NSC concentration (starch and soluble sugars), and tissue volumetric water content (VWC) in roots, stems and leaves. At each measurement time, a separate set of seedlings were re-watered to estimate the probability of mortality at the population level. Linear models were used to explore whether PLC and NSC were linked to VWC and to determine which of the three variables predicted mortality the best. As expected, plants lost hydraulic conductivity in stems and roots during the dry down. Starch concentrations also decreased in all organs as the drought proceeded. In contrast, soluble sugars increased in stems and roots, consistent with the conversion of stored NSCs into osmotically active compounds. Models containing both PLC and NSC concentrations as predictors of VWC were highly significant in all organs and at the whole plant level, indicating that water content is influenced by both PLC and NSCs. PLC, NSC, and VWC explained mortality across organs and at the whole plant level, but VWC was the best predictor (R2 = 0.99). Our results indicate that plant water

Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis β-ketoacyl-acyl carrier protein reductase MabA.

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Küssau, Tanja; Flipo, Marion; Van Wyk, Niel; Viljoen, Albertus; Olieric, Vincent; Kremer, Laurent; Blaise, Mickaël

2018-05-01

In mycobacteria, the ketoacyl-acyl carrier protein (ACP) reductase MabA (designated FabG in other bacteria) catalyzes the NADPH-dependent reduction of β-ketoacyl-ACP substrates to β-hydroxyacyl-ACP products. This first reductive step in the fatty-acid biosynthesis elongation cycle is essential for bacteria, which makes MabA/FabG an interesting drug target. To date, however, very few molecules targeting FabG have been discovered and MabA remains the only enzyme of the mycobacterial type II fatty-acid synthase that lacks specific inhibitors. Despite the existence of several MabA/FabG crystal structures, the structural rearrangement that occurs upon cofactor binding is still not fully understood. Therefore, unlocking this knowledge gap could help in the design of new inhibitors. Here, high-resolution crystal structures of MabA from Mycobacterium smegmatis in its apo, NADP + -bound and NADPH-bound forms are reported. Comparison of these crystal structures reveals the structural reorganization of the lid region covering the active site of the enzyme. The crystal structure of the apo form revealed numerous residues that trigger steric hindrance to the binding of NADPH and substrate. Upon NADPH binding, these residues are pushed away from the active site, allowing the enzyme to adopt an open conformation. The transition from an NADPH-bound to an NADP + -bound form is likely to facilitate release of the product. These results may be useful for subsequent rational drug design and/or for in silico drug-screening approaches targeting MabA/FabG.

Monoclonal antibody proteomics: use of antibody mimotope displaying phages and the relevant synthetic peptides for mAb scouting.

Science.gov (United States)

Hajdú, István; Flachner, Beáta; Bognár, Melinda; Végh, Barbara M; Dobi, Krisztina; Lőrincz, Zsolt; Lázár, József; Cseh, Sándor; Takács, László; Kurucz, István

2014-08-01

Monoclonal antibody proteomics uses nascent libraries or cloned (Plasmascan™, QuantiPlasma™) libraries of mAbs that react with individual epitopes of proteins in the human plasma. At the initial phase of library creation, cognate protein antigen and the epitope interacting with the antibodies are not known. Scouting for monoclonal antibodies (mAbs) with the best binding characteristics is of high importance for mAb based biomarker assay development. However, in the absence of the identity of the cognate antigen the task represents a challenge. We combined phage display, and surface plasmon resonance (Biacore) experiments to test whether specific phages and the respective mimotope peptides obtained from large scale studies are applicable to determine key features of antibodies for scouting. We show here that mAb captured phage-mimotope heterogeneity that is the diversity of the selected peptide sequences, is inversely correlated with an important binding descriptor; the off-rate of the antibodies and that represents clues for driving the selection of useful mAbs for biomarker assay development. Carefully chosen synthetic mimotope peptides are suitable for specificity testing in competitive assays using the target proteome, in our case the human plasma. Copyright © 2014 Elsevier B.V. All rights reserved.

Detection of high CD44 expression in oral cancers using the novel monoclonal antibody, C44Mab-5

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Shinji Yamada

2018-07-01

Full Text Available CD44 is a transmembrane glycoprotein that regulates a variety of genes related to cell-adhesion, migration, proliferation, differentiation, and survival. A large number of alternative splicing isoforms of CD44, containing various combinations of alternative exons, have been reported. CD44 standard (CD44s, which lacks variant exons, is widely expressed on the surface of most tissues and all hematopoietic cells. In contrast, CD44 variant isoforms show tissue-specific expression patterns and have been extensively studied as both prognostic markers and therapeutic targets in cancer and other diseases. In this study, we immunized mice with CHO-K1 cell lines overexpressing CD44v3-10 to obtain novel anti-CD44 mAbs. One of the clones, C44Mab-5 (IgG1, kappa, recognized both CD44s and CD44v3-10. C44Mab-5 also reacted with oral cancer cells such as Ca9-22, HO-1-u-1, SAS, HSC-2, HSC-3, and HSC-4 using flow cytometry. Moreover, immunohistochemical analysis revealed that C44Mab-5 detected 166/182 (91.2% of oral cancers. These results suggest that the C44Mab-5 antibody may be useful for investigating the expression and function of CD44 in various cancers.

Detection of high CD44 expression in oral cancers using the novel monoclonal antibody, C44Mab-5.

Science.gov (United States)

Yamada, Shinji; Itai, Shunsuke; Nakamura, Takuro; Yanaka, Miyuki; Kaneko, Mika K; Kato, Yukinari

2018-07-01

CD44 is a transmembrane glycoprotein that regulates a variety of genes related to cell-adhesion, migration, proliferation, differentiation, and survival. A large number of alternative splicing isoforms of CD44, containing various combinations of alternative exons, have been reported. CD44 standard (CD44s), which lacks variant exons, is widely expressed on the surface of most tissues and all hematopoietic cells. In contrast, CD44 variant isoforms show tissue-specific expression patterns and have been extensively studied as both prognostic markers and therapeutic targets in cancer and other diseases. In this study, we immunized mice with CHO-K1 cell lines overexpressing CD44v3-10 to obtain novel anti-CD44 mAbs. One of the clones, C 44 Mab-5 (IgG 1 , kappa), recognized both CD44s and CD44v3-10. C 44 Mab-5 also reacted with oral cancer cells such as Ca9-22, HO-1-u-1, SAS, HSC-2, HSC-3, and HSC-4 using flow cytometry. Moreover, immunohistochemical analysis revealed that C 44 Mab-5 detected 166/182 (91.2%) of oral cancers. These results suggest that the C 44 Mab-5 antibody may be useful for investigating the expression and function of CD44 in various cancers.

TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging.

Directory of Open Access Journals (Sweden)

Shijing Luo

2009-12-01

Full Text Available Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15-20 day adulthood. All of the known mutations and treatments that extend C. elegans' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-beta signaling pathways. We recently found that the TGF-beta Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-beta Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-beta Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways.

Approaches to modeling landscape-scale drought-induced forest mortality

Science.gov (United States)

Gustafson, Eric J.; Shinneman, Douglas

2015-01-01

Drought stress is an important cause of tree mortality in forests, and drought-induced disturbance events are projected to become more common in the future due to climate change. Landscape Disturbance and Succession Models (LDSM) are becoming widely used to project climate change impacts on forests, including potential interactions with natural and anthropogenic disturbances, and to explore the efficacy of alternative management actions to mitigate negative consequences of global changes on forests and ecosystem services. Recent studies incorporating drought-mortality effects into LDSMs have projected significant potential changes in forest composition and carbon storage, largely due to differential impacts of drought on tree species and interactions with other disturbance agents. In this chapter, we review how drought affects forest ecosystems and the different ways drought effects have been modeled (both spatially and aspatially) in the past. Building on those efforts, we describe several approaches to modeling drought effects in LDSMs, discuss advantages and shortcomings of each, and include two case studies for illustration. The first approach features the use of empirically derived relationships between measures of drought and the loss of tree biomass to drought-induced mortality. The second uses deterministic rules of species mortality for given drought events to project changes in species composition and forest distribution. A third approach is more mechanistic, simulating growth reductions and death caused by water stress. Because modeling of drought effects in LDSMs is still in its infancy, and because drought is expected to play an increasingly important role in forest health, further development of modeling drought-forest dynamics is urgently needed.

Structures and Stability of Metal Amidoboranes (MAB): Density Functional Calculations

International Nuclear Information System (INIS)

Li Cailin; Wu Chaoling; Chen Yungui; Zhou Jingjing; Zheng Xin; Pang Lijuan; Deng Gang

2010-01-01

Molecule geometry structures, frequencies, and energetic stabilities of ammonia borane (AB, NH 3 BH 3 ) and metal amidoboranes (MAB, MNH 2 BH 3 ), formed by substituting H atom in AB with one of main group metal atoms, have been investigated by density-functional theory and optimized at the B3LYP levels with 6-311G++ (3df, 3pd) basic set. Their structural parameters and infrared spectrum characteristic peaks have been predicted, which should be the criterion of a successfully synthesized material. Several parameters such as binding energies, vibrational frequencies, and the energy gaps between the HOMO and the LUMO have been adopted to characterize and evaluate their structure stabilities. It is also found that the binding energies and HOMO-LUMO energy gaps of the MAB obviously change with the substitution of the atoms. MgAB has the lowest binding energy and is easier to decompose than any other substitutional structures under same conditions, while CaAB has the highest chemical activity. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

A biological approach to the interspecies prediction of radiation-induced mortality risk

International Nuclear Information System (INIS)

Carnes, B.A.; Grahn, D.; Olshansky, S.J.

1997-01-01

Evolutionary explanations for why sexually reproducing organisms grow old suggest that the forces of natural selection affect the ages when diseases occur that are subject to a genetic influence (referred to here as intrinsic diseases). When extended to the population level for a species, this logic leads to the general prediction that age-specific death rates from intrinsic causes should begin to rise as the force of selection wanes once the characteristic age of sexual maturity is attained. Results consistent with these predictions have been found for laboratory mice, beagles, and humans where, after adjusting for differences in life span, it was demonstrated that these species share a common age pattern of mortality for intrinsic causes of death. In quantitative models used to predict radiation-induced mortality, risks are often expressed as multiples of those observed in a control population. A control population, however, is an aging population. As such, mortality risks related to exposure must be interpreted relative to the age-specific risk of death associated with aging. Given the previous success in making interspecies predictions of age-related mortality, the purpose of this study was to determine whether radiation-induced mortality observed in one species could also be predicted quantitatively from a model used to describe the mortality consequences of exposure to radiation in a different species. Mortality data for B6CF 1 mice and beagles exposed to 60 Co γ-rays for the duration of life were used for analysis

Immuno-PET of undifferentiated thyroid carcinoma with radioiodine-labelled antibody cMAb U36: application to antibody tumour uptake studies

Energy Technology Data Exchange (ETDEWEB)

Fortin, Marc-Andre [Centre Hospitalier Universitaire de Quebec and Laval University, Laboratory for Biomaterials and Bioengineering, Quebec City (Canada); Uppsala University, Biomedical Radiation Sciences, Department of Oncology, Radiology, and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Salnikov, Alexei V. [Uppsala University, BMC, Department of Medical Biochemistry and Microbiology, Uppsala (Sweden); German Cancer Research Center, Division of Molecular Immunology, Heidelberg (Germany); Nestor, Marika [Uppsala University, Division of Otolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala (Sweden); Heldin, Nils-Erik [Uppsala University, Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala (Sweden); Rubin, Kristofer [Uppsala University, BMC, Department of Medical Biochemistry and Microbiology, Uppsala (Sweden); Lundqvist, Hans [Uppsala University, Biomedical Radiation Sciences, Department of Oncology, Radiology, and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden)

2007-09-15

We tested the suitability of the chimeric monoclonal anti-human CD44 splice version 6 antibody (cMAb U36) for targeting and visualising human anaplastic thyroid carcinoma with PET. We also performed experiments aimed at elucidating the relation between tumour interstitial fluid pressure (TIFP) and the tumour uptake of antibodies. The affinity and specificity of the cMAb U36 for KAT-4 cells were evaluated in vitro, as was the Na{sup +}/I{sup -} symporter (NIS) expression. Biodistribution studies were performed on KAT-4 carcinoma-bearing mice injected with {sup 124}I-cMAb U36 or free iodine. Biodistribution studies were also performed in animals treated with the specific TGF-{beta}1 and -{beta}3 inhibitor Fc:T{beta}RII, which lowers TIFP. Treated and non-treated animals were scanned by microPET. Cultured human undifferentiated/anaplastic thyroid carcinoma KAT-4 cells expressed low levels of NIS and uptake of free iodine was insignificant. The cMAb U36 expressed an affinity (K{sub D}) of 11 {+-} 2 nM. Tumour radioactivity uptake reached maximum values 48 h after injection of {sup 124}I-cMAb U36 ({proportional_to}22%IA/g). KAT-4 carcinomas were readily identified in all {sup 124}I-immuno-PET images. Radioactivity tumour uptake in Fc:T{beta}RII-treated animals was significantly lower at 24 and 48 h after injection, and five times higher thyroid uptake was also noted. We successfully used {sup 124}I-cMAb U36 to visualise CD44v6-expressing human anaplastic thyroid carcinoma. Given the lack of NIS expression in KAT-4, tumour visualisation is not due to free iodine uptake. Lowering the TIFP in KAT-4 carcinomas did not increase the uptake of mAbs into tumour tissue. (orig.)

Pilot Study on Potential Impacts of Fisheries-Induced Changes in Zooplankton Mortality on Marine Biogeochemistry

Science.gov (United States)

Getzlaff, Julia; Oschlies, Andreas

2017-11-01

In this pilot study we link the yield of industrial fisheries to changes in the zooplankton mortality in an idealized way accounting for different target species (planktivorous fish—decreased zooplankton mortality; large predators—increased zooplankton mortality). This indirect approach is used in a global coupled biogeochemistry circulation model to estimate the range of the potential impact of industrial fisheries on marine biogeochemistry. The simulated globally integrated response on phytoplankton and primary production is in line with expectations—a high (low) zooplankton mortality results in a decrease (increase) of zooplankton and an increase (decrease) of phytoplankton. In contrast, the local response of zooplankton and phytoplankton depends on the region under consideration: In nutrient-limited regions, an increase (decrease) in zooplankton mortality leads to a decrease (increase) in both zooplankton and phytoplankton biomass. In contrast, in nutrient-replete regions, such as upwelling regions, we find an opposing response: an increase (decrease) of the zooplankton mortality leads to an increase (decrease) in both zooplankton and phytoplankton biomass. The results are further evaluated by relating the potential fisheries-induced changes in zooplankton mortality to those driven by CO2 emissions in a business-as-usual 21st century emission scenario. In our idealized case, the potential fisheries-induced impact can be of similar size as warming-induced changes in marine biogeochemistry.

Preparation for gluing of Carbon prototype MAB at INEGI, Porto

CERN Multimedia

Miguel Moreira, Porto, INEGI

2001-01-01

MAB's will assure the alignment of the CMS detector. It is equipped with muon cameras, measuring the position of the barrel muon stations and at the same time linking via the link elements, connecting the barrel muon detectors with the Tracker. In addition there is a connection with the endcap. More details can be found on the muon/alignment homepage on the web

Post induced abortion morbidity and mortality in Oleh, Nigeria ...

African Journals Online (AJOL)

The aim of this retrospective study was to determine the maternal morbidity and mortality among 87patient treated at the Central Hospital, Oleh, Delta State, Nigeria, for complications of induced abortion from January 1st 2004 to December 31st 2008. The total number of maternal admissions and deaths, over the period ...

Freeze-dried formulation for direct 99mTc-labeling ior-egf/r3 MAb: additives, biodistribution, and stability

International Nuclear Information System (INIS)

Morales, Alejo A. Morales; Nunez-Gandolff, Gilda; Perez, Niuvis Perez; Veliz, Belkis Chico; Caballero-Torres, Idania; Duconge, Jorge; Fernandez, Eduardo; Crespo, Francisco Zayas; Veloso, Ana; Iznaga-Escobar, Normando

1999-01-01

Monoclonal antibodies (MAbs) have been useful for immunoscintigraphic applications in clinical diagnosis since they were introduced in nuclear medicine practice. The MAb ior egf/r3 developed at the Center of Molecular Immunology (Havana, Cuba) is a murine antibody that recognizes the human epidermal growth factor receptor (EGF-R) and has been used widely in the radioimmunodiagnosis of tumors of epithelial origin. Based on the direct Schwarz method, the present report describes the preparation of a freeze-dried formulation for radiolabeling the MAb ior egf/r3 with 99m Tc for immunoscintigraphic applications. Radiolabeling efficiency, effects on immunoreactivity, biodistribution, pharmacokinetic, and stability of the formulation are reported. The study demonstrated that the freeze-dried formulation can be labeled with 99m Tc at high yield. The resulting 99m Tc-labeled ior egf/r3 MAb can be used to visualize in vivo human tumors of epithelial origin by immunoscintigraphy studies. The kit does not need any other addition or purification at the time of tagging other than the requisite amount of pertechnetate (40-50 mCi). Because the contents of the kit are lyophilized, no special storage or transportation is required

Are Scots pine forest edges particularly prone to drought-induced mortality?

Science.gov (United States)

Buras, Allan; Schunk, Christian; Zeiträg, Claudia; Herrmann, Corinna; Kaiser, Laura; Lemme, Hannes; Straub, Christoph; Taeger, Steffen; Gößwein, Sebastian; Klemmt, Hans-Joachim; Menzel, Annette

2018-02-01

Climate change is expected to exacerbate the frequency of drought-induced tree mortality world-wide. To better predict the associated change of species composition and forest dynamics on various scales and develop adequate adaptation strategies, more information on the mechanisms driving the often observed patchiness of tree die-back is needed. Although forest-edge effects may play an important role within the given context, only few corresponding studies exist. Here, we investigate the regional die-back of Scots pine in Franconia, Germany, after a hot and dry summer in 2015, thereby emphasizing possible differences in mortality between forest edge and interior. By means of dendroecological investigations and close-range remote sensing, we assess long-term growth performance and current tree vitality along five different forest-edge distance gradients. Our results clearly indicate a differing growth performance between edge and interior trees, associated with a higher vulnerability to drought, increased mortality rates, and lower tree vitality at the forest edge. Prior long-lasting growth decline of dead trees compared to live trees suggests depletion of carbon reserves in course of a long-term drought persisting since the 1990s to be the cause of regional Scots pine die-back. These findings highlight the forest edge as a potential focal point of forest management adaptation strategies in the context of drought-induced mortality.

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Science.gov (United States)

Elvington, Michelle; Huang, Yuxiang; Morgan, B. Paul; Qiao, Fei; van Rooijen, Nico; Atkinson, Carl

2012-01-01

Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. PMID:22442351

Aree Protette del Po e della Collina Torinese: studi propedeutici alla Candidatura MAB - Man and the Biosphere

Directory of Open Access Journals (Sweden)

Cimnaghi Elisabetta

2014-03-01

Full Text Available Il programma MAB fu lanciato dall’UNESCO negli anni ’70 al fine di migliorare il rapporto tra uomo e ambiente. Negli anni il programma ha portato al riconoscimento di Riserve della Biosfera che gli Stati Membri si impegnano a gestire nella prospettiva della conservazione delle risorse. L’Organismo Gestore dell’Area Protetta, partendo, da un lato, dalla consapevolezza della ricchezza ambientale che caratterizza il suo territorio e, dall’altro, del contesto di sviluppo antropico elevato in cui essa è situata, ha riconosciuto nel programma MAB un’opportunità per incrementare le sue attività di protezione e potenziamento delle risorse. Questo articolo descrive i primi risultati ottenuti negli studi preliminari per la Designazione al MAB, con particolare attenzione sia alle opportunità di implementazione di progetti legati al marchio “Collina Po”, creato dall’Organo di Gestione del Parco, si ain termini di scambio di ‘best practices’ con altre Riserve di Biosfera.

Conservative fluid management prevents age-associated ventilator induced mortality.

Science.gov (United States)

Herbert, Joseph A; Valentine, Michael S; Saravanan, Nivi; Schneck, Matthew B; Pidaparti, Ramana; Fowler, Alpha A; Reynolds, Angela M; Heise, Rebecca L

2016-08-01

Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hospital mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. 2month old and 20month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4h with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. At 4h, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1h in advanced age HVT subjects. In 4h ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in

Freeze-dried formulation for direct {sup 99m}Tc-labeling ior-egf/r3 MAb: additives, biodistribution, and stability

Energy Technology Data Exchange (ETDEWEB)

Morales, Alejo A. Morales; Nunez-Gandolff, Gilda; Perez, Niuvis Perez; Veliz, Belkis Chico; Caballero-Torres, Idania; Duconge, Jorge; Fernandez, Eduardo; Crespo, Francisco Zayas; Veloso, Ana; Iznaga-Escobar, Normando E-mail: normando@ict.sld.cu

1999-08-01

Monoclonal antibodies (MAbs) have been useful for immunoscintigraphic applications in clinical diagnosis since they were introduced in nuclear medicine practice. The MAb ior egf/r3 developed at the Center of Molecular Immunology (Havana, Cuba) is a murine antibody that recognizes the human epidermal growth factor receptor (EGF-R) and has been used widely in the radioimmunodiagnosis of tumors of epithelial origin. Based on the direct Schwarz method, the present report describes the preparation of a freeze-dried formulation for radiolabeling the MAb ior egf/r3 with {sup 99m}Tc for immunoscintigraphic applications. Radiolabeling efficiency, effects on immunoreactivity, biodistribution, pharmacokinetic, and stability of the formulation are reported. The study demonstrated that the freeze-dried formulation can be labeled with {sup 99m}Tc at high yield. The resulting {sup 99m}Tc-labeled ior egf/r3 MAb can be used to visualize in vivo human tumors of epithelial origin by immunoscintigraphy studies. The kit does not need any other addition or purification at the time of tagging other than the requisite amount of pertechnetate (40-50 mCi). Because the contents of the kit are lyophilized, no special storage or transportation is required.

Radiation-Induced Breast Cancer Incidence and Mortality From Digital Mammography Screening: A Modeling Study.

Science.gov (United States)

Miglioretti, Diana L; Lange, Jane; van den Broek, Jeroen J; Lee, Christoph I; van Ravesteyn, Nicolien T; Ritley, Dominique; Kerlikowske, Karla; Fenton, Joshua J; Melnikow, Joy; de Koning, Harry J; Hubbard, Rebecca A

2016-02-16

Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results. To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women. 2 simulation-modeling approaches. U.S. population. Women aged 40 to 74 years. Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years. Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100,000 women screened. Annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100,000 women) than other women (113 cancer cases and 15 deaths per 100,000 women). Biennial screening starting at age 50 years reduced risk for radiation-induced cancer 5-fold. Life-years lost from radiation-induced breast cancer could not be estimated. Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer. Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute.

Experimental Treatment of Bladder Cancer with Bi-213-anti-EGFR MAb

International Nuclear Information System (INIS)

Seidl, Christof; Pfost, Birgit; Müller, Felix

2013-01-01

Therapy of non-muscle-invasive bladder cancer (carcinoma in situ) comprises transurethral resection of the tumour and subsequent instillation of the chemotherapeutic drug mitomycin C in order to eradicate remaining tumour cells. Yet 15 – 40% of treated patients relapse within 5 years. Therefore, new therapeutic strategies to combat tumour recurrence are needed. Alpha-particle emitting radionuclides efficiently kill single tumour cells or small tumour cell clusters. Because the epidermal growth factor receptor (EGFR) is overexpressed on bladder cancer cells, conjugates composed of the alpha-emitter Bi-213 and the anti-EGFR antibody matuzumab should provide a powerful drug to eliminate disseminated bladder cancer cells. Therefore, the aims of our study were (i) to analyse the cytotoxic effects of Bi-213-anti-EGFR radioimmunoconjugates at the cellular level, (ii) to evaluate therapeutic efficacy of intravesically applied Bi-213- anti-EGFR-Mab in a nude mouse model with intravesical human bladder cancer xenografts, (iii) to compare Bi- 213-anti-EGFR-Mab efficacy with chemotherapy using mitomycin C and (iv) to demonstrate that radioimmunotherapy is not toxic to cells of the bladder wall and of the kidneys

Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing activity

Directory of Open Access Journals (Sweden)

Li H

2015-07-01

Full Text Available Hua-Fei Li,1–3,* Cong Wu,4,* Ting Chen,5,* Ge Zhang,1 He Zhao,1 Chang-Hong Ke,1 Zheng Xu21International Joint Cancer Institute, Translation Medicine Institute, 2Planning Division, Scientific Research Department, 3Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, 4Department of Laboratory Diagnosis, Changhai Hospital, 5Department of Cardiology, Changhai Hospital, the Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: The CD20-directed monoclonal antibody rituximab (RTX established a new era in the treatment of non-Hodgkin lymphoma (NHL; however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD, they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer–RTX–tositumomab [PPRT nanocomb] was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced “off-rate” to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, “cross-cell link”-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With

Technical Note: PLASTIMATCH MABS, an open source tool for automatic image segmentation

International Nuclear Information System (INIS)

Zaffino, Paolo; Spadea, Maria Francesca; Raudaschl, Patrik; Fritscher, Karl; Sharp, Gregory C.

2016-01-01

Purpose: Multiatlas based segmentation is largely used in many clinical and research applications. Due to its good performances, it has recently been included in some commercial platforms for radiotherapy planning and surgery guidance. Anyway, to date, a software with no restrictions about the anatomical district and image modality is still missing. In this paper we introduce PLASTIMATCH MABS, an open source software that can be used with any image modality for automatic segmentation. Methods: PLASTIMATCH MABS workflow consists of two main parts: (1) an offline phase, where optimal registration and voting parameters are tuned and (2) an online phase, where a new patient is labeled from scratch by using the same parameters as identified in the former phase. Several registration strategies, as well as different voting criteria can be selected. A flexible atlas selection scheme is also available. To prove the effectiveness of the proposed software across anatomical districts and image modalities, it was tested on two very different scenarios: head and neck (H&N) CT segmentation for radiotherapy application, and magnetic resonance image brain labeling for neuroscience investigation. Results: For the neurological study, minimum dice was equal to 0.76 (investigated structures: left and right caudate, putamen, thalamus, and hippocampus). For head and neck case, minimum dice was 0.42 for the most challenging structures (optic nerves and submandibular glands) and 0.62 for the other ones (mandible, brainstem, and parotid glands). Time required to obtain the labels was compatible with a real clinical workflow (35 and 120 min). Conclusions: The proposed software fills a gap in the multiatlas based segmentation field, since all currently available tools (both for commercial and for research purposes) are restricted to a well specified application. Furthermore, it can be adopted as a platform for exploring MABS parameters and as a reference implementation for comparing against

Technical Note: PLASTIMATCH MABS, an open source tool for automatic image segmentation

Energy Technology Data Exchange (ETDEWEB)

Zaffino, Paolo; Spadea, Maria Francesca [Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro 88100 (Italy); Raudaschl, Patrik; Fritscher, Karl [Institute for Biomedical Image Analysis, Private University of Health Sciences, Medical Informatics and Technology, Hall in Tirol 6060 (Austria); Sharp, Gregory C. [Department for Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114 (United States)

2016-09-15

Purpose: Multiatlas based segmentation is largely used in many clinical and research applications. Due to its good performances, it has recently been included in some commercial platforms for radiotherapy planning and surgery guidance. Anyway, to date, a software with no restrictions about the anatomical district and image modality is still missing. In this paper we introduce PLASTIMATCH MABS, an open source software that can be used with any image modality for automatic segmentation. Methods: PLASTIMATCH MABS workflow consists of two main parts: (1) an offline phase, where optimal registration and voting parameters are tuned and (2) an online phase, where a new patient is labeled from scratch by using the same parameters as identified in the former phase. Several registration strategies, as well as different voting criteria can be selected. A flexible atlas selection scheme is also available. To prove the effectiveness of the proposed software across anatomical districts and image modalities, it was tested on two very different scenarios: head and neck (H&N) CT segmentation for radiotherapy application, and magnetic resonance image brain labeling for neuroscience investigation. Results: For the neurological study, minimum dice was equal to 0.76 (investigated structures: left and right caudate, putamen, thalamus, and hippocampus). For head and neck case, minimum dice was 0.42 for the most challenging structures (optic nerves and submandibular glands) and 0.62 for the other ones (mandible, brainstem, and parotid glands). Time required to obtain the labels was compatible with a real clinical workflow (35 and 120 min). Conclusions: The proposed software fills a gap in the multiatlas based segmentation field, since all currently available tools (both for commercial and for research purposes) are restricted to a well specified application. Furthermore, it can be adopted as a platform for exploring MABS parameters and as a reference implementation for comparing against

Relationship of Climatic and Forest Factors to Drought- and Heat-Induced Tree Mortality.

Directory of Open Access Journals (Sweden)

Qingyin Zhang

Full Text Available Tree mortality due to warming and drought is a critical aspect of forest ecosystem in responding to climate change. Spatial patterns of tree mortality induced by drought and its influencing factors, however, have yet to be documented at the global scale. We collected observations from 248 sites globally where trees have died due to drought and then assessed the effects of climatic and forest factors on the rate of tree mortality. The global mean annual mortality rate was 5.5%. The rate of tree mortality was significantly and negatively correlated with mean annual precipitation (P 2000 mm and was severe in regions with mean annual precipitation <1000 mm. Mortality rates varied amongst species. The global annual rate of mortality was much higher for gymnosperms (7.1% than angiosperms (4.8% but did not differ significantly between evergreen (6.2% and deciduous (6.1% species. Stand age and wood density affected the mortality rate. Saplings (4.6% had a higher mortality rate than mature trees (3.2%, and mortality rates significantly decreased with increasing wood density for all species (P < 0.01. We therefore concluded that the tree mortality around the globe varied with climatic and forest factors. The differences between tree species, wood density, stand density, and stand age should be considered when evaluating tree mortality at a large spatial scale during future climatic extremes.

Preparation of monoclonal antibodies against radiation-induced protein

International Nuclear Information System (INIS)

Nozawa, R.; Tanaka, A.; Watanabe, H.; Kitayama, S.

1992-01-01

We obtained the 6 monoclonal antibodies against gamma-induced proteins of Deinococcus radiodurans, and these antibodies were designated as Mab-3F, 4B, 4D, 4F, 4G and 12G. Using these antibodies, we investigated the relations between gamma-induced proteins and other stress protein in strain R1, and the induction of proteins were compared among strain R1, resistant mutant (rec1) and radiosensitive mutant (rec30). We found new 6 proteins recognized by these monoclonal antibodies which were induced after gamma-irradiation especially in strain R1 and rec 1, but not induced in strain rec30. We suppose that these proteins participate in repair of DNA damages including double strand breaks caused by gamma-irradiation. One of them was around 46kDa protein band recognized by Mab-12G, and this protein was so induced in a large quantity after irradiation that the protein could detect by gold staining. In addition to this observation, we found some proteins which were induced in R1 and rec 1 by gamma-irradiation and other stress, but not in strain rec30, such as 31kDa protein band recognized by Mab-3F, 4B and 4G, and other 11 proteins which were especially induced in irradiated strain R1. The latter proteins might be reinforcement factor to radioresistance such as GroE and DnaK, or participant in repair of damage by gamma-irradiation in strain R1. (author)

Different signaling pathways induced by alpha-CD3 monoclonal antibody versus alloantigen on the basis of differential ornithine sensitivity.

Science.gov (United States)

Mehrotra nee Tandon, P; Lind, D S; Bear, H D; Susskind, B M

1992-08-01

Previously we reported that 10 mM ornithine (Orn) selectively inhibits the development of CD8+ CTL in MLC. Herein we show that induction by alpha-CD3 mAb of CD8+ killer cells which manifest antibody-redirected cytotoxicity (ARC) of FcR+ targets is not Orn sensitive. Orn resistance was independent of activation kinetics or alpha-CD3 mAb concentration. alpha-CD3 mAb added to the cytotoxicity assay did not reveal a cytolytic potential in CTL from an Orn-treated MLC when the target cells bore both the inducing alloantigen and FcR. Addition of alpha-CD3 mAb to MLC failed to overcome Orn inhibition of CTL and yet induced ARC activity in the same culture. Expression of mRNA for pore-forming proteins (PFP) and granzyme B was inhibited by Orn in CTL but not in ARC killer cells. Our results demonstrate differences in the T cell activation process stimulated by alloantigen or alpha-CD3 mAb.

Monitoring and Predicting Traffic Induced Vertebrate Mortality Near Wetlands

OpenAIRE

DeWoody, J. Andrew; Nogle, Jamie M.; Hoover, Melissa; Dunning, Barny

2010-01-01

Animal-vehicle collisions are undesirable to the general public, to drivers, to insurance providers, to biologists, and presumably to the animals themselves. However, traffic-induced mortality (―roadkill‖) is difficult to mitigate in large part because scientists lack the empirical data required to understand the patterns and processes associated with roadkill. Roadkill is not randomly distributed in space or in time, but what are the primary determinants of roadkill? And do they differ acros...

Nonstructural leaf carbohydrate dynamics of Pinus edulis during drought-induced tree mortality reveal role for carbon metabolism in mortality mechanism.

Science.gov (United States)

Adams, Henry D; Germino, Matthew J; Breshears, David D; Barron-Gafford, Greg A; Guardiola-Claramonte, Maite; Zou, Chris B; Huxman, Travis E

2013-03-01

Vegetation change is expected with global climate change, potentially altering ecosystem function and climate feedbacks. However, causes of plant mortality, which are central to vegetation change, are understudied, and physiological mechanisms remain unclear, particularly the roles of carbon metabolism and xylem function. We report analysis of foliar nonstructural carbohydrates (NSCs) and associated physiology from a previous experiment where earlier drought-induced mortality of Pinus edulis at elevated temperatures was associated with greater cumulative respiration. Here, we predicted faster NSC decline for warmed trees than for ambient-temperature trees. Foliar NSC in droughted trees declined by 30% through mortality and was lower than in watered controls. NSC decline resulted primarily from decreased sugar concentrations. Starch initially declined, and then increased above pre-drought concentrations before mortality. Although temperature did not affect NSC and sugar, starch concentrations ceased declining and increased earlier with higher temperatures. Reduced foliar NSC during lethal drought indicates a carbon metabolism role in mortality mechanism. Although carbohydrates were not completely exhausted at mortality, temperature differences in starch accumulation timing suggest that carbon metabolism changes are associated with time to death. Drought mortality appears to be related to temperature-dependent carbon dynamics concurrent with increasing hydraulic stress in P. edulis and potentially other similar species. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Susceptibility of different subsets of immature thymocytes to apoptosis induced by anti-TCRmAb

International Nuclear Information System (INIS)

Li Hongmei; Zhong Renqian; Yu Jiaping; Kong Xiantao; Chen Weifeng

2003-01-01

To analysis the susceptibility of different subsets of immature mice thymocytes to apoptosis induced by anti-TCRmAbs in vitro apoptosis was induced in unfractionated mice thymocytes by anti-TCRmAb. In Vivo apoptosis was induced in BALB/c mice by anti-TCR mAb, and thymocytes were examined by FACS. Results showed that CD4 + CD8 + DP thymocytes and CD4 - CD8 + CD3 - thymocytes were equally sensitive to apoptosis after treatment with the anti-TCR mAb. In sharp contrast, the early migrants or precursor containing thymocytes which are CD4 - CD8 - CD3 - TN have a lower spontaneous apoptosis rate and were relatively resistant to the anti-TCR mAb. The findings showed a breakpoint in thymocyte sensitivity to apoptosis which occurs after the onset of CD4 - CD8 + CD3 expression, suggesting that susceptibility of thymocytes to apoptosis is developmentally regulated

Long-term divergent tidal flat benthic community recovery following hypoxia-induced mortality

NARCIS (Netherlands)

Colen, van C.; Montserrat, F.; Vincx, M.; Herman, P.M.J.; Ysebaert, T.; Degraer, S.

2010-01-01

Macrobenthos recovery after hypoxia-induced mass mortality was assessed in an estuarine tidal mudflat during 3 years. During the first 2 years, a Pearson-Rosenberg type of community recovery took place along with the improving bottom water oxygen conditions. After 3 months, spionid polychaetes

Detecting mortality induced structural and functional changes in a pinon-juniper woodland using Landsat and RapidEye time series

Science.gov (United States)

Dan J. Krofcheck; Jan U. H. Eitel; Lee A. Vierling; Urs Schulthess; Timothy M. Hilton; Eva Dettweiler-Robinson; Rosemary Pendleton; Marcy E. Litvak

2014-01-01

Pinon-juniper (PJ) woodlands have recently undergone dramatic drought-induced mortality, triggering broad scale structural changes in this extensive Southwestern US biome. Given that climate projections for the region suggest widespread conifer mortality is likely to continue into the next century, it is critical to better understand how this climate-induced change in...

Research frontiers for improving our understanding of drought‐induced tree and forest mortality

Science.gov (United States)

Hartmann, Henrik; Moura, Catarina; Anderegg, William R. L.; Ruehr, Nadine; Salmon, Yann; Allen, Craig D.; Arndt, Stefan K.; Breshears, David D.; Davi, Hendrik; Galbraith, David; Ruthrof, Katinka X.; Wunder, Jan; Adams, Henry D.; Bloemen, Jasper; Cailleret, Maxime; Cobb, Richard; Gessler, Arthur; Grams, Thorsten E. E.; Jansen, Steven; Kautz, Markus; Lloret, Francisco; O’Brien, Michael

2018-01-01

Accumulating evidence highlights increased mortality risks for trees during severe drought, particularly under warmer temperatures and increasing vapour pressure deficit (VPD). Resulting forest die‐off events have severe consequences for ecosystem services, biophysical and biogeochemical land–atmosphere processes. Despite advances in monitoring, modelling and experimental studies of the causes and consequences of tree death from individual tree to ecosystem and global scale, a general mechanistic understanding and realistic predictions of drought mortality under future climate conditions are still lacking. We update a global tree mortality map and present a roadmap to a more holistic understanding of forest mortality across scales. We highlight priority research frontiers that promote: (1) new avenues for research on key tree ecophysiological responses to drought; (2) scaling from the tree/plot level to the ecosystem and region; (3) improvements of mortality risk predictions based on both empirical and mechanistic insights; and (4) a global monitoring network of forest mortality. In light of recent and anticipated large forest die‐off events such a research agenda is timely and needed to achieve scientific understanding for realistic predictions of drought‐induced tree mortality. The implementation of a sustainable network will require support by stakeholders and political authorities at the international level.

A Bacterial Quorum-Sensing Precursor Induces Mortality in the Marine Coccolithophore, Emiliania huxleyi.

Science.gov (United States)

Harvey, Elizabeth L; Deering, Robert W; Rowley, David C; El Gamal, Abrahim; Schorn, Michelle; Moore, Bradley S; Johnson, Matthew D; Mincer, Tracy J; Whalen, Kristen E

2016-01-01

Interactions between phytoplankton and bacteria play a central role in mediating biogeochemical cycling and food web structure in the ocean. However, deciphering the chemical drivers of these interspecies interactions remains challenging. Here, we report the isolation of 2-heptyl-4-quinolone (HHQ), released by Pseudoalteromonas piscicida, a marine gamma-proteobacteria previously reported to induce phytoplankton mortality through a hitherto unknown algicidal mechanism. HHQ functions as both an antibiotic and a bacterial signaling molecule in cell-cell communication in clinical infection models. Co-culture of the bloom-forming coccolithophore, Emiliania huxleyi with both live P. piscicida and cell-free filtrates caused a significant decrease in algal growth. Investigations of the P. piscicida exometabolome revealed HHQ, at nanomolar concentrations, induced mortality in three strains of E. huxleyi. Mortality of E. huxleyi in response to HHQ occurred slowly, implying static growth rather than a singular loss event (e.g., rapid cell lysis). In contrast, the marine chlorophyte, Dunaliella tertiolecta and diatom, Phaeodactylum tricornutum were unaffected by HHQ exposures. These results suggest that HHQ mediates the type of inter-domain interactions that cause shifts in phytoplankton population dynamics. These chemically mediated interactions, and other like it, ultimately influence large-scale oceanographic processes.

Growth suppression of colorectal cancer by plant-derived multiple mAb CO17-1A × BR55 via inhibition of ERK1/2 phosphorylation.

Science.gov (United States)

Kwak, Dong Hoon; Moussavou, Ghislain; Lee, Ju Hyoung; Heo, Sung Youn; Ko, Kisung; Hwang, Kyung-A; Jekal, Seung-Joo; Choo, Young-Kug

2014-11-14

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs (anti-epithelial cellular adhesion molecule (EpCAM), plant-derived monoclonal antibody (mAb(P)) CO17-1A and mAb(P) CO17-1A × BR55) with RAW264.7 cells significantly inhibited the cell growth in SW620 cancer cells. In particular, multi mAb(P) CO17-1A × BR55 significantly and efficiently suppressed the growth of SW620 cancer cells compared to another mAbs. Apoptotic death-positive cells were significantly increased in the mAb(P) CO17-1A × BR55-treated. The mAb(P) CO17-1A × BR55 treatment significantly decreased the expression of B-Cell lymphoma-2 (BCl-2), but the expression of Bcl-2-associated X protein (Bax), and cleaved caspase-3 were markedly increased. In vivo, the mAb(P) CO17-1A × BR55 significantly and efficiently inhibited the growth of colon tumors compared to another mAbs. The apoptotic cell death and inhibition of pro-apoptotic proteins expression were highest by treatment with mAb(P) CO17-1A × BR55. In addition, the mAb(P) CO17-1A × BR55 significantly inhibited the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in cancer cells and tumors. Therefore, this study results suggest that multiple mAb(P) CO17-1A × BR55 has a significant effect on apoptosis-mediated anticancer by suppression of ERK1/2 phosphorylation in colon cancer compared to another mAbs. In light of these results, further clinical investigation should be conducted on mAb(P) CO17-1A × BR55 to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer.

Mortality of induced abortion, other outpatient surgical procedures and common activities in the United States.

Science.gov (United States)

Raymond, Elizabeth G; Grossman, Daniel; Weaver, Mark A; Toti, Stephanie; Winikoff, Beverly

2014-11-01

The recent surge of new legislation regulating induced abortion in the United States is ostensibly motivated by the desire to protect women's health. To provide context for interpreting the risk of abortion, we compared abortion-related mortality to mortality associated with other outpatient surgical procedures and selected nonmedical activities. We calculated the abortion-related mortality rate during 2000-2009 using national data. We searched PubMed and other sources for contemporaneous data on mortality associated with other outpatient procedures commonly performed on healthy young women, marathon running, bicycling and driving. The abortion-related mortality rate in 2000-2009 in the United States was 0.7 per 100,000 abortions. Studies in approximately the same years found mortality rates of 0.8-1.7 deaths per 100,000 plastic surgery procedures, 0-1.7deaths per 100,000 dental procedures, 0.6-1.2 deaths per 100,000 marathons run and at least 4 deaths among 100,000 cyclists in a large annual bicycling event. The traffic fatality rate per 758 vehicle miles traveled by passenger cars in the United States in 2007-2011 was about equal to the abortion-related mortality rate. The safety of induced abortion as practiced in the United States for the past decade met or exceeded expectations for outpatient surgical procedures and compared favorably to that of two common nonmedical voluntary activities. The new legislation restricting abortion is unnecessary; indeed, by reducing the geographic distribution of abortion providers and requiring women to travel farther for the procedure, these laws are potentially detrimental to women's health. Copyright © 2014 Elsevier Inc. All rights reserved.

γ-irradiation-induced mortality: protective effect of protease inhibitors in chickens and mice

International Nuclear Information System (INIS)

Palladino, M.A.; Galton, J.E.; Troll, W.; Thorbecke, G.J.

1982-01-01

Chickens (Gallus domesticus) were protected from the acute γ-irradiation-induced mortality (within 24 hours) by the proteolytic enzyme inhibitors, soy-bean trypsin inhibitor (SBTI), lima bean inhibitor (LBTI), antipain, α-N-benzoyl-L-arginine ethyl ester HCl (BAEE), trasylol, and leupeptin. Several other enzyme inhibitors, p-tosyl-L-arginine methyl ester HCl (TAME), α-tosyl-lysyl-chloromethyl ketone HCl (TLCK) and epsilon-amino caproic acid (EACA), did not protect. EACA even increased the mortality caused by γ-irradiation. The pattern of protective enzyme inhibitors suggests involvement of a kallikrein-like enzyme. SBTI and antipain also protected against low range lethal γ-irradiation exposures, 690 R in BALB/c and 880 R in SJL/J mice. It is suggested that enhanced vascular permeability, which in chickens is known to be the cause of the irradiation mortality during the first 24 hours, may also contribute to the mortality in mice during the first week after irradiation. (author)

Quantitative risk assessment of salmon louse-induced mortality of seaward-migrating post-smolt Atlantic salmon

Directory of Open Access Journals (Sweden)

Anja Bråthen Kristoffersen

2018-06-01

Full Text Available The Norwegian government recently implemented a new management system to regulate salmon farming in Norway, aiming to promote environmentally sustainable growth in the aquaculture industry. The Norwegian coast has been divided into 13 production zones and the volume of salmonid production in the zones will be regulated based on salmon lice effects on wild salmonids. Here we present a model for assessing salmon louse-induced mortality of seaward-migrating post-smolts of Atlantic salmon. The model quantifies expected salmon lice infestations and louse-induced mortality of migrating post-smolt salmon from 401 salmon rivers draining into Norwegian coastal waters. It is assumed that migrating post-smolts follow the shortest path from river outlets to the high seas, at constant progression rates. During this migration, fish are infested by salmon lice of farm origin according to an empirical infestation model. Furthermore, louse-induced mortality is estimated from the estimated louse infestations. Rivers draining into production zones on the West Coast of Norway were at the highest risk of adverse lice effects. In comparison, rivers draining into northerly production zones, along with the southernmost production zone, were at lower risk. After adjusting for standing stock biomass, estimates of louse-egg output varied by factors of up to 8 between production zones. Correlation between biomass adjusted output of louse infestation and densities of farmed salmon in the production zones suggests that a large-scale density-dependent host-parasite effect is a major driver of louse infestation rates and parasite-induced mortality. The estimates are sensitive to many of the processes in the chain of events in the model. Nevertheless, we argue that the model is suited to assess spatial and temporal risks associated with farm-origin salmon lice. Keywords: Density dependent, Sea lice, Transmission, Farmed salmon, Migration pathway, Migration time

64Cu-DOTA-Anti-CTLA-4 mAb Enabled PET Visualization of CTLA-4 on the T-Cell Infiltrating Tumor Tissues

Science.gov (United States)

Higashikawa, Kei; Yagi, Katsuharu; Watanabe, Keiko; Kamino, Shinichiro; Ueda, Masashi; Hiromura, Makoto; Enomoto, Shuichi

2014-01-01

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) targeted therapy by anti-CTLA-4 monoclonal antibody (mAb) is highly effective in cancer patients. However, it is extremely expensive and potentially produces autoimmune-related adverse effects. Therefore, the development of a method to evaluate CTLA-4 expression prior to CTLA-4-targeted therapy is expected to open doors to evidence-based and cost-efficient medical care and to avoid adverse effects brought about by ineffective therapy. In this study, we aimed to develop a molecular imaging probe for CTLA-4 visualization in tumor. First, we examined CTLA-4 expression in normal colon tissues, cultured CT26 cells, and CT26 tumor tissues from tumor-bearing BALB/c mice and BALB/c nude mice by reverse transcription polymerase chain reaction (RT-PCR) analysis and confirmed whether CTLA-4 is strongly expressed in CT26 tumor tissues. Second, we newly synthesized 64Cu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-anti-mouse CTLA-4 mAb (64Cu-DOTA-anti-CTLA-4 mAb) and evaluated its usefulness in positron emission tomography (PET) and ex-vivo biodistribution analysis in CT26-bearing BALB/c mice. High CTLA-4 expression was confirmed in the CT26 tumor tissues of tumor-bearing BALB/c mice. However, CTLA-4 expression was extremely low in the cultured CT26 cells and the CT26 tumor tissues of tumor-bearing BALB/c nude mice. The results suggested that T cells were responsible for the high CTLA-4 expression. Furthermore, 64Cu-DOTA-anti-CTLA-4 mAb displayed significantly high accumulation in the CT26 tumor, thereby realizing non-invasive CTLA-4 visualization in the tumor. Together, the results indicate that 64Cu-DOTA-anti-CTLA-4 mAb would be useful for the evaluation of CTLA-4 expression in tumor. PMID:25365349

A bacterial quorum-sensing precursor induces mortality in the marine coccolithophore, Emiliania huxleyi

Directory of Open Access Journals (Sweden)

Elizabeth L Harvey

2016-02-01

Full Text Available Interactions between phytoplankton and bacteria play a central role in mediating biogeochemical cycling and food web structure in the ocean. However, deciphering the chemical drivers of these interspecies interactions remains challenging. Here we report the isolation of 2-heptyl-4-quinolone (HHQ, released by Pseudoalteromonas piscicida, a marine gamma-proteobacteria previously reported to induce phytoplankton mortality through a hitherto unknown algicidal mechanism. HHQ functions as both an antibiotic and a bacterial signaling molecule in cell-cell communication in clinical infection models. Co-culture of the bloom-forming coccolithophore, Emiliania huxleyi with both live P. piscicida and cell-free filtrates caused a significant decrease in algal growth. Investigations of the P. piscicida exometabolome revealed HHQ, at nanomolar concentrations, induced mortality in three strains of E. huxleyi. Mortality of E. huxleyi in response to HHQ occurred slowly, implying static growth rather than a singular loss event (e.g. rapid cell lysis. In contrast, the marine chlorophyte, Dunaliella tertiolecta and diatom, Phaeodactylum tricornutum were unaffected by HHQ exposures. These results suggest that HHQ mediates the type of interkingdom interactions that cause shifts in phytoplankton population dynamics. These chemically mediated interactions, and other like it, ultimately influence large-scale oceanographic processes.

Development of monoclonal antibodies (MAbs) to feline interferon (fIFN)-γ as tools to evaluate cellular immune responses to feline infectious peritonitis virus (FIPV).

Science.gov (United States)

Satoh, Ryoichi; Kaku, Ayumi; Satomura, Megumi; Kohori, Michiyo; Noura, Kanako; Furukawa, Tomoko; Kotake, Masako; Takano, Tomomi; Hohdatsu, Tsutomu

2011-06-01

Feline infectious peritonitis virus (FIPV) can cause a lethal disease in cats, feline infectious peritonitis (FIP). The antibody-dependent enhancement (ADE) of FIPV infection has been recognised in experimentally infected cats, and cellular immunity is considered to play an important role in preventing the onset of FIP. To evaluate the importance of cellular immunity for FIPV infection, monoclonal antibodies (MAbs) against feline interferon (fIFN)-γ were first created to establish fIFN-γ detection systems using the MAbs. Six anti-fIFN-γ MAbs were created. Then, the difference in epitope which those MAbs recognise was demonstrated by competitive enzyme-linked immunosorbent assay (ELISA) and IFN-γ neutralisation tests. Detection systems for fIFN-γ (sandwich ELISA, ELISpot assay, and two-colour flow cytometry) were established using anti-fIFN-γ MAbs that recognise different epitopes. In all tests, fIFN-γ production from peripheral blood mononuclear cells (PBMCs) obtained from cats experimentally infected with an FIPV isolate that did not develop the disease was significantly increased by heat-inactivated FIPV stimulation in comparison with medium alone. Especially, CD8(+)fIFN-γ(+) cells, but not CD4(+)fIFN-γ(+) cells, were increased. In contrast, fIFN-γ production from PBMCs isolated from cats that had developed FIP and specific pathogen-free (SPF) cats was not increased by heat-inactivated FIPV stimulation. These results suggest that cellular immunity plays an important role in preventing the development of FIP. Measurement of fIFN-γ production with the anti-fIFN-γ MAbs created in this study appeared to be useful in evaluating cellular immunity in cats. Copyright © 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis.

Science.gov (United States)

Khodoun, Marat V; Kucuk, Zeynep Yesim; Strait, Richard T; Krishnamurthy, Durga; Janek, Kevin; Clay, Corey D; Morris, Suzanne C; Finkelman, Fred D

2013-12-01

Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis. We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis. Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which FcγRI, FcγRIII, and/or FcγRIV had been deleted or blocked. Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG(2a)-mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV were probably crucial for its complete inhibition of IgG(2a)-mediated anaphylaxis. IgG(2a)-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils. IgG-mediated anaphylaxis can be induced by ligation of FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology. Published by Mosby, Inc.

Climate-Induced Mortality of Siberian Pine and Fir in the Lake Baikal Watershed, Siberia

Science.gov (United States)

Kharuk, Viacheslav I.; Im, Sergei T.; Petrova, IIya A.; Golyukov, Alexei S.; Ranson, Kenneth J.; Yagunov, Mikhail N.

2016-01-01

Siberian pine (Pinus sibirica) and fir (Abies sibirica) (so called "dark needle conifers", DNC) showed decreased radial growth increment within the Lake Baikal watershed since the 1980s with increasing mortality recorded since the year 2000. Tree ring width was strongly correlated with vapor pressure deficit, aridity and root zone moisture. Water stress from droughts made trees more susceptible to insect attacks causing mortality in about 10% of DNC stands within the Lake Baikal watershed. Within Siberia DNC mortality increased in the southern part of the DNC range. Biogeographically, tree mortality was located within the DNC - forest-steppes transition. Tree mortality was significantly correlated with drought and soil moisture anomalies. Within the interior of the DNC range mortality occurred within relief features with high water stress risk (i.e., steep convex south facing slopes with shallow well-drained soils). In general, DNC mortality in Siberia was induced by increased aridity and severe drought (inciting factors) in synergy with biotic attacks (contributing factor). In future climate scenarios with predicted increase in aridity DNC could be eliminated from the southern part of its current range and will be replaced by drought-resistant conifers and broadleaf species (e.g., Larix sibirica, Pinus silvestris, and Betula pubescence).

A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses

OpenAIRE

Grenga, Italia; Donahue, Renee N; Lepone, Lauren M; Richards, Jacob; Schlom, Jeffrey

2016-01-01

Monoclonal antibodies (MAbs) that interfere with checkpoint molecules are being investigated for the treatment of infectious diseases and cancer, with the aim of enhancing the function of an impaired immune system. Avelumab (MSB0010718C) is a fully human IgG1 MAb targeting programmed death-ligand 1 (PD-L1), which differs from other checkpoint-blocking antibodies in its ability to mediate antibody-dependent cell-mediated cytotoxicity. These studies were conducted to define whether avelumab cou...

Immunoreactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Epithelial Malignant Tumors from Digestive System

OpenAIRE

Blanco, Rancés; Rengifo, Enrique; Cedeño, Mercedes; Rengifo, Charles E.; Alonso, Daniel F.; Carr, Adriana

2011-01-01

The limited expression of N-Glycolyl GM3 (NeuGcGM3) ganglioside in human normal tissues, as well as its presence in melanoma and breast carcinoma using 14F7 Mab (anti-NeuGcGM3), has been previously reported. In this work we evaluated for the first time the 14F7 Mab immunorecognition in some digestive system tumors. Immunohistochemical assays were made with 14F7, followed by anti-mouse biotinylated antibody and ABC/HRP system in normal and pathological human tissues were made. No immunoreactio...

Tree mortality predicted from drought-induced vascular damage

Science.gov (United States)

Anderegg, William R.L.; Flint, Alan L.; Huang, Cho-ying; Flint, Lorraine E.; Berry, Joseph A.; Davis, Frank W.; Sperry, John S.; Field, Christopher B.

2015-01-01

The projected responses of forest ecosystems to warming and drying associated with twenty-first-century climate change vary widely from resiliency to widespread tree mortality1, 2, 3. Current vegetation models lack the ability to account for mortality of overstorey trees during extreme drought owing to uncertainties in mechanisms and thresholds causing mortality4, 5. Here we assess the causes of tree mortality, using field measurements of branch hydraulic conductivity during ongoing mortality in Populus tremuloides in the southwestern United States and a detailed plant hydraulics model. We identify a lethal plant water stress threshold that corresponds with a loss of vascular transport capacity from air entry into the xylem. We then use this hydraulic-based threshold to simulate forest dieback during historical drought, and compare predictions against three independent mortality data sets. The hydraulic threshold predicted with 75% accuracy regional patterns of tree mortality as found in field plots and mortality maps derived from Landsat imagery. In a high-emissions scenario, climate models project that drought stress will exceed the observed mortality threshold in the southwestern United States by the 2050s. Our approach provides a powerful and tractable way of incorporating tree mortality into vegetation models to resolve uncertainty over the fate of forest ecosystems in a changing climate.

Radioprotective effects of chlorogenic acid against mortality induced by gamma irradiation in mice

International Nuclear Information System (INIS)

Seyed Jalal Hosseinimehr; Amirhossein Ahmadi; Shahram Akhlaghpoor; Tehran University of Medical Sciences, Tehran

2007-01-01

Complete text of publication follows. The radioprotective effects of the naturally occurring compound chlorogenic acid has been investigated against mortality induced by gamma irradiation in mice. Chlorogenic acid administrated at single doses of 100, 200 and 400 mg/kg 1 and 24 h prior to lethal dose of gamma irradiation (8.5 Gy). At 30 days after treatment, the percentage of animal survival in each group was: control, 20%; 100 mg/kg, 20% and 15%; 200 mg/kg, 45% and 15%; 400 mg/kg, 25% and 35% for 1 h and 24 h treatment prior gamma irradiation, respectively. Percentage of survival increased in animal treated with this agent at 200 mg/kg at 1 h statistically compared with irradiated alone group. Other doses of chlorogenic acid have not showed any enhanced survival at 1 and 24 h before irradiation. Chlorogenic acid exhibited concentration-dependent activity on 1, 1-diphenyl 2-picrylhydrazyl free radical to show strong antioxidant activity. It appeared that chlorogenic acid with antioxidant activity reduced mortality induced by gamma irradiation.

Kinetics of platelets in dogs with thrombocytopenia induced by antiglycoprotein IIb/IIIa receptor monoclonal antibody

International Nuclear Information System (INIS)

Hosono, Makoto; Sone, Naoaki; Endo, Keigo; Saga, Tsuneo; Kobayashi, Hisataka; Hosono, Masako N.; Sakahara, Harumi; Yasunaga, Kojiro; Konishi, Junji

1995-01-01

To experimentally assess the kinetics of platelets in thrombocytopenia, we constructed a canine model using 111 In-oxine labeled autologous platelets and an intact antiplatelet monoclonal antibody (MAb) NNKY2-11 (IgG2a). With the infusion of radiolabeled autologous platelets into dogs, the peripheral platelet count and blood radioactivity level were examined, and the radioactivity in the liver, spleen and heart was determined with scintigraphic analysis. Thereafter, i.v. injection of 100 μg/kg of NNKY2-11 had no effect on platelet counts or the biodistribution of radiolabeled platelets. However, 200 and 300 μg/kg of MAb reduced the platelets, and the radioactivity of the liver and spleen augmented clearly after injection of MAb. Platelet radioactivity in serum, which had decreased after MAb infusion, did not recover, even when peripheral platelet counts returned to the normal levels, indicating that these new platelets might be derived from the platelet-storage pool or new thrombocytogenesis. This model of antiplatelet MAb induced thrombocytopenia seems to be useful for analyzing the kinetics of platelets in thrombocytopenia

Tissue Reactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Tumors of Neuroectodermal, Mesodermal, and Epithelial Origin

Science.gov (United States)

Blanco, Rancés; Quintana, Yisel; Blanco, Damián; Cedeño, Mercedes; Rengifo, Charles E.; Frómeta, Milagros; Ríos, Martha; Rengifo, Enrique; Carr, Adriana

2013-01-01

The expression of N-glycolylneuraminic acid forming the structure of gangliosides and/or other glycoconjugates (Hanganutziu-Deicher antigen) in human has been considered as a tumor-associated antigen. Specifically, some reports of 14F7 Mab (a highly specific Mab raised against N-glycolyl GM3 ganglioside) reactivity in human tumors have been recently published. Nevertheless, tumors of epithelial origin have been mostly evaluated. The goal of the present paper was to evaluate the immunohistochemical recognition of 14F7 Mab in different human tumors of neuroectodermal, mesodermal, and epithelial origins using an immunoperoxidase staining method. Samples of fetal, normal, and reactive astrocytosis of the brain were also included in the study. In general, nontumoral tissues, as well as, low-grade brain tumors showed no or a limited immunoreaction with 14F7 Mab. Nevertheless, high-grade astrocytomas (III-IV) and neuroblastomas, as well as, sarcomas and thyroid carcinomas were mostly reactive with 14F7. No reaction was evidenced in medulloblastomas and ependymoblastomas. Our data suggest that the expression of N-glycolyl GM3 ganglioside could be related to the aggressive behavior of malignant cells, without depending on the tumor origin. Our data could also support the possible use of N-glycolyl GM3 as a target for both active and passive immunotherapies of malignancies expressing this molecule. PMID:26317019

Influence of Housing System and Number of Transported Animals on Transport-induced Mortality in Slaughter Pigs

Directory of Open Access Journals (Sweden)

Eva Voslářová

2010-01-01

Full Text Available The study monitored the effect of the housing system and the number of animals transported together on transport-induced mortality of slaughter pigs in the Czech Republic in the period from 2004 to 2008. Concerning the type of housing during the fattening, the lowest mortality rate during the subsequent transport to slaughter houses was detected among pigs fattened on solid floor (0.047% and on deep bedding (0.084%. The highest mortality during transport was detected among pigs fattened on fully or partially slatted floor (0.139%, a significant difference (p p < 0.01 compared to the load sizes of up to 40 animals.

Evaluation of anti-IL-6 monoclonal antibody therapy using murine type II collagen-induced arthritis

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Shealy David

2009-04-01

Full Text Available Abstract Interleukin-6 is a multifunctional cytokine that is critical for T/B-cell differentiation and maturation, immunoglobulin secretion, acute-phase protein production, and macrophage/monocyte functions. Extensive research into the biology of IL-6 has implicated IL-6 in the pathophysiology and pathogenesis of RA. An anti-murine IL-6 mAb that neutralizes mouse IL-6 activities was tested in animal model of collagen-induced arthritis. Prophylactic treatment with anti-IL-6 mAb significantly reduced the incidence and severity of arthritis compared to control mAb treated mice. The mitogenic response of B and T cells isolated from the lymph nodes of anti-IL-6 treated mice was significantly reduced compared to cells isolated from control mAb treated mice. The overall histopathology score for paws from the anti-IL-6 treated mice was significantly reduced when compared to paws from mice treated with control mAb, including both inflammatory (synovitis and pannus and erosive (erosions and architecture parameters. Reduced loss of cartilage matrix components was also observed in the anti-IL-6 treated mice. Collectively, these data suggest that IL-6 plays a major role in the pathophysiology of rheumatoid arthritis, and thus support the potential benefit of anti-IL-6 mAb treatment in rheumatoid arthritis patients.

Russian biosphere reserves at the youth MAB-2017 Forum in Italy

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Elena A. Shuyskaya

2018-02-01

Full Text Available Russia was represented by 9 participants from Biosphere Reserves at the MAB Youth Forum in Italy. The main question of the Forum was «How to involve the young in the work of biosphere reserves?» The debate resulted in a Declaration, elaborated by participants from around the world (282 delegates from 85 countries. Measures to improve scientific cooperation, data exchange in the sphere of educational tourism and administrative management, development of joint projects in environmental education were formulated. The article contains a number of recommendations for the network of biosphere reserves in Russia, based on Seville strategy and Lima Action Plan.

Anti-osteopontin monoclonal antibody prevents ovariectomy-induced osteoporosis in mice by promotion of osteoclast apoptosis

Energy Technology Data Exchange (ETDEWEB)

Zhang, Bo [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); PLA General Hospital Cancer Center and PLA Cancer Research Institute, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing (China); Dai, Jianxin [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); PLA General Hospital Cancer Center and PLA Cancer Research Institute, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing (China); National Engineering Research Center for Antibody Medicine and Shanghai Key Lab. of Cell Engineering and Antibody, 399 Libing Road, Shanghai 201203 (China); Wang, Huaqing [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); Wei, Huafeng [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); PLA General Hospital Cancer Center and PLA Cancer Research Institute, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing (China); Zhao, Jian [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); National Engineering Research Center for Antibody Medicine and Shanghai Key Lab. of Cell Engineering and Antibody, 399 Libing Road, Shanghai 201203 (China); Guo, Yajun, E-mail: yguo_smmu@163.com [International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433 (China); PLA General Hospital Cancer Center and PLA Cancer Research Institute, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing (China); National Engineering Research Center for Antibody Medicine and Shanghai Key Lab. of Cell Engineering and Antibody, 399 Libing Road, Shanghai 201203 (China); and others

2014-09-26

Highlight: • We first report that anti-osteopontin mAb could protect osteoporosis in mice. • Anti-osteopontin mAb could promote the osteoclast apoptosis. • Targeting osteopontin might have therapeutic potentials for osteoporosis. - Abstract: Osteopontin (OPN) is abundant in mineralized tissues and has long been implicated in bone remodeling. However, the therapeutic effect of targeting OPN in bone loss diseases and the underlying molecular mechanism remain largely unknown. Here, we reported that anti-OPN mAb (23C3) could protect against ovariectomy-induced osteoporosis in mice, demonstrated by microcomputed tomography analysis and histopathology evaluation. In vitro assay showed that 23C3 mAb reduced osteoclasts (OCs)-mediated bone resorption through promotion of mature OC apoptosis. Thus, the study has important implications for understanding the role of OPN in OC bone resorption and survival, and OPN antagonists may have therapeutic potential for osteoporosis and other osteopenic diseases.

Anti-osteopontin monoclonal antibody prevents ovariectomy-induced osteoporosis in mice by promotion of osteoclast apoptosis

International Nuclear Information System (INIS)

Zhang, Bo; Dai, Jianxin; Wang, Huaqing; Wei, Huafeng; Zhao, Jian; Guo, Yajun

2014-01-01

Highlight: • We first report that anti-osteopontin mAb could protect osteoporosis in mice. • Anti-osteopontin mAb could promote the osteoclast apoptosis. • Targeting osteopontin might have therapeutic potentials for osteoporosis. - Abstract: Osteopontin (OPN) is abundant in mineralized tissues and has long been implicated in bone remodeling. However, the therapeutic effect of targeting OPN in bone loss diseases and the underlying molecular mechanism remain largely unknown. Here, we reported that anti-OPN mAb (23C3) could protect against ovariectomy-induced osteoporosis in mice, demonstrated by microcomputed tomography analysis and histopathology evaluation. In vitro assay showed that 23C3 mAb reduced osteoclasts (OCs)-mediated bone resorption through promotion of mature OC apoptosis. Thus, the study has important implications for understanding the role of OPN in OC bone resorption and survival, and OPN antagonists may have therapeutic potential for osteoporosis and other osteopenic diseases

Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

Science.gov (United States)

Krawczyk, Adalbert; Dirks, Miriam; Kasper, Maren; Buch, Anna; Dittmer, Ulf; Giebel, Bernd; Wildschütz, Lena; Busch, Martin; Goergens, Andre; Schneweis, Karl E.; Eis-Hübinger, Anna M.; Sodeik, Beate; Heiligenhaus, Arnd; Roggendorf, Michael; Bauer, Dirk

2015-01-01

The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans. PMID:25587898

Prevention of herpes simplex virus induced stromal keratitis by a glycoprotein B-specific monoclonal antibody.

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Adalbert Krawczyk

Full Text Available The increasing incidence of acyclovir (ACV and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis or 24, 40, and 56 hours after infection (post-exposure immunotherapy. Topical treatment was performed by periodical inoculations (5 times per day of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans.

Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract

Energy Technology Data Exchange (ETDEWEB)

Park, Sun Hong; Roh, Eunmiri [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of); Kim, Hyun Soo [Pharmaceutical R and D Center, Huons Co., Ltd., Anyang (Korea, Republic of); Baek, Seung-Il [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of); Choi, Nam Song [Pharmaceutical R and D Center, Huons Co., Ltd., Anyang (Korea, Republic of); Kim, Narae; Hwang, Bang Yeon; Han, Sang-Bae [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of); Kim, Youngsoo, E-mail: youngsoo@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju 361-763 (Korea, Republic of)

2013-12-13

Highlights: •Lonicerae flos extract (HS-23) is a clinical candidate, Phase I for sepsis treatment. •Here, HS-23 or its major constituents rescued LPS-induced septic mortality in mice. •As a mechanism, they directly inhibited IRAK-4-catalyzed kinase activity. •Thus, they suppressed LPS-induced expression of NF-κB/AP-1-target inflammatory genes. -- Abstract: Lonicerae flos extract (HS-23) is a clinical candidate currently undergoing Phase I trial in lipopolysaccharide (LPS)-injected healthy human volunteers, but its molecular basis remains to be defined. Here, we investigated protective effects of HS-23 or its major constituents on Escherichia coli LPS-induced septic mortality in mice. Intravenous treatment with HS-23 rescued LPS-intoxicated C57BL/6J mice under septic conditions, and decreased the levels of cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and high-mobility group box-1 (HMGB-1) in the blood. Chlorogenic acid (CGA) and its isomers were assigned as major constituents of HS-23 in the protection against endotoxemia. As a molecular mechanism, HS-23 or CGA isomers inhibited endotoxin LPS-induced autophosphorylation of the IL-1 receptor-associated kinase 4 (IRAK-4) in mouse peritoneal macrophages as well as the kinase activity of IRAK-4 in cell-free reactions. HS-23 consequently suppressed downstream pathways critical for LPS-induced activation of nuclear factor (NF)-κB or activating protein 1 (AP-1) in the peritoneal macrophages. HS-23 also inhibited various toll-like receptor agonists-induced nitric oxide (NO) production, and down-regulated LPS-induced expression of NF-κB/AP-1-target inflammatory genes in the cells. Taken together, HS-23 or CGA isomers exhibited anti-inflammatory therapy against LPS-induced septic mortality in mice, at least in part, mediated through the inhibition of IRAK-4.

A literatura como resistência política: traços neorrealistas na produção literária do Movimento dos Atingidos por Barragens (MAB

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Carolina Alves Pereira

2018-04-01

Full Text Available Este trabalho busca analisar as relações existentes entre as produções literárias do inicio do século XX, com o surgimento da corrente neo-realista, e a literatura produzida pelo Movimento dos Atingidos por Barragens (MAB, como manifestação de resistência à cultura elitista, no que tange ao espaço das criações artísticas. Para tanto, discute-se a característica do neo-realismo como expressão literária definidora dos aspectos sociais e políticos representados nas obras da época. Analisa-se, também, o conceito de resistência como determinante para a definição da literatura marginalizada do movimento campesino (MAB. Por fim, a seguinte pesquisa ratifica a importância da literatura e das artes produzida para além das universidades e dos cânones habituais. Palavras-chave: Literatura de resistência, Neorrealismo, Movimento dos Atingidos por Barragens (MAB. _________________________ This paper analyzes the relationship between the literary productions of the early twentieth century, with the rise of neo-realist current, and the literature produced by the Brazilian social group called Movimento do Atingidos por Barragens (MAB as a manifestation of resistance to elitist culture in terms the space of artistic creations. To this aim, I discuss the characteristic of neorealism as the defining literary expression of social and political represented in the works of the time aspects. In addition, I analyze the concept of resistance as a determinant for defining the literature of marginalized campesino movement (MAB. Finally, the following research confirms the importance of literature and the arts produced in excess of the usual canons and universities. Keywords: Literature of Resistance, Neorealism, Movimento dos Atingidos por Barragens (MAB.

Monoclonal antibodies (MAb) made against insect-derived metacyclic trypomastigotes (IMT) of Trypanosoma cruzi (TC) cross-react with other parasite forms

International Nuclear Information System (INIS)

Kirchhoff, L.V.; Gilliam, F.C.

1986-01-01

Considerable information has been generated in recent years about stage-specific surface membrane antigens of a number of protozoa, and this phenomenon has been observed among several stages of TC as well. However, little is known about the surface antigens of IMT, the true infective stage of TC, because of the difficulty of obtaining sufficient numbers of these organisms for analysis. The Tulahuen strain of TC was maintained in the reduviid vector Dipetalogaster maximus by repeated feeding on mice with high parasitemias. IMT collected with insect urine were irradiated (150 krad) and used to immunize a BALB/c mouse for hybridoma production. Supernatants were screened by immunofluorescence assay for the presence of IgG MAb that react with methanol-fixed IMT, epimastogotes (EPI) and culture-derived metacyclic trypomastigoes (CMT). Of 41 MAb obtained, 40 reacted with IMT, 37 with EPI and 38 with CMT. Four MAb immunoprecipitated radioiodinated proteins or protein conjugates of M/sub r/ 80, 72, 45 and 45 from lysates of 125 I surface-labeled EPI. These results indicate that, at least at the epitopic level, there is considerable overlap among IMT, EPI and CMT surface antigens. This finding suggests that analysis of surface proteins of the latter 2 parasite forms may lead to identification of molecules useful for vaccine development

Meta-analysis Reveals that Hydraulic Traits Explain Cross-Species Patterns of Drought-Induced Tree Mortality across the Globe

Science.gov (United States)

Anderegg, W.

2016-12-01

Drought-induced tree mortality has been observed globally and is expected to increase under climate change scenarios, with large potential consequences for the terrestrial carbon sink. Predicting mortality across species is crucial for assessing the effects of climate extremes on forest community biodiversity, composition, and carbon sequestration. However, the physiological traits associated with elevated risk of mortality in diverse ecosystems remain unknown, though these could greatly improve understanding and prediction of tree mortality in forests. We performed a meta-analysis on species' mortality rates across 475 species from 33 studies around the globe to assess which traits determine a species' mortality risk. We found that species-specific mortality anomalies from community mortality rate in a given drought were associated with plant hydraulic traits. Across all species, mortality was best predicted by a low hydraulic safety margin - the difference between typical minimum xylem water potential and that causing xylem dysfunction - and xylem vulnerability to embolism. Angiosperms and gymnosperms experienced roughly equal mortality risk. Our results provide broad support that hydraulic traits capture key mechanisms determining tree death and highlight that physiological traits can improve vegetation models' prediction of tree mortality during climate extremes. We conclude with thoughts about a revised framework for future tree mortality research.

Immunoreactivity of the 14F7 Mab (Raised against N-Glycolyl GM3 Ganglioside as a Positive Prognostic Factor in Non-Small-Cell Lung Cancer

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Rancés Blanco

2012-01-01

Full Text Available Lung carcinoma is the leading cause of cancer-related mortality worldwide. Therefore, numerous studies are focusing on the assessment of other biological and molecular prognostic factors in these tumors. We evaluated the relationship between 14F7 Mab reactivity, pathological features, DNA-content and S-phase fraction (SPF, and their impact in the survival of NSCLC patients. Hematoxylin and eosin staining and immunohistochemistry optical microscopy assays as well as DNA content and SPF measuring using flow cytometry were performed. The 14F7 reactivity was widely observed in NSCLC sections, no depending of the clinicopathological characteristics. We also obtained differences in the intensity of reaction with 14F7 as well as in the SPF between diploid and aneuploid carcinomas. Patients with diploid tumors showing higher SPF and 14F7 reaction joint to a low mitotic index displayed higher survival rates. Our results are in agreement with the assumption of the possible positive prognostic value of 14F7 staining in NSCLC.

Immunoreactivity of the 14F7 Mab (Raised against N-Glycolyl GM3 Ganglioside) as a Positive Prognostic Factor in Non-Small-Cell Lung Cancer

Science.gov (United States)

Blanco, Rancés; Rengifo, Charles E.; Cedeño, Mercedes; Frómeta, Milagros; Rengifo, Enrique; Carr, Adriana

2012-01-01

Lung carcinoma is the leading cause of cancer-related mortality worldwide. Therefore, numerous studies are focusing on the assessment of other biological and molecular prognostic factors in these tumors. We evaluated the relationship between 14F7 Mab reactivity, pathological features, DNA-content and S-phase fraction (SPF), and their impact in the survival of NSCLC patients. Hematoxylin and eosin staining and immunohistochemistry optical microscopy assays as well as DNA content and SPF measuring using flow cytometry were performed. The 14F7 reactivity was widely observed in NSCLC sections, no depending of the clinicopathological characteristics. We also obtained differences in the intensity of reaction with 14F7 as well as in the SPF between diploid and aneuploid carcinomas. Patients with diploid tumors showing higher SPF and 14F7 reaction joint to a low mitotic index displayed higher survival rates. Our results are in agreement with the assumption of the possible positive prognostic value of 14F7 staining in NSCLC. PMID:22482082

The ability of winter grazing to reduce wildfire size, intensity, and fire-induced plant mortality was not demonstrated: A comment on Davies et al. (2015)

Science.gov (United States)

A recent study by Davies et al. sought to test whether winter grazing could reduce wildfire size, fire behavior metrics, and fire-induced plant mortality in shrub-grasslands. The authors concluded that ungrazed rangelands may experience more fire-induced mortality of native peren...

IL-2/anti-IL-2 mAb immunocomplexes: A renascence of IL-2 in cancer immunotherapy?

Czech Academy of Sciences Publication Activity Database

Tomala, Jakub; Kovář, Marek

2016-01-01

Roč. 5, č. 3 (2016), e1102829 ISSN 2162-402X R&D Projects: GA ČR GA13-12885S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : Anti-IL-2 mAb * cancer immunotherapy * IL-2 Subject RIV: EE - Microbiology, Virology Impact factor: 7.719, year: 2016

Temperature sensitivity of drought-induced tree mortality portends increased regional die-off under global-change-type drought

Science.gov (United States)

Adams, Henry D.; Guardiola-Claramonte, Maite; Barron-Gafford, Greg A.; Villegas, Juan Camilo; Breshears, David D.; Zou, Chris B.; Troch, Peter A.; Huxman, Travis E.

2009-01-01

Large-scale biogeographical shifts in vegetation are predicted in response to the altered precipitation and temperature regimes associated with global climate change. Vegetation shifts have profound ecological impacts and are an important climate-ecosystem feedback through their alteration of carbon, water, and energy exchanges of the land surface. Of particular concern is the potential for warmer temperatures to compound the effects of increasingly severe droughts by triggering widespread vegetation shifts via woody plant mortality. The sensitivity of tree mortality to temperature is dependent on which of 2 non-mutually-exclusive mechanisms predominates—temperature-sensitive carbon starvation in response to a period of protracted water stress or temperature-insensitive sudden hydraulic failure under extreme water stress (cavitation). Here we show that experimentally induced warmer temperatures (≈4 °C) shortened the time to drought-induced mortality in Pinus edulis (piñon shortened pine) trees by nearly a third, with temperature-dependent differences in cumulative respiration costs implicating carbon starvation as the primary mechanism of mortality. Extrapolating this temperature effect to the historic frequency of water deficit in the southwestern United States predicts a 5-fold increase in the frequency of regional-scale tree die-off events for this species due to temperature alone. Projected increases in drought frequency due to changes in precipitation and increases in stress from biotic agents (e.g., bark beetles) would further exacerbate mortality. Our results demonstrate the mechanism by which warmer temperatures have exacerbated recent regional die-off events and background mortality rates. Because of pervasive projected increases in temperature, our results portend widespread increases in the extent and frequency of vegetation die-off. PMID:19365070

Differential expression of Meis2, Mab21l2 and Tbx3 during limb development associated with diversification of limb morphology in mammals.

Science.gov (United States)

Dai, Mengyao; Wang, Yao; Fang, Lu; Irwin, David M; Zhu, Tengteng; Zhang, Junpeng; Zhang, Shuyi; Wang, Zhe

2014-01-01

Bats are the only mammals capable of self-powered flight using wings. Differing from mouse or human limbs, four elongated digits within a broad wing membrane support the bat wing, and the foot of the bat has evolved a long calcar that spread the interfemoral membrane. Our recent mRNA sequencing (mRNA-Seq) study found unique expression patterns for genes at the 5' end of the Hoxd gene cluster and for Tbx3 that are associated with digit elongation and wing membrane growth in bats. In this study, we focused on two additional genes, Meis2 and Mab21l2, identified from the mRNA-Seq data. Using whole-mount in situ hybridization (WISH) we validated the mRNA-Seq results for differences in the expression patterns of Meis2 and Mab21l2 between bat and mouse limbs, and further characterize the timing and location of the expression of these two genes. These analyses suggest that Meis2 may function in wing membrane growth and Mab21l2 may have a role in AP and DV axial patterning. In addition, we found that Tbx3 is uniquely expressed in the unique calcar structure found in the bat hindlimb, suggesting a role for this gene in calcar growth and elongation. Moreover, analysis of the coding sequences for Meis2, Mab21l2 and Tbx3 showed that Meis2 and Mab21l2 have high sequence identity, consistent with the functions of genes being conserved, but that Tbx3 showed accelerated evolution in bats. However, evidence for positive selection in Tbx3 was not found, which would suggest that the function of this gene has not been changed. Together, our findings support the hypothesis that the modulation of the spatiotemporal expression patterns of multiple functional conserved genes control limb morphology and drive morphological change in the diversification of mammalian limbs.

Comparison between anti-CEA and anti-HER2 212Pb-labeled mAbs during α-RIT of small volume peritoneal carcinomatosis - Role of activity distribution on therapeutic efficacy and toxicity?

International Nuclear Information System (INIS)

Elgqvist, J.; Boudousq, V.; Bobyk, L.; Busson, M.; Lozza, C.; Navarro-Teulon, I.; Pouget, J.P.; Maquaire, P.; Torgue, J.

2015-01-01

Full text of publication follows. Objectives: we investigated the role of internalizing/non-internalizing monoclonal antibodies (mAbs) on the final outcome (efficacy/toxicity) of mice treated with alpha radioimmunotherapy (α- RIT) using 212 Pb-labeled mAbs. The relationship between distribution of radioactivity at the tissue level and biological parameters was also assessed. Methods: nude mice bearing 2-3 mm peritoneal nodules obtained by xenograft of A-431 tumor cells, expressing low and high level of HER2 and CEA receptors, respectively, were intraperitoneally (i.p.) injected with increasing activities (370-1480 kBq; 37 MBq/mg) of either 35A7 (non-internalising anti-CEA), Trastuzumab (internalizing anti-HER2) or PX (non-specific) 212 Pb-labeled mAbs. Control groups were injected with corresponding amount of unlabeled mAbs or with NaCl. Tumor growth was followed by bioluminescence and median survival (MS) of control and treated mice was determined. 212 Pb-35A7 and 212 Pb-Trastuzumab biodistribution was used to determine the cumulative uptake of radioactivity (UOR) in organs and tumors. Mean absorbed doses were calculated using the MIRD formalism. Haematological, liver and kidney toxicities were also assessed. Distribution of radioactivity at the tissue level was determined by digital micro-autoradiography and the relationship with biological markers of tissue damage was investigated using immunohistochemistry. Results: a mild and transient haematological toxicity in groups treated with the highest amount of activity was observed. MS of the groups treated either with internalizing or non-internalizing 212 Pb-labeled mAbs was significantly improved compared to those treated with non-specific 212 Pb-PX or those only given unlabeled mAbs or just NaCl. MS ranged from 42 days to 94 days using various activity levels of anti-CEA 212 Pb-35A7 while MS was not reached over the follow-up period of 130 days for mice treated with anti-HER2 212 Pb-Trastuzumab. However, UOR and

The Role of Interleukin-6 in Lipopolysaccharide-Induced Weight Loss, Hypoglycemia and Fibrinogen Production, in Vivo

Science.gov (United States)

1994-07-01

result in chronic wasting or cachexia. In neoplastic severe weight loss in syngeneic hosts.6 In this model, diseases, the presence of wasting of muscle...48 h post-endotoxin). Anti-TNF MAb tribution of TNF and IL-6 in several metabolic changes reduced by c. 50% the LPS-induced weight loss, but...similar results. Also, the addi- hypertriglyceridemia , hypoglycemia as well as stimu- tion of fresh 20F3 MAb to diluted serum sample from late the

Solid-state mAbs and ADCs subjected to heat-stress stability conditions can be covalently modified with buffer and excipient molecules.

Science.gov (United States)

Valliere-Douglass, John F; Lewis, Patsy; Salas-Solano, Oscar; Jiang, Shan

2015-02-01

We report that a unique type of chemical modification occurs on lyophilized proteins. Freeze-dried mAbs and antibody-drug conjugates (ADCs) can be covalently modified with buffer and excipient molecules on the side chains of Glu, Asp, Thr, and Ser amino acids when subjected to temperature stress. The reaction occurs primarily via condensation of common buffers and excipients such as histidine, tris, trehalose and sucrose, with Glu and Asp carboxylates in the primary sequence of proteins. The reaction was also found to proceed through condensation of carboxylate containing buffers such as citrate, with Thr and Ser hydroxyls in the primary sequence of proteins. Based on the mass of the covalent adducts observed on mAbs and ADCs, it is apparent that the reaction produces water as a product and is thus favored in a low moisture environments such as a lyophilized protein cake. Herein, we present the evidence for the covalent modification of proteins drawn from case studies of in-depth characterization of heat-stressed mAbs and ADCs in the solid state. We also demonstrate how common charge variant assays such as imaged capillary isoelectric focusing and mass spectrometry can be used to monitor this specific class of protein modification. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Chemical changes demonstrated in cartilage by synchrotron infrared microspectroscopy in an antibody-induced murine model of rheumatoid arthritis

Science.gov (United States)

Croxford, Allyson M.; Selva Nandakumar, Kutty; Holmdahl, Rikard; Tobin, Mark J.; McNaughton, Don; Rowley, Merrill J.

2011-06-01

Collagen antibody-induced arthritis develops in mice following passive transfer of monoclonal antibodies (mAbs) to type II collagen (CII) and is attributed to effects of proinflammatory immune complexes, but transferred mAbs may react directly and damagingly with CII. To determine whether such mAbs cause cartilage damage in vivo in the absence of inflammation, mice lacking complement factor 5 that do not develop joint inflammation were injected intravenously with two arthritogenic mAbs to CII, M2139 and CIIC1. Paws were collected at day 3, decalcified, paraffin embedded, and 5-μm sections were examined using standard histology and synchrotron Fourier-transform infrared microspectroscopy (FTIRM). None of the mice injected with mAb showed visual or histological evidence of inflammation but there were histological changes in the articular cartilage including loss of proteoglycan and altered chondrocyte morphology. Findings using FTIRM at high lateral resolution revealed loss of collagen and the appearance of a new peak at 1635 cm-1 at the surface of the cartilage interpreted as cellular activation. Thus, we demonstrate the utility of synchrotron FTIRM for examining chemical changes in diseased cartilage at the microscopic level and establish that arthritogenic mAbs to CII do cause cartilage damage in vivo in the absence of inflammation.

Aggregate complexes of HIV-1 induced by multimeric antibodies.

Science.gov (United States)

Stieh, Daniel J; King, Deborah F; Klein, Katja; Liu, Pinghuang; Shen, Xiaoying; Hwang, Kwan Ki; Ferrari, Guido; Montefiori, David C; Haynes, Barton; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Michael, Nelson L; Robb, Merlin L; Kim, Jerome H; Denny, Thomas N; Tomaras, Georgia D; Shattock, Robin J

2014-10-02

Antibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry. The potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA. These results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry.

Climate-induced mortality of spruce stands in Belarus

Science.gov (United States)

Kharuk, Viacheslav I.; Im, Sergei T.; Dvinskaya, Maria L.; Golukov, Alexei S.; Ranson, Kenneth J.

2015-12-01

The aim of this work is an analysis of the causes of spruce (Picea abies L.) decline and mortality in Belarus. The analysis was based on forest inventory and Landsat satellite (land cover classification, climate variables (air temperature, precipitation, evaporation, vapor pressure deficit, SPEI drought index)), and GRACE-derived soil moisture estimation (equivalent of water thickness anomalies, EWTA). We found a difference in spatial patterns between dead stands and all stands (i.e., before mortality). Dead stands were located preferentially on relief features with higher water stress risk (i.e., higher elevations, steeper slopes, south and southwestern exposure). Spruce mortality followed a series of repeated droughts between 1990 and 2010. Mortality was negatively correlated with air humidity (r = -0.52), and precipitation (r = -0.57), and positively correlated with the prior year vapor pressure deficit (r = 0.47), and drought increase (r = 0.57). Mortality increased with the increase in occurrence of spring frosts (r = 0.5), and decreased with an increase in winter cloud cover (r = -0.37). Spruce mortality was negatively correlated with snow water accumulation (r = -0.81) and previous year anomalies in water soil content (r = -0.8). Weakened by water stress, spruce stands were attacked by pests and phytopathogens. Overall, spruce mortality in Belarussian forests was caused by drought episodes and drought increase in synergy with pest and phytopathogen attacks. Vast Picea abies mortality in Belarus and adjacent areas of Russia and Eastern Europe is a result of low adaptation of that species to increased drought. This indicates the necessity of spruce replacement by drought-tolerant indigenous (e.g., Pinus sylvestris, Querqus robur) or introduced (e.g., Larix sp. or Pseudotsuga menzieslii) species to obtain sustainable forest growth management.

Role of visible light-activated photocatalyst on the reduction of anthrax spore-induced mortality in mice.

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Jyh-Hwa Kau

Full Text Available BACKGROUND: Photocatalysis of titanium dioxide (TiO(2 substrates is primarily induced by ultraviolet light irradiation. Anion-doped TiO(2 substrates were shown to exhibit photocatalytic activities under visible-light illumination, relative environmentally-friendly materials. Their anti-spore activity against Bacillus anthracis, however, remains to be investigated. We evaluated these visible-light activated photocatalysts on the reduction of anthrax spore-induced pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Standard plating method was used to determine the inactivation of anthrax spore by visible light-induced photocatalysis. Mouse models were further employed to investigate the suppressive effects of the photocatalysis on anthrax toxin- and spore-mediated mortality. We found that anti-spore activities of visible light illuminated nitrogen- or carbon-doped titania thin films significantly reduced viability of anthrax spores. Even though the spore-killing efficiency is only approximately 25%, our data indicate that spores from photocatalyzed groups but not untreated groups have a less survival rate after macrophage clearance. In addition, the photocatalysis could directly inactivate lethal toxin, the major virulence factor of B. anthracis. In agreement with these results, we found that the photocatalyzed spores have tenfold less potency to induce mortality in mice. These data suggest that the photocatalysis might injury the spores through inactivating spore components. CONCLUSION/SIGNIFICANCE: Photocatalysis induced injuries of the spores might be more important than direct killing of spores to reduce pathogenicity in the host.

Radioimmunoscintigraphy with monoclonal antibody Technetium-99m-Anti-EGF-Receptor (R3-MAB) for the detection of head and neck tumours, metastasis and recurrence. Final report for the period 15 April 1995 - 15 April 1997

International Nuclear Information System (INIS)

Oliva Gonzalez, J.P.

1998-03-01

A clinical study was carried out to determine the sensitivity of radioimmunoscintigraphy (RIS) using indigenously produced mouse monoclonal antibody (MAB) against epidermal growth factor receptor in the detection of primary, recurrent and metastatic malignant epithelial tumours of the head and neck region in 13 patients. The MAB was labelled with 99m Tc and imaging was carried out using gamma camera and SPECT. The results were correlated with histopathological findings. RIS gave a sensitivity of 76.9%. This study showed that the indigenously produced MAB can be used for the detection of malignant epithelial tumours in the head and neck region but the MAB will be further characterized to improve its sensitivity in the detection of the neoplasia. (author)

Mortality and sterility induced in Piophila casei by x-ray and neutron irradiation

International Nuclear Information System (INIS)

Sacchi, L.; Gasperi, G.; Grigolo, A.; Caprotti, M.; Pinelli, T.; Altieri, S.

1977-01-01

Different doses of neutrons and X-rays were given to 5-day-old pupae of Piophila casei L. (Diptera, Piophilidae), just before their emergence. The mortality and sterility induced by the different types of radiation were measured. Neutrons are more effective than X-rays in provoking lethal lesions in somatic cells. Females are more resistant than males to the sterilizing action of neutrons, the relative biological efficiency of neutrons being 6 and 3.5, respectively

Mortality and sterility induced in Piophila casei by x-ray and neutron irradiation

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Sacchi, L; Gasperi, G [Pavia Univ. (Italy). Ist. di Zoologia; Grigolo, A [Bari Univ. (Italy). Ist. di Zoologia e Anatomia Comparata; Caprotti, M [Pavia Univ. (Italy). Fondazio Clinica del Lavoro. Reparto di Radiologia; Pinelli, T; Altieri, S [Pavia Univ. (Italy). Istituto di Fisica Nucleare

1977-01-01

Different doses of neutrons and X-rays were given to 5-day-old pupae of Piophila casei L. (Diptera, Piophilidae), just before their emergence. The mortality and sterility induced by the different types of radiation were measured. Neutrons are more effective than X-rays in provoking lethal lesions in somatic cells. Females are more resistant than males to the sterilizing action of neutrons, the relative biological efficiency of neutrons being 6 and 3.5, respectively.

Age dependent mortality in the pilocarpine model of status epilepticus

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Blair, Robert E.; Deshpande, Laxmikant S.; Holbert, William H.; Churn, Severn B.; DeLorenzo, Robert J.

2010-01-01

Status epilepticus (SE) is an acute neurological emergency associated with significant morbidity and mortality. Age has been shown to be a critical factor in determining outcome after SE. Understanding the causes of this increased mortality with aging by developing an animal model to study this condition would play a major role in studying mechanisms to limit the mortality due to SE. Here we employed pilocarpine to induce SE in rats aged between 5 to 28 weeks. Similar to clinical studies in man, we observed that age was a significant predictor of mortality following SE. While no deaths were observed in 5-week old animals, mortality due to SE increased progressively with age and reached 90% in 28-week old animals. There was no correlation between the age of animals and severity of SE. With increasing age mortality occurred earlier after the onset of SE. These results indicate that pilocarpine-induced SE in the rat provides a useful model to study age-dependent SE-induced mortality and indicates the importance of using animal models to elucidate the mechanisms contributing to SE-induced mortality and the development of novel therapeutic interventions to prevent SE-induced death. PMID:19429042

Age-dependent mortality in the pilocarpine model of status epilepticus.

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Blair, Robert E; Deshpande, Laxmikant S; Holbert, William H; Churn, Severn B; DeLorenzo, Robert J

2009-04-10

Status epilepticus (SE) is an acute neurological emergency associated with significant morbidity and mortality. Age has been shown to be a critical factor in determining outcome after SE. Understanding the causes of this increased mortality with aging by developing an animal model to study this condition would play a major role in studying mechanisms to limit the mortality due to SE. Here we employed pilocarpine to induce SE in rats aged between 5 and 28 weeks. Similar to clinical studies in man, we observed that age was a significant predictor of mortality following SE. While no deaths were observed in 5-week-old animals, mortality due to SE increased progressively with age and reached 90% in 28-week-old animals. There was no correlation between the age of animals and severity of SE. With increasing age mortality occurred earlier after the onset of SE. These results indicate that pilocarpine-induced SE in the rat provides a useful model to study age-dependent SE-induced mortality and indicates the importance of using animal models to elucidate the mechanisms contributing to SE-induced mortality and the development of novel therapeutic interventions to prevent SE-induced death.

Inhibition of IKKβ in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality.

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Dominguez, Jessica A; Samocha, Alexandr J; Liang, Zhe; Burd, Eileen M; Farris, Alton B; Coopersmith, Craig M

2013-10-01

Nuclear factor-κB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase. Prospective, randomized controlled study. Animal laboratories in university medical centers. Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkβ) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival. Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkβ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβ mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkβ mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkβ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkβ mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkβ mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkβ mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkβ mice. Enterocyte

Inhibition of IKKß in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality

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Dominguez, Jessica A.; Samocha, Alexandr J.; Liang, Zhe; Burd, Eileen M.; Farris, Alton B.; Coopersmith, Craig M.

2013-01-01

Objective NF-kB is a critical regulator of cell survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase (IKK)-ß. Design Prospective, randomized, controlled study. Setting Animal laboratories in university medical centers. Subjects and Interventions Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkßf/Δ) and wild type (WT) mice were subjected to sham laparotomy or cecal ligation and puncture (CLP). Animals were sacrified at 24 hours or followed seven days for survival. Measurements and Main Results Septic WT mice had decreased villus length compared to sham mice while villus atrophy was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared to sham mice which was further exacerbated in Vil-Cre/Ikkßf/Δ mice. Sepsis induced intestinal hyperpermeability in WT mice compared to sham mice, which was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. This was associated with increased intestinal expression of claudin-2 in septic WT mice, which was further increased in septic Vil-Cre/Ikkßf/Δ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following CLP, and IL-10 and MCP-1 levels were higher in septic Vil-Cre/Ikkßf/Δ mice than septic WT mice. All septic mice were bacteremic, but no differences in bacterial load were identified between WT and Vil-Cre/Ikkßf/Δ mice. To determine the functional significance of these results, animals were followed for survival. Septic WT mice had lower mortality than septic Vil-Cre/Ikkßf/Δ mice (47% vs. 80%, p<0.05). Anti-TNF administration decreased intestinal apoptosis, permeability and mortality in WT septic mice and a similar improvement in intestinal integrity and survival were seen when anti-TNF was given to Vil-Cre/Ikkßf/Δ mice. Conclusions Enterocyte-specific NF

Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in High Glucose-Induced Apoptosis in Rat Cardiac Myocytes and Murine Pancreatic β-Cells.

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Yao, Takako; Fujimura, Tsutomu; Murayama, Kimie; Okumura, Ko; Seko, Yoshinori

2017-10-18

We previously identified a novel apoptosis-inducing humoral factor in the conditioned medium of hypoxic/reoxygenated-cardiac myocytes. We named this novel post-translationally-modified secreted-form of eukaryotic translation initiation factor 5A Oxidative stress-Responsive Apoptosis-Inducing Protein (ORAIP). We confirmed that myocardial ischemia/reperfusion markedly increased plasma ORAIP levels and rat myocardial ischemia/reperfusion injury was clearly suppressed by neutralizing anti-ORAIP monoclonal antibodies (mAbs) in vivo. In this study, to investigate the mechanism of cell injury of cardiac myocytes and pancreatic β-cells involved in diabetes mellitus (DM), we analyzed plasma ORAIP levels in DM model rats and the role of ORAIP in high glucose-induced apoptosis of cardiac myocytes in vitro. We also examined whether recombinant-ORAIP induces apoptosis in pancreatic β-cells. Plasma ORAIP levels in DM rats during diabetic phase were about 18 times elevated as compared with non-diabetic phase. High glucose induced massive apoptosis in cardiac myocytes (66.2 ± 2.2%), which was 78% suppressed by neutralizing anti-ORAIP mAb in vitro. Furthermore, recombinant-ORAIP clearly induced apoptosis in pancreatic β-cells in vitro. These findings strongly suggested that ORAIP plays a pivotal role in hyperglycemia-induced myocardial injury and pancreatic β-cell injury in DM. ORAIP will be a biomarker and a critical therapeutic target for cardiac injury and progression of DM itself.

A monoclonal antibody against PDGF B-chain inhibits PDGF-induced DNA synthesis in C3H fibroblasts and prevents binding of PDGF to its receptor.

Science.gov (United States)

Vassbotn, F S; Langeland, N; Hagen, I; Holmsen, H

1990-09-01

A monoclonal antibody (MAb 6D11) against platelet-derived growth factor (PDGF) was studied. We found that the MAb 6D11 in concentrations equimolar to PDGF blocked the [3H]thymidine incorporation in C3H/10T1/2 C18 fibroblasts stimulated by PDGF B-B and PDGF A-B. This inhibition was overcome by high doses of PDGF. The [3H]thymidine incorporation stimulated by other growth factors (aFGF, bFGF and bombesin) was not inhibited by the antibody. The MAb 6D11 blocked receptor binding of PDGF B-B, but not PDGF A-A. These findings suggest that the MAb 6D11 abolishes PDGF-induced DNA synthesis by blocking PDGF receptor binding. In this communication we demonstrate an isoform-specific monoclonal antibody against PDGF.

Myeloablative radioimmunotherapy with {sup 188}Re-CD66mAb before stem cell transplantation. No increase of proinflammatory cytokine levels of TNF-{alpha}; Myeloablative Radioimmuntherapie mit {sup 188}Re-CD66mAb vor Stammzelltransplantation. Kein Anstieg proinflammatorischer Zytokinspiegel von TNF-{alpha}

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Mutschler, J.; Reske, S.N. [Universitaetsklinik Ulm (Germany). Klinik fuer Nuklearmedizin; Steinbach, G. [Universitaetsklinik Ulm (Germany). Abt. Klinische Chemie; Bunjes, D. [Universitaetsklinik Ulm (Germany). Medizinische Klinik III; Buchmann, I. [Universitaetsklinik Heidelberg (Germany). Abt. fuer Nuklearmedizin

2009-07-01

Tumour necrosis factor-{alpha} (TNF-{alpha}) serum levels may increase due to intensive conditioning regimes with high-dose chemotherapy and total body irradiation (TBI) before stem cell transplantation. This increases the risk for developing acute graft versus host disease (aGvHD) after stem cell transplantation. In this prospective study we investigated the influence of radioimmunotherapy with {sup 188}Re-CD-66-mAb on changes on TNF-{alpha} serum levels. Patients, methods: In 18 patients we measured TNF-{alpha} before and up to 96 hours after radioimmunotherapy, in 2 patients in addition following TBI, in 9 patients also following chemotherapy. For measuring TNF-{alpha} we used an automated immunochemiluminescence assay (Immulite 1000 DPC Biermann, Bad Nauheim). The mean follow up period to record incidence of aGVHD was 100 days after stem cell transplantation. Compared to the basal levels before, the levels of TNF-{alpha} after conditioning with {sup 188}Re-CD-66-mAb did not increase significantly and remained in the physiological range. In contrast, these initial physiological cytokine levels increased and became pathological following 48 h after total body irradiation (13.2 {+-} 6.6 pg/ml) and chemotherapy (10.8 {+-} 15.7 pg/ml). In our study we found a low incidence of aGvHD (22.2%, n = 4/18). Conclusion: These results demonstrate that additional conditioning therapy with {sup 188}Re-CD-66-mAb does not increase proinflammatory cytokine levels of TNF-{alpha}. This finding may indicate that additive radioimmunotherapy may not be a significant factor for increasing the rate of conditioning- associated aGvHD. (orig.)

Temperature extremes reduce seagrass growth and induce mortality

International Nuclear Information System (INIS)

Collier, C.J.; Waycott, M.

2014-01-01

Highlights: • Temperature extremes occur during low tide in shallow seagrass meadows. • The effects of temperature extremes were tested experimentally at 35 °C, 40 °C and 43 °C. • 40 °C was a critical threshold with a large impact on growth and mortality. • At 43 °C there was complete mortality after 2–3 days. • Lower light conditions (e.g. poor water quality) led to a greater negative impact. - Abstract: Extreme heating (up to 43 °C measured from five-year temperature records) occurs in shallow coastal seagrass meadows of the Great Barrier Reef at low tide. We measured effective quantum yield (ϕ PSII ), growth, senescence and mortality in four tropical seagrasses to experimental short-duration (2.5 h) spikes in water temperature to 35 °C, 40 °C and 43 °C, for 6 days followed by one day at ambient temperature. Increasing temperature to 35 °C had positive effects on ϕ PSII (the magnitude varied between days and was highly correlated with PPFD), with no effects on growth or mortality. 40 °C represented a critical threshold as there were strong species differences and there was a large impact on growth and mortality. At 43 °C there was complete mortality after 2–3 days. These findings indicate that increasing duration (more days in a row) of thermal events above 40 °C is likely to affect the ecological function of tropical seagrass meadows

A global overview of drought and heat-induced tree mortality reveals emerging climate change risks for forests

Science.gov (United States)

Allen, Craig D.; Macalady, A.K.; Chenchouni, H.; Bachelet, D.; McDowell, N.; Vennetier, Michel; Kitzberger, T.; Rigling, A.; Breshears, D.D.; Hogg, E.H.(T.); Gonzalez, P.; Fensham, R.; Zhang, Z.; Castro, J.; Demidova, N.; Lim, J.-H.; Allard, G.; Running, S.W.; Semerci, A.; Cobb, N.

2010-01-01

Greenhouse gas emissions have significantly altered global climate, and will continue to do so in the future. Increases in the frequency, duration, and/or severity of drought and heat stress associated with climate change could fundamentally alter the composition, structure, and biogeography of forests in many regions. Of particular concern are potential increases in tree mortality associated with climate-induced physiological stress and interactions with other climate-mediated processes such as insect outbreaks and wildfire. Despite this risk, existing projections of tree mortality are based on models that lack functionally realistic mortality mechanisms, and there has been no attempt to track observations of climate-driven tree mortality globally. Here we present the first global assessment of recent tree mortality attributed to drought and heat stress. Although episodic mortality occurs in the absence of climate change, studies compiled here suggest that at least some of the world's forested ecosystems already may be responding to climate change and raise concern that forests may become increasingly vulnerable to higher background tree mortality rates and die-off in response to future warming and drought, even in environments that are not normally considered water-limited. This further suggests risks to ecosystem services, including the loss of sequestered forest carbon and associated atmospheric feedbacks. Our review also identifies key information gaps and scientific uncertainties that currently hinder our ability to predict tree mortality in response to climate change and emphasizes the need for a globally coordinated observation system. Overall, our review reveals the potential for amplified tree mortality due to drought and heat in forests worldwide.

In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model.

Directory of Open Access Journals (Sweden)

Zhiqun Li

Full Text Available Enterovirus 71 (EV71 is a neurotropic virus capable of inducing severe neurological symptoms and death. No direct targeting antivirals are useful in the treatment of severe EV71 infection. Because of low toxicity and good specificity, monoclonal antibodies (MAb are a potential candidate for the treatment of viral infections. Therefore, we developed an EV71-specific conformational MAb with high in vitro cross-neutralization activity to heterologous EV71 subgenotypes. The in vivo treatment experiment at different days post-infection indicated that a single treatment of MAb CT11F9 within day 3 post-infection fully protected mice from morbidity and mortality (0% PBS vs. 100% at 10 µg/g per body weight ***P<0.0001. Immunohistochemical and histological analysis confirmed that CT11F9 significantly prohibited EV71 VP1 expression in various tissues and prevented EV71-induced myonecrosis. Moreover, thrice-treatment at day 4, 5, 6 post-infection was associated with an increased survival rate (18.2% single vs. 50% thrice at 20 µg/g per body weight, and the mice recovered from limb paralysis. Competitive ELISA also confirmed that CT11F9-recognized epitopes were immunodominant in humans. In conclusion, MAb CT11F9 is an ideal candidate to be humanized and used in severe EV71 infection.

Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

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Geng, Jie-jie; Zhang, Kui; Chen, Li-na; Miao, Jin-lin; Yao, Meng; Ren, Ying; Fu, Zhi-guang; Chen, Zhi-nan; Zhu, Ping

2014-09-01

Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1β, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug induced mortality: a multiple cause approach on Italian causes of death Register

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Francesco Grippo

2015-04-01

Full Text Available Background: Drug-related mortality is a complex phenomenon that has several health, social and economic effects. In this paper trends of drug-induced mortality in Italy are analysed. Two approaches have been followed: the traditional analysis of the underlying cause of death (UC (data refers to the Istat mortality database from 1980 to 2011, and the multiple cause (MCanalysis, that is the analysis of all conditions reported on the death certificate (data for 2003-2011 period.Methods: Data presented in this paper are based on the Italian mortality register. The selection of Icd codes used for the analysis follows the definition of the European Monitoring Centre for Drugs and Drug Addiction. Using different indicators (crude and standardized rates, ratio multiple to underlying, the results obtained from the two approaches (UC and MC have been compared. Moreover, as a measure of association between drug-related causes and specific conditions on the death certificate, an estimation of the age-standardized relative risk (RR has been used.Results: In the years 2009-2011, the total number of certificates whit mention of drug use was 1,293, 60% higher than the number UC based. The groups of conditions more strongly associated with drug-related causes are the mental and behavioral disorders (especially alcohol consumption, viral hepatitis, cirrhosis and fibrosis of liver, AIDS and endocarditis.Conclusions : The analysis based on multiple cause approach shows, for the first time, a more detailed picture of the drug related death; it allows to better describe the mortality profiles and to re-evaluate  the contribution of a specific cause to death.

Reliable LC-MS quantitative glycomics using iGlycoMab stable isotope labeled glycans as internal standards.

Science.gov (United States)

Zhou, Shiyue; Tello, Nadia; Harvey, Alex; Boyes, Barry; Orlando, Ron; Mechref, Yehia

2016-06-01

Glycans have numerous functions in various biological processes and participate in the progress of diseases. Reliable quantitative glycomic profiling techniques could contribute to the understanding of the biological functions of glycans, and lead to the discovery of potential glycan biomarkers for diseases. Although LC-MS is a powerful analytical tool for quantitative glycomics, the variation of ionization efficiency and MS intensity bias are influencing quantitation reliability. Internal standards can be utilized for glycomic quantitation by MS-based methods to reduce variability. In this study, we used stable isotope labeled IgG2b monoclonal antibody, iGlycoMab, as an internal standard to reduce potential for errors and to reduce variabililty due to sample digestion, derivatization, and fluctuation of nanoESI efficiency in the LC-MS analysis of permethylated N-glycans released from model glycoproteins, human blood serum, and breast cancer cell line. We observed an unanticipated degradation of isotope labeled glycans, tracked a source of such degradation, and optimized a sample preparation protocol to minimize degradation of the internal standard glycans. All results indicated the effectiveness of using iGlycoMab to minimize errors originating from sample handling and instruments. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

47-mG2a: A Mouse IgG2a-Type of PcMab-47 Useful for Detecting Podocalyxin in Esophageal Cancers by Immunohistochemistry.

Science.gov (United States)

Kaneko, Mika K; Itai, Shunsuke; Yamada, Shinji; Kato, Yukinari

2018-04-09

Esophageal cancer is one of the highly malignant cancers. It comprises two of the most common histological tumor types: squamous cell carcinoma (SCC) and adenocarcinoma. SCC accounts for about 90% of esophageal cancers. Despite developments in treatment strategies, the prognosis and survival rate remain poor. Podocalyxin (PODXL) is a highly glycosylated type-I transmembrane protein. It is expressed in normal tissues such as kidney, heart, breast, and pancreas. Upregulation of PODXL correlates with tumor progression, invasion, and metastasis. Therefore, this glycoprotein could be a potential biomarker for predicting the prognosis of some cancers, for instance, brain, colorectal, oral, lung, bladder, prostate, and ovarian cancers. We previously developed a specific and sensitive anti-PODXL monoclonal antibody (mAb), PcMab-47 (mouse IgG 1 , kappa) and its mouse IgG 2a -type (47-mG 2a ). We showed their utility in immunohistochemical analysis of oral cancers. Herein, we demonstrate that PcMab-47 and 47-mG 2a can also be used to detect esophageal squamous cell carcinoma (ESCC) with this technique. These two antibodies, respectively, stained 123/130 (94.6%) and 127/130 (97.7%) ESCC cases, indicating that they can detect PODXL with high sensitivity in this carcinoma. Of more than 3+ cases, 47-mG 2a was more effective than PcMab-47, respectively, staining 56/127 (44.1%) and 41/123 (33.3%). Therefore, 47-mG 2a can be used for the detection of PODXL in ESCC using immunohistochemical analysis.

The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via fcg receptor-mediated cross-linking

DEFF Research Database (Denmark)

Overdijk, Marije B.; Jansen, J. H. Marco; Nederend, Maaike

2016-01-01

RIIb as well as activating FcgRs induce DARA cross-linking-mediated PCD. In conclusion, our in vitro and in vivo data show that FcgRmediated cross-linking of DARA induces PCD of CD38-expressing multiple myeloma tumor cells, which potentially contributes to the depth of response observed in DARA......Emerging evidence suggests that FcgR-mediated cross-linking of tumor-bound mAbs may induce signaling in tumor cells that contributes to their therapeutic activity. In this study, we show that daratumumab (DARA), a therapeutic human CD38 mAb with a broad-spectrum killing activity, is able to induce...... programmed cell death (PCD) of CD38+ multiple myeloma tumor cell lines when cross-linked in vitro by secondary Abs or via an FcgR. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcRg-chain knockout or NOTAM mice carrying a signaling-inactive FcRg-chain, we found that the inhibitory Fcg...

Aeroallergen analyses and their clinical relevance. I. Immunochemical quantification of allergens by RAST-inhibition, Mab-ELISA, basophil histamine release, and counter current immuno electrophoresis

DEFF Research Database (Denmark)

Johnsen, C R; Abrahamsen, L; Stahl Skov, P

1991-01-01

The aim was to compare IgE and IgG4 RAST-inhibition assay (RI), monoclonal antibody ELISA (Mab-ELISA), counter current immuno electrophoresis (CCIE) and histamine release from basophil leukocytes (HR) for allergen quantification with special reference to aeroallergen detection. As components......-U/ml) than IgE-RI (2*10(3) SQ-U/ml). The ranges of allergen detection limits for the Mab-ELISA were equal for cat and Derm. pter. (10-10(2) SQ-U/ml). The range of allergen detection limits for CCIE, assaying dog were 10(4)-10(5) SQ-U/ml. The ranges of allergen detection limits for HR were equal for cat...

Hydraulic and carbohydrate changes in experimental drought-induced mortality of saplings in two conifer species.

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Anderegg, William R L; Anderegg, Leander D L

2013-03-01

Global patterns of drought-induced forest die-off indicate that many forests may be sensitive to climate-driven mortality, but the lack of understanding of how trees and saplings die during drought hinders the projections of die-off, demographic bottlenecks and ecosystem trajectories. In this study, we performed a severe controlled drought experiment on saplings of Pinus edulis Engelm. and Juniperus osteosperma (Torr.) Little, two species that both experienced die-off in a recent 'climate change-type' drought. We examined the roles of carbohydrate and hydraulic changes in multiple tissues as the saplings died. We found that saplings of both species exhibited large degrees of loss of hydraulic conductivity prior to death. Neither species exhibited significant changes in carbohydrate concentrations in any tissue during the relatively short and severe imposed drought. Native hydraulic conductivity successfully predicted the degree of canopy mortality in both species, highlighting the importance of drought characteristics and tree attributes in influencing physiological pathways to mortality. The relationships elucidated here, as well as the differences between our results and previous findings in adult trees, can help inform mortality mechanisms in climate-vegetation models, especially for young trees, and to understand species response to severe drought across ontogeny.

The expression analysis of ICOS-L on activated T cells and immature dendritic cells as well as malignant B cells and Grave's-disease-derived thyroid tissues by two novel mAbs against human ICOS-L.

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Wang, F; Zhu, W; Liu, T; Sun, Z; Ju, S; Ju, S; Yu, G; Xie, W; Deng, Z; Lu, B; Zhang, X

2007-01-01

ICOS-L, a newly identified member of B7 superfamily, plays an important role in immune responses. In this article, we report on two novel mouse anti-human ICOS-L monoclonal antibodies (mAbs) named as 11C4 and 12B11, whose specificities were verified by methods of flow cytometry, western blotting, and epitope competition assay. The two mAbs bound to distinct ICOS-L epitopes on B cells. Interestingly, mAb 11C4 could well recognize ICOS-L molecule on activated T cells and Jurkat cell lines, which is different from commercial anti-ICOS-L mAb (clone number MIH12) and the other mAb 12B11. In addition, we found that the expression of ICOS-L molecule was only detected on the surface of immature monocyte-derived dendritic cells (Mo-DCs) and was sharply decreased after induction of mature Mo-DCs activated by tumor necrosis factor-alpha or CD40. Furthermore, we showed that 11C4 could effectively suppress the maturation of Mo-DCs in vitro as evidenced by the low expression of CD80, CD86, CD83, and human leukocyte antigen-DR, which suggested that ICOS-L may be involved in the maturation of Mo-DCs. Using immunohistochemistry staining with mAb 11C4, the expression of ICOS-L was found in B lymphoma tissues and thyroid tissues from the Grave's disease but not in thyroid adenoma and normal thyroid tissues.

Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

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Okazaki, Shogo [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nakatani, Fumi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Masuko, Kazue; Tsuchihashi, Kenji [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Ueda, Shiho; Masuko, Takashi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Saya, Hideyuki [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nagano, Osamu, E-mail: osmna@sb3.so-net.ne.jp [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

2016-01-29

The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-based cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.

Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

International Nuclear Information System (INIS)

Okazaki, Shogo; Nakatani, Fumi; Masuko, Kazue; Tsuchihashi, Kenji; Ueda, Shiho; Masuko, Takashi; Saya, Hideyuki; Nagano, Osamu

2016-01-01

The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-based cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.

Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality

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Jaimin M. Patel

2018-01-01

Full Text Available Background. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods. This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman’s rho. Results. Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p=0.002. PMA NETosis from patients with septic shock was reduced further (p<0.001 compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p<0.001, and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p=0.002 and 90-day mortality (p=0.014 in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions. Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced

Temperature extremes reduce seagrass growth and induce mortality.

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Collier, C J; Waycott, M

2014-06-30

Extreme heating (up to 43 °C measured from five-year temperature records) occurs in shallow coastal seagrass meadows of the Great Barrier Reef at low tide. We measured effective quantum yield (ϕPSII), growth, senescence and mortality in four tropical seagrasses to experimental short-duration (2.5h) spikes in water temperature to 35 °C, 40 °C and 43 °C, for 6 days followed by one day at ambient temperature. Increasing temperature to 35 °C had positive effects on ϕPSII (the magnitude varied between days and was highly correlated with PPFD), with no effects on growth or mortality. 40 °C represented a critical threshold as there were strong species differences and there was a large impact on growth and mortality. At 43 °C there was complete mortality after 2-3 days. These findings indicate that increasing duration (more days in a row) of thermal events above 40 °C is likely to affect the ecological function of tropical seagrass meadows. Copyright © 2014 Elsevier Ltd. All rights reserved.

Elevated [CO2] does not ameliorate the negative effects of elevated temperature on drought-induced mortality in Eucalyptus radiata seedlings.

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Duan, Honglang; Duursma, Remko A; Huang, Guomin; Smith, Renee A; Choat, Brendan; O'Grady, Anthony P; Tissue, David T

2014-07-01

It has been reported that elevated temperature accelerates the time-to-mortality in plants exposed to prolonged drought, while elevated [CO(2)] acts as a mitigating factor because it can reduce stomatal conductance and thereby reduce water loss. We examined the interactive effects of elevated [CO(2)] and temperature on the inter-dependent carbon and hydraulic characteristics associated with drought-induced mortality in Eucalyptus radiata seedlings grown in two [CO(2)] (400 and 640 μL L(-1)) and two temperature (ambient and ambient +4 °C) treatments. Seedlings were exposed to two controlled drying and rewatering cycles, and then water was withheld until plants died. The extent of xylem cavitation was assessed as loss of stem hydraulic conductivity. Elevated temperature triggered more rapid mortality than ambient temperature through hydraulic failure, and was associated with larger water use, increased drought sensitivities of gas exchange traits and earlier occurrence of xylem cavitation. Elevated [CO(2)] had a negligible effect on seedling response to drought, and did not ameliorate the negative effects of elevated temperature on drought. Our findings suggest that elevated temperature and consequent higher vapour pressure deficit, but not elevated [CO(2)], may be the primary contributors to drought-induced seedling mortality under future climates. © 2013 John Wiley & Sons Ltd.

Ozone Induced Premature Mortality and Crop Yield Loss in China

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Lin, Y.; Jiang, F.; Wang, H.

2017-12-01

Exposure to ambient ozone is a major risk factor for health impacts such as chronic obstructive pulmonary disease (COPD) and cause damage to plant and agricultural crops. But these impacts were usually evaluated separately in earlier studies. We apply Community Multi-scale Air Quality model to simulate the ambient O3 concentration at a resolution of 36 km×36 km across China. Then, we follow Global Burden of Diseases approach and AOT40 (i.e., above a threshold of 40 ppb) metric to estimate the premature mortalities and yield losses of major grain crops (i.e., winter wheat, rice and corn) across China due to surface ozone exposure, respectively. Our results show that ozone exposure leads to nearly 67,700 premature mortalities and 145 billion USD losses in 2014. The ozone induced yield losses of all crop production totaled 78 (49.9-112.6)million metric tons, worth 5.3 (3.4-7.6)billion USD, in China. The relative yield losses ranged from 8.5-14% for winter wheat, 3.9-15% for rice, and 2.2-5.5% for maize. We can see that the top four health affected provinces (Sichuan, Henan, Shandong, Jiangsu) are also ranking on the winter wheat and rice crop yield loss. Our results provide further evidence that surface ozone pollution is becoming urgent air pollution in China, and have important policy implications for China to alleviate the impacts of air pollution.

Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice.

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Zhang, Yiqiang; Fischer, Kathleen E; Soto, Vanessa; Liu, Yuhong; Sosnowska, Danuta; Richardson, Arlan; Salmon, Adam B

2015-06-15

Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. Published by Elsevier Inc.

The optimal definition of contrast-induced acute kidney injury for prediction of inpatient mortality in patients undergoing percutaneous coronary interventions.

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Parsh, Jessica; Seth, Milan; Briguori, Carlo; Grossman, Paul; Solomon, Richard; Gurm, Hitinder S

2016-05-01

It is unknown which definition of contrast-induced acute kidney injury (CI-AKI) in the setting of percutaneous coronary interventions is best associated with inpatient mortality and whether this association is stable across patients with various preprocedural serum creatinine (SCr) values. We applied logistic regression models to multiple CI-AKI definitions used by the Kidney Disease Improving Global Outcomes guidelines and previously published studies to examine the impact of preprocedural SCr on a candidate definition's correlation with the adverse outcome of inpatient mortality. We used likelihood ratio tests to examine candidate definitions and identify those where association with inpatient mortality remained constant regardless of preprocedural SCr. These definitions were assessed for specificity, sensitivity, and positive and negative predictive values to identify an optimal definition. Our study cohort included 119,554 patients who underwent percutaneous coronary intervention in Michigan between 2010 and 2014. Most commonly used definitions were not associated with inpatient mortality in a constant fashion across various preprocedural SCr values. Of the 266 candidate definitions examined, 16 definition's association with inpatient mortality was not significantly altered by preprocedural SCr. Contrast-induced acute kidney injury defined as an absolute increase of SCr ≥0.3 mg/dL and a relative SCr increase ≥50% was selected as the optimal candidate using Perkins and Shisterman decision theoretic optimality criteria and was highly predictive of and specific for inpatient mortality. We identified the optimal definition for CI-AKI to be an absolute increase in SCr ≥0.3 mg/dL and a relative SCr increase ≥50%. Further work is needed to validate this definition in independent studies and to establish its utility for clinical trials and quality improvement efforts. Copyright © 2016 Elsevier Inc. All rights reserved.

Trends and Tipping Points of Drought-induced Tree Mortality

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Huang, K.; Yi, C.; Wu, D.; Zhou, T.; Zhao, X.; Blanford, W. J.; Wei, S.; Wu, H.; Du, L.

2014-12-01

Drought-induced tree mortality worldwide has been recently reported in a review of the literature by Allen et al. (2010). However, a quantitative relationship between widespread loss of forest from mortality and drought is still a key knowledge gap. Specifically, the field lacks quantitative knowledge of tipping point in trees when coping with water stress, which inhibits the assessments of how climate change affects the forest ecosystem. We investigate the statistical relationships for different (seven) conifer species between Ring Width Index (RWI) and Standardized Precipitation Evapotranspiration Index (SPEI), based on 411 chronologies from the International Tree-Ring Data Bank across 11 states of the western United States. We found robust species-specific relationships between RWI and SPEI for all seven conifer species at dry condition. The regression models show that the RWI decreases with SPEI decreasing (drying) and more than 76% variation of tree growth (RWI) can be explained by the drought index (SPEI). However, when soil water is sufficient (i.e., SPEI>SPEIu), soil water is no longer a restrictive factor for tree growth and, therefore, the RWI shows a weak correlation with SPEI. Based on the statistical models, we derived the tipping point of SPEI (SPEItp) where the RWI equals 0, which means the carbon efflux by tree respiration equals carbon influx by tree photosynthesis. When the severity of drought exceeds this tipping point(i.e. SPEIsupported by the Fund for Creative Research Groups of National Natural Science Foundation of China (No. 41321001), the National Basic Research Program of China (No. 2012CB955401), the New Century Excellent Talents in University (No. NCET-10-0251), U.S. PSC-CUNY Award (PSC-CUNY-ENHC-44-83) and the High Technology Research and Development Program of China (No. 2013AA122801).

Remotely sensed predictors of conifer tree mortality during severe drought

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Brodrick, P. G.; Asner, G. P.

2017-11-01

Widespread, drought-induced forest mortality has been documented on every forested continent over the last two decades, yet early pre-mortality indicators of tree death remain poorly understood. Remotely sensed physiological-based measures offer a means for large-scale analysis to understand and predict drought-induced mortality. Here, we use laser-guided imaging spectroscopy from multiple years of aerial surveys to assess the impact of sustained canopy water loss on tree mortality. We analyze both gross canopy mortality in 2016 and the change in mortality between 2015 and 2016 in millions of sampled conifer forest locations throughout the Sierra Nevada mountains in California. On average, sustained water loss and gross mortality are strongly related, and year-to-year water loss within the drought indicates subsequent mortality. Both relationships are consistent after controlling for location and tree community composition, suggesting that these metrics may serve as indicators of mortality during a drought.

Myeloablative radioimmunotherapy with 188Re-CD66mAb before stem cell transplantation. No increase of proinflammatory cytokine levels of TNF-α

International Nuclear Information System (INIS)

Mutschler, J.; Reske, S.N.; Steinbach, G.; Bunjes, D.; Buchmann, I.

2009-01-01

Tumour necrosis factor-α (TNF-α) serum levels may increase due to intensive conditioning regimes with high-dose chemotherapy and total body irradiation (TBI) before stem cell transplantation. This increases the risk for developing acute graft versus host disease (aGvHD) after stem cell transplantation. In this prospective study we investigated the influence of radioimmunotherapy with 188 Re-CD-66-mAb on changes on TNF-α serum levels. Patients, methods: In 18 patients we measured TNF-α before and up to 96 hours after radioimmunotherapy, in 2 patients in addition following TBI, in 9 patients also following chemotherapy. For measuring TNF-α we used an automated immunochemiluminescence assay (Immulite 1000 DPC Biermann, Bad Nauheim). The mean follow up period to record incidence of aGVHD was 100 days after stem cell transplantation. Compared to the basal levels before, the levels of TNF-α after conditioning with 188 Re-CD-66-mAb did not increase significantly and remained in the physiological range. In contrast, these initial physiological cytokine levels increased and became pathological following 48 h after total body irradiation (13.2 ± 6.6 pg/ml) and chemotherapy (10.8 ± 15.7 pg/ml). In our study we found a low incidence of aGvHD (22.2%, n = 4/18). Conclusion: These results demonstrate that additional conditioning therapy with 188 Re-CD-66-mAb does not increase proinflammatory cytokine levels of TNF-α. This finding may indicate that additive radioimmunotherapy may not be a significant factor for increasing the rate of conditioning- associated aGvHD. (orig.)

Estimating the Magnitude and Field-Size Dependence of Radiotherapy-Induced Mortality and Tumor Control After Postoperative Radiotherapy For Non-Small-Cell Lung Cancer: Calculations From Clinical Trials

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Miles, Edward F.; Kelsey, Chris R.; Kirkpatrick, John P.; Marks, Lawrence B.

2007-01-01

Purpose: To create, on the basis of available data, a mathematical model to describe the tumor stage- and field size-dependent risks/benefits of postoperative radiotherapy (PORT) for non-small-cell lung cancer (NSCLC), and to assess whether this simple model can accurately describe the reported changes in overall survival. Methods and Materials: The increase in overall survival afforded by PORT is assumed equal to the increase in cancer-specific survival minus the rate of RT-induced mortality. The increase in cancer-specific survival is the product of the probabilities of (residual local disease) x (sterilization of residual disease with PORT) x (absence of metastatic disease). Data were extracted from the literature to estimate these probabilities. Different models were considered to relate the RT-induced mortality to field size. Results: The rate of RT-induced mortality seems to be proportional to the cube of the field size. When these mortality rates are included in the model, the predicted changes in overall survival approximate the literature values. Conclusion: Clinical data can be explained by a simple model that suggests that RT-induced mortality is strongly dependent on field size and at least partly offsets the benefit afforded by PORT. Smaller RT fields, tailored to treat the areas most at risk for recurrence, provide the highest therapeutic ratio. The data used do not reflect the impact of chemotherapy, which will reduce the rate of distant metastases and enhance the efficacy of RT

CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.

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Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P; Morrione, Andrea; Scotlandi, Katia

2016-11-29

CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.

Nosema ceranae induced mortality in honey bees (Apis mellifera) depends on infection methods.

Science.gov (United States)

Milbrath, Meghan O; Xie, Xianbing; Huang, Zachary Y

2013-09-01

Nosema ceranae infection can reduce survival of the Western honey bee, Apis mellifera, but experiments examining its virulence have highly variable results. This variation may arise from differences in experimental techniques. We examined survival effects of two techniques: Nosema infection at day 1 without anesthesia and infection at day 5 using CO2 anesthesia. All bees infected with the latter method had poorer survival. Interestingly, these bees also had significantly fewer spores than bees infected without anesthesia. These results indicate that differences in Nosema ceranae-induced mortality in honey bees may be partially due to differences in experimental techniques. Copyright © 2013 Elsevier Inc. All rights reserved.

Kaempferol protects against gamma radiation-induced mortality and damage via inhibiting oxidative stress and modulating apoptotic molecules in vivo and vitro.

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Wang, Jing; Li, Tiejun; Feng, Jingjing; Li, Li; Wang, Rong; Cheng, Hao; Yuan, Yongfang

2018-04-20

To investigate the potential protective effect of kaempferol, a representative flavonoid, against radiation induced mortality and injury in vivo and vitro.C57BL/6 male mice and human umbilical venous endothelial cells (HUVECs) were pretreated with kaempferol before radiation. We found that kaempferol can effectively increase 30-day survival rate after 8.5 Gy lethal total body irradiation (TBI). Mice were sacrificed at 7th day after 7 Gy TBI, we found kaempferol against radiation-induced tissues damage, by inhibiting the oxidative stress, and attenuating morphological changes and cell apoptosis. In vitro, kaempferol increased HUVECs cell viability and decrease apoptosis. It also mitigated oxidative stress and restored the abnormal expression of prx-5, Cyt-c, Caspase9 and Caspase3 in mRNA and protein level in HUVECs after radiation. Taken together, it suggests kaempferol can protect against gamma-radiation induced tissue damage and mortality. The present study is the first report of the radioprotective role of kaempferol in vivo and vitro. Copyright © 2018 Elsevier B.V. All rights reserved.

Economic assessment of wild bird mortality induced by the use of lead gunshot in European wetlands.

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Andreotti, Alessandro; Guberti, Vittorio; Nardelli, Riccardo; Pirrello, Simone; Serra, Lorenzo; Volponi, Stefano; Green, Rhys E

2018-01-01

In European wetlands, at least 40 bird species are exposed to the risk of lead poisoning caused by ingestion of spent lead gunshot. Adopting a methodology developed in North America, we estimated that about 700,000 individuals of 16 waterbird species die annually in the European Union (EU) (6.1% of the wintering population) and one million in whole Europe (7.0%) due to acute effects of lead poisoning. Furthermore, threefold more birds suffer sub-lethal effects. We assessed the economic loss due to this lead-induced mortality of these 16 species by calculating the costs of replacing lethally poisoned wild birds by releasing captive-bred ones. We assessed the cost of buying captive-bred waterbirds for release from market surveys and calculated how many captive-bred birds would have to be released to compensate for the loss, taking into account the high mortality rate of captive birds (72.7%) in the months following release into the wild. Following this approach, the annual cost of waterbird mortality induced by lead shot ingestion is estimated at 105 million euros per year in the EU countries and 142 million euros in the whole of Europe. An alternative method, based upon lost opportunities for hunting caused by deaths due to lead poisoning, gave similar results of 129 million euros per year in the EU countries and 185 million euros per year in the whole of Europe. For several reasons these figures should be regarded as conservative. Inclusion of deaths of species for which there were insufficient data and delayed deaths caused indirectly by lead poisoning and effects on reproduction would probably increase the estimated losses substantially. Nevertheless, our results suggest that the benefits of a restriction on the use of lead gunshot over wetlands could exceed the cost of adapting to non-lead ammunition. Copyright © 2017 Elsevier B.V. All rights reserved.

Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo

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Pollen K.F. Yeung

2014-09-01

Full Text Available The benefit of calcium channel blockers for cardiovascular prevention against heart attack and stroke has not been firmly supported. We investigated the possible cardiovascular protective effect of diltiazem (DTZ against injury induced by isoproterenol using a freely moving rat model in vivo. Sprague Dawley rats were injected subcutaneously (sc with either 5 or 10 mg/kg of DTZ, or saline as control, twice daily for five doses. One hour after the last injection, a single dose of isoproterenol (30 mg/kg was injected sc to each rat. Blood samples were collected serially for 6 h for measurement of adenine nucleotides (ATP, ADP and AMP in red blood cell (RBC by a validated HPLC. The study has shown isoproterenol induced 50% mortality and also increased RBC concentrations of AMP from 0.04 ± 0.02 to 0.29 ± 0.21 mM at the end of the experiment (p < 0.05. Treatment with 10 mg/kg of DTZ reduced mortality from 50% to <20% and attenuated the increase of RBC concentrations of AMP from +0.25 ± 0.22 in the control rats to +0.072 ± 0.092 mM (p < 0.05. The study concluded that 10 mg/kg of DTZ reduced mortality and breakdown of ATP induced by isoproterenol in rats.

A comparison of targetting of neuroblastoma with MIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

International Nuclear Information System (INIS)

Hoefnagel, C.A.; Rutgers, M.; Buitenhuis, C.K.M.; Smets, L.A.; Kraker, J. de; Meli, M.; Carrel, F.; Schubiger, P.A.; Novak-Hofer, I.; Amstutz, H.

2001-01-01

Modine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131 I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targetting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131 I-MIBG (110 MBq) and with 131 I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131 I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131 I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131 I-mAb chCE7 and of 24 days with 131 I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131 I-chCE7 compared with 131 I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131 I-MIBG and 131 I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131 I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not

An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy

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Talavera, Jesús; Fernández-Del-Palacio, María Josefa; García-Nicolás, Obdulio; Seva, Juan; Brooks, Gavin; Moraleda, Jose M.

2015-01-01

Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality. PMID:26788502

Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice.

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Holgersen, Kristine; Kvist, Peter Helding; Hansen, Axel Kornerup; Holm, Thomas Lindebo

2014-07-01

Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFα mAb, cyclosporine A (CsA) and oral prednisolone treatment. To evaluate cell involvement in the disease pathogenesis, specific cell subsets were depleted by treatment with anti-CD4 mAb, anti-CD8 mAb or clodronate-encapsulated liposomes. T cell receptor co-stimulation was blocked by CTLA4-Ig. Cytokine profiling ELISAs and calprotectin immunohistochemistry were performed on colon tissue. Treatments with anti-IL-12/23p40 mAb and CsA prevented disease in PAC IL-10 k.o. mice and reduced IFNγ, IL-17A, MPO and calprotectin levels in colon. Anti-TNFα mAb treatment caused amelioration of selected clinical parameters. No effect of prednisolone was detected. Depletion of CD8(+) cells tended to increase mortality, whereas treatment with anti-CD4 mAb or CTLA4-Ig had no significant effect on disease development. Clodronate liposome treatment induced a loss of body weight; nevertheless macrophage depletion was associated with a significant reduction in colonic pathology. In conclusion, reference drugs with known efficacy in severe inflammatory bowel disease were efficacious in the PAC IL-10 k.o. model. Our data indicate that in this model macrophages are a main driver of colitis, whereas CD4(+) cells are not. Copyright © 2014 Elsevier B.V. All rights reserved.

Seagrass proliferation precedes mortality during hypo-salinity events: a stress-induced morphometric response.

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Catherine J Collier

Full Text Available Halophytes, such as seagrasses, predominantly form habitats in coastal and estuarine areas. These habitats can be seasonally exposed to hypo-salinity events during watershed runoff exposing them to dramatic salinity shifts and osmotic shock. The manifestation of this osmotic shock on seagrass morphology and phenology was tested in three Indo-Pacific seagrass species, Halophila ovalis, Halodule uninervis and Zostera muelleri, to hypo-salinity ranging from 3 to 36 PSU at 3 PSU increments for 10 weeks. All three species had broad salinity tolerance but demonstrated a moderate hypo-salinity stress response--analogous to a stress induced morphometric response (SIMR. Shoot proliferation occurred at salinities <30 PSU, with the largest increases, up to 400% increase in shoot density, occurring at the sub-lethal salinities <15 PSU, with the specific salinity associated with peak shoot density being variable among species. Resources were not diverted away from leaf growth or shoot development to support the new shoot production. However, at sub-lethal salinities where shoots proliferated, flowering was severely reduced for H. ovalis, the only species to flower during this experiment, demonstrating a diversion of resources away from sexual reproduction to support the investment in new shoots. This SIMR response preceded mortality, which occurred at 3 PSU for H. ovalis and 6 PSU for H. uninervis, while complete mortality was not reached for Z. muelleri. This is the first study to identify a SIMR in seagrasses, being detectable due to the fine resolution of salinity treatments tested. The detection of SIMR demonstrates the need for caution in interpreting in-situ changes in shoot density as shoot proliferation could be interpreted as a healthy or positive plant response to environmental conditions, when in fact it could signal pre-mortality stress.

Contributions of gut bacteria to Bacillus thuringiensis-induced mortality vary across a range of Lepidoptera

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Holt Jonathan

2009-03-01

treatment significantly increased mortality of Pectinophora gossypiella (Saunders, which was also the only species with detectable gut bacteria that lacked a Gram-negative component. Further, mortality of P. gossypiella larvae reared on diet amended with B. thuringiensis toxin and Enterobacter sp. NAB3 was generally faster than with B. thuringiensis toxin alone. Conclusion This study demonstrates that in some larval species, indigenous gut bacteria contribute to B. thuringiensis susceptibility. Moreover, the contribution of enteric bacteria to host mortality suggests that perturbations caused by toxin feeding induce otherwise benign gut bacteria to exert pathogenic effects. The interaction between B. thuringiensis and the gut microbiota of Lepidoptera may provide a useful model with which to identify the factors involved in such transitions.

Neutralization of White Spot Syndrome Virus by Monoclonal Antibodies against Viral Envelope Proteins

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Hsiu-Hui Shih

2004-09-01

Full Text Available Two monoclonal antibodies (MAbs recognizing envelope proteins of the white spot syndrome virus (WSSV, 6E1 against VP28 and 3E8 against VP19, were applied to demonstrate their neutralizing ability to this virus by using both in vitro and in vivo assays. Mixtures of MAb 6E1 with virus filtrate were inoculated into the primary explant monolayer culture derived from the lymphoid Oka organs of Penaeus monodon. Mab was likely to neutralize the infectivity of virus to monolayer since cytopathic effects were apparently blocked in experiment group. WSSV was titrated using Blue-Cell ELISA and the neutralizing index was calculated to be 6.90 for 6EI and 5.83 for 3E8. Neutralized virus fluids injected intramuscularly into post larvae of P. monodon. The shrimp in the positive control, which were injected with WSSV only showed an increasing mortality and a 100% mortality was reached at day 34, whereas no shrimp died in the negative control. The mortality for 6E1 was 6.7% and for 3E8 was 13.3%. These results suggest that Mabs recognizing the WSSV envelope proteins could neutralize viral infectivity to both cultured cells and shrimp.

Studies of the mortality of A-bomb survivors. 8. Cancer mortality, 1950-1982

International Nuclear Information System (INIS)

Preston, D.L.; Kato, H.; Kopecky, K.; Fujita, S.

1987-01-01

This study extends an earlier one by 4 years (1979-1982) and includes mortality data on 11,393 additional Nagasaki survivors. Significant dose responses are observed for leukemia, multiple myeloma, and cancers of the lung, female breast, stomach, colon, esophagus, and urinary tract. Due to diagnostic difficulties, results for liver and ovarian cancers, while suggestive of significant dose responses, do not provide convincing evidence for radiogenic effects. No significant dose responses are seen for cancers of the gallbladder, prostate, rectum, pancreas, or uterus, or for lymphoma. For solid tumors, largely due to sex-specific differences in the background rates, the relative risk of radiation-induced mortality is greater for women than for men. For nonleukemic cancers the relative risk seen in those who were young when exposed has decreased with time, while the smaller risks for those who were older at exposure have tended to increase. While the absolute excess risks of radiation-induced mortality due to nonleukemic cancer have increased with time for all age-at-exposure groups, both excess and relative risks of leukemia have generally decreased with time. For leukemia, the rate of decrease in risk and the initial level of risk are inversely related to age at exposure

Simulation of Drought-induced Tree Mortality Using a New Individual and Hydraulic Trait-based Model (S-TEDy)

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Sinha, T.; Gangodagamage, C.; Ale, S.; Frazier, A. G.; Giambelluca, T. W.; Kumagai, T.; Nakai, T.; Sato, H.

2017-12-01

Drought-related tree mortality at a regional scale causes drastic shifts in carbon and water cycling in Southeast Asian tropical rainforests, where severe droughts are projected to occur more frequently, especially under El Niño conditions. To provide a useful tool for projecting the tropical rainforest dynamics under climate change conditions, we developed the Spatially Explicit Individual-Based (SEIB) Dynamic Global Vegetation Model (DGVM) applicable to simulating mechanistic tree mortality induced by the climatic impacts via individual-tree-scale ecophysiology such as hydraulic failure and carbon starvation. In this study, we present the new model, SEIB-originated Terrestrial Ecosystem Dynamics (S-TEDy) model, and the computation results were compared with observations collected at a field site in a Bornean tropical rainforest. Furthermore, after validating the model's performance, numerical experiments addressing a future of the tropical rainforest were conducted using some global climate model (GCM) simulation outputs.

A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. elegans vit-2 vitellogenin gene is directly regulated by ELT-2, MAB-3, FKH-9 and DAF-16 and indirectly regulated by the germline, by daf-2/insulin signaling and by the TGF-β/Sma/Mab pathway.

Science.gov (United States)

Goszczynski, Barbara; Captan, Vasile V; Danielson, Alicia M; Lancaster, Brett R; McGhee, James D

2016-05-01

The Caenorhabditis elegans vitellogenin genes are transcribed in the intestine of adult hermaphrodites but not of males. A 44-bp region from the vit-2 gene promoter is able largely to reconstitute this tissue-, stage- and sex-specific-expression. This "enhancer" contains a binding site for the DM-domain factor MAB-3, the male-specific repressor of vitellogenesis, as well as an activator site that we show is the direct target of the intestinal GATA factor ELT-2. We further show that the enhancer is directly activated by the winged-helix/forkhead-factor FKH-9, (whose gene has been shown by others to be a direct target of DAF-16), by an unknown activator binding to the MAB-3 site, and by the full C. elegans TGF-β/Sma/Mab pathway acting within the intestine. The vit-2 gene has been shown by others to be repressed by the daf-2/daf-16 insulin signaling pathway, which so strongly influences aging and longevity in C. elegans. We show that the activity of the 44 bp vit-2 enhancer is abolished by loss of daf-2 but is restored by simultaneous loss of daf-16. DAF-2 acts from outside of the intestine but DAF-16 acts both from outside of the intestine and from within the intestine where it binds directly to the same non-canonical target site that interacts with FKH-9. Activity of the 44 bp vit-2 enhancer is also inhibited by loss of the germline, in a manner that is only weakly influenced by DAF-16 but that is strongly influenced by KRI-1, a key downstream effector in the pathway by which germline loss increases C. elegans lifespan. The complex behavior of this enhancer presumably allows vitellogenin gene transcription to adjust to demands of body size, germline proliferation and nutritional state but we suggest that the apparent involvement of this enhancer in aging and longevity "pathways" could be incidental. Copyright © 2016 Elsevier Inc. All rights reserved.

Soluble TWEAK and Cardiovascular Morbidity and Mortality in ...

African Journals Online (AJOL)

Introduction: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in chronic kidney patients (CKD). The aim of this study was to demonstrate the role of soluble tumor necrosis factor (TNF) weak inducer of apoptosis (sTWEAK) as a marker of cardiovascular morbidity and mortality in CKD patients.

MHC class II ligation induces CD58 (LFA-3)-mediated adhesion in human T cells

DEFF Research Database (Denmark)

Nielsen, M; Gerwien, J; Geisler, C

1998-01-01

ligation induces homotypic adhesion in both beta2-integrin-positive and negative, CD4-positive T cell lines. Anti-CD18 monoclonal antibody (mAb) weakly inhibited the adhesion response in beta2-integrin-positive T cells and had no effect on beta2-integrin-negative T cells. In contrast, an anti-CD58 (LFA-3...

Small scale affinity purification and high sensitivity reversed phase nanoLC-MS N-glycan characterization of mAbs and fusion proteins.

Science.gov (United States)

Higel, Fabian; Seidl, Andreas; Demelbauer, Uwe; Sörgel, Fritz; Frieß, Wolfgang

2014-01-01

N-glycosylation is a complex post-translational modification with potential effects on the efficacy and safety of therapeutic proteins and known influence on the effector function of biopharmaceutical monoclonal antibodies (mAbs). Comprehensive characterization of N-glycosylation is therefore important in biopharmaceutical development. In early development, e.g. during pool or clone selection, however, only minute protein amounts of multiple samples are available for analytics. High sensitivity and high throughput methods are thus needed. An approach based on 96-well plate sample preparation and nanoLC-MS of 2- anthranilic acid or 2-aminobenzoic acid (AA) labeled N-glycans for the characterization of biopharmaceuticals in early development is reported here. With this approach, 192 samples can be processed simultaneously from complex matrices (e.g., cell culture supernatant) to purified 2-AA glycans, which are then analyzed by reversed phase nanoLC-MS. Attomolar sensitivity has been achieved by use of nanoelectrospray ionization, resulting in detailed glycan maps of mAbs and fusion proteins that are exemplarily shown in this work. Reproducibility, robustness and linearity of the approach are demonstrated, making use in a routine manner during pool or clone selection possible. Other potential fields of application, such as glycan biomarker discovery from serum samples, are also presented.

Assessment of sampling mortality of larval fishes

International Nuclear Information System (INIS)

Cada, G.F.; Hergenrader, G.L.

1978-01-01

A study was initiated to assess the mortality of larval fishes that were entrained in the condenser cooling systems of two nuclear power plants on the Missouri River in Nebraska. High mortalities were observed not only in the discharge collections but also in control samples taken upriver from the plants where no entrainment effects were possible. As a result, entrainment mortality generally could not be demonstrated. A technique was developed which indicated that (1) a significant portion of the observed mortality above the power plants was the result of net-induced sampling mortality, and (2) a direct relationship existed between observed mortality and water velocity in the nets when sampling at the control sites, which was described by linear regression equations. When these equations were subsequently used to remove the effects of wide differences in sampling velocities between control and discharge collections, significant entrainment mortality was noted in all cases. The equations were also used to derive estimates of the natural mortality of ichthyoplankton in this portion of the Missouri River

Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity.

Science.gov (United States)

Koobkokkruad, Thongchai; Kadotani, Tatsuya; Hutamekalin, Pilaiwanwadee; Mizutani, Nobuaki; Yoshino, Shin

2011-11-04

The collagen antibody-induced arthritis (CAIA) model, which employs a cocktail of monoclonal antibodies (mAbs) to type II collagen (CII), has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes induces arthritis, suggesting that a combination of mAbs showing strong ability to bind mouse CII and activate the complement may effectively induce arthritis in mice. In the present study, we examined the relationship between the induction of arthritis by the combination of IgG2a (CII-6 and C2A-12), IgG2b (CII-3, C2B-14 and C2B-16) and IgM (CM-5) subclones of monoclonal antibodies (mAb) of anti-bovine or chicken CII and the ability of mAbs to activate complement and bind mouse CII. DBA/1J mice were injected with several combinations of mAbs followed by lipopolysaccharide. Furthermore, the ability of mAbs to activate the complement and bind mouse CII was examined by ELISA. First, DBA/1J mice were injected with the combined 4 mAbs (CII-3, CII-6, C2B-14, and CM-5) followed by lipopolysaccharide, resulting in moderate arthritis. Excluding one of the mAbs, i.e., using only CII-3, CII-6, and C2B-14, induced greater inflammation of the joints. Next, adding C2A-12 but not C2B-16 to these 3 mAbs produced more severe arthritis. A combination of five clones, consisting of all 5 mAbs, was less effective. Histologically, mice given the newly developed 4-clone cocktail had marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone. Furthermore, 4 of the 6 clones (CII-3, CII-6, C2B-14, and C2A-12) showed not only a strong cross-reaction with mouse CII but also marked activation of the complement in vitro. The combination of 4 mAbs showing

Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity

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Mizutani Nobuaki

2011-11-01

Full Text Available Abstract Background The collagen antibody-induced arthritis (CAIA model, which employs a cocktail of monoclonal antibodies (mAbs to type II collagen (CII, has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes induces arthritis, suggesting that a combination of mAbs showing strong ability to bind mouse CII and activate the complement may effectively induce arthritis in mice. In the present study, we examined the relationship between the induction of arthritis by the combination of IgG2a (CII-6 and C2A-12, IgG2b (CII-3, C2B-14 and C2B-16 and IgM (CM-5 subclones of monoclonal antibodies (mAb of anti-bovine or chicken CII and the ability of mAbs to activate complement and bind mouse CII. Methods DBA/1J mice were injected with several combinations of mAbs followed by lipopolysaccharide. Furthermore, the ability of mAbs to activate the complement and bind mouse CII was examined by ELISA. Results First, DBA/1J mice were injected with the combined 4 mAbs (CII-3, CII-6, C2B-14, and CM-5 followed by lipopolysaccharide, resulting in moderate arthritis. Excluding one of the mAbs, i.e., using only CII-3, CII-6, and C2B-14, induced greater inflammation of the joints. Next, adding C2A-12 but not C2B-16 to these 3 mAbs produced more severe arthritis. A combination of five clones, consisting of all 5 mAbs, was less effective. Histologically, mice given the newly developed 4-clone cocktail had marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone. Furthermore, 4 of the 6 clones (CII-3, CII-6, C2B-14, and C2A-12 showed not only a strong cross-reaction with mouse CII but also marked activation of the

Exercise-induced hypertension, cardiovascular events, and mortality in patients undergoing exercise stress testing: a systematic review and meta-analysis.

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Schultz, Martin G; Otahal, Petr; Cleland, Verity J; Blizzard, Leigh; Marwick, Thomas H; Sharman, James E

2013-03-01

The prognostic relevance of a hypertensive response to exercise (HRE) is ill-defined in individuals undergoing exercise stress testing. The study described here was intended to provide a systematic review and meta-analysis of published literature to determine the value of exercise-related blood pressure (BP) (independent of office BP) for predicting cardiovascular (CV) events and mortality. Online databases were searched for published longitudinal studies reporting exercise-related BP and CV events and mortality rates. We identified for review 12 longitudinal studies with a total of 46,314 individuals without significant coronary artery disease, with total CV event and mortality rates recorded over a mean follow-up of 15.2±4.0 years. After adjustment for age, office BP, and CV risk factors, an HRE at moderate exercise intensity carried a 36% greater rate of CV events and mortality (95% CI, 1.02-1.83, P = 0.039) than that of subjects without an HRE. Additionally, each 10mm Hg increase in systolic BP during exercise at moderate intensity was accompanied by a 4% increase in CV events and mortality, independent of office BP, age, or CV risk factors (95% CI, 1.01-1.07, P = 0.02). Systolic BP at maximal workload was not significantly associated with the outcome of an increased rate of CV, whether analyzed as a categorical (HR=1.49, 95% CI, 0.90-2.46, P = 0.12) or a continuous (HR=1.01, 95% CI, 0.98-1.04, P = 0.53) variable. An HRE at moderate exercise intensity during exercise stress testing is an independent risk factor for CV events and mortality. This highlights the need to determine underlying pathophysiological mechanisms of exercise-induced hypertension.

Recurrent exposure to subclinical lipopolysaccharide increases mortality and induces cardiac fibrosis in mice.

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Wilbur Y W Lew

Full Text Available BACKGROUND: Circulating subclinical lipopolysaccharide (LPS occurs in health and disease. Ingesting high fatty meals increases LPS that cause metabolic endotoxemia. Subclinical LPS in periodontal disease may impair endothelial function. The heart may be targeted as cardiac cells express TLR4, the LPS receptor. It was hypothesized that recurrent exposure to subclinical LPS increases mortality and causes cardiac fibrosis. METHODS: C57Bl/6 mice were injected with intraperitoneal saline (control, low dose LPS (0.1 or 1 mg/kg, or moderate dose LPS (10 or 20 mg/kg, once a week for 3 months. Left ventricular (LV function (echocardiography, hemodynamics (tail cuff pressure and electrocardiograms (telemetry were measured. Cardiac fibrosis was assessed by picrosirius red staining and LV expression of fibrosis related genes (QRT-PCR. Adult cardiac fibroblasts were isolated and exposed to LPS. RESULTS: LPS injections transiently increased heart rate and blood pressure (<6 hours and mildly decreased LV function with full recovery by 24 hours. Mice tolerated weekly LPS for 2-3 months with no change in activity, appearance, appetite, weight, blood pressure, LV function, oximetry, or blood chemistries. Mortality increased after 60-90 days with moderate, but not low dose LPS. Arrhythmias occurred a few hours before death. LV collagen fraction area increased dose-dependently from 3.0±0.5% (SEM in the saline control group, to 5.6±0.5% with low dose LPS and 9.7±0.9% with moderate dose LPS (P<0.05 moderate vs low dose LPS, and each LPS dose vs control. LPS increased LV expression of collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, periostin and IL-6 (P<0.05 moderate vs low dose LPS and vs control. LPS increased α-SMA immunostaining of myofibroblasts. LPS dose-dependently increased IL-6 in isolated adult cardiac fibroblasts. CONCLUSIONS: Recurrent exposure to subclinical LPS increases mortality and induces cardiac fibrosis.

Pinyon pine mortality alters communities of ground-dwelling arthropods

Science.gov (United States)

Robert J. Delph; Michael J. Clifford; Neil S. Cobb; Paulette L. Ford; Sandra L. Brantley

2014-01-01

We documented the effect of drought-induced mortality of pinyon pine (Pinus edulis Engelm.) on communities of ground-dwelling arthropods. Tree mortality alters microhabitats utilized by ground-dwelling arthropods by increasing solar radiation, dead woody debris, and understory vegetation. Our major objectives were to determine (1) whether there were changes in...

Life‐cycle and cost of goods assessment of fed‐batch and perfusion‐based manufacturing processes for mAbs

Science.gov (United States)

Bunnak, Phumthep; Allmendinger, Richard; Ramasamy, Sri V.; Lettieri, Paola

2016-01-01

Life‐cycle assessment (LCA) is an environmental assessment tool that quantifies the environmental impact associated with a product or a process (e.g., water consumption, energy requirements, and solid waste generation). While LCA is a standard approach in many commercial industries, its application has not been exploited widely in the bioprocessing sector. To contribute toward the design of more cost‐efficient, robust and environmentally‐friendly manufacturing process for monoclonal antibodies (mAbs), a framework consisting of an LCA and economic analysis combined with a sensitivity analysis of manufacturing process parameters and a production scale‐up study is presented. The efficiency of the framework is demonstrated using a comparative study of the two most commonly used upstream configurations for mAb manufacture, namely fed‐batch (FB) and perfusion‐based processes. Results obtained by the framework are presented using a range of visualization tools, and indicate that a standard perfusion process (with a pooling duration of 4 days) has similar cost of goods than a FB process but a larger environmental footprint because it consumed 35% more water, demanded 17% more energy, and emitted 17% more CO2 than the FB process. Water consumption was the most important impact category, especially when scaling‐up the processes, as energy was required to produce process water and water‐for‐injection, while CO2 was emitted from energy generation. The sensitivity analysis revealed that the perfusion process can be made more environmentally‐friendly than the FB process if the pooling duration is extended to 8 days. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1324–1335, 2016 PMID:27390260

Some reproductive health indicators in Ukraine : A study with special emphasis on factors behind induced aboartion and perinatal mortality

OpenAIRE

Mogilevkina, Iryna

2002-01-01

Objectives: To study indicators specifically reflecting the reproductive health of Ukrainian women and to analyse factors behind the indicators. Methods: Induced abortion and maternal mortality were studied in some countries/regions of the former Soviet Union, using official statistics. Abortion rates, contraceptive practices and intentions in Ukrainian women were analysed by a large self-completion survey in 1996, and by a classroom questionnaire to first year medical students in 1999 in Do...

[Mortality cost of smoking in Spain].

Science.gov (United States)

Cobacho Tornel, Ma Belén; López Nicolás, Angel; Ramos Parreño, José María

2010-01-01

Public policies are crucial for smoking prevention and improving health among the population. Despite the positive impact in Spain of the law for smoking prevention in 2006, there is room for further improvement in this area of public policy. The estimate of the mortality cost per pack of cigarretes is a crucial factor in cost-benefit analysis for policies aimed to reducing smoking induced mortality. The aim of this paper is twofold. First, we estimate the Value of Statistical Life (VSL) among Spanish smokers. Secondly, we quantify the mortality cost of smoking. We use a hedonic wage model to quantify the marginal value of an increase in the mortality risk in monetary terms. We estimate the model for the Spanish labour market using the European Community Household Data and the Encuesta de Accidentes de Trabajo from the Ministerio de Trabajo e Inmigración. We estimate a VSL of 3.78 million Euros for Spanish smokers. Using this value, in conjunction with the increase in the mortality risk over the life cycle due to smoking, the private mortality cost of smoking is 78 Euros per pack for men, and 54 Euros per pack for women (in 2000 Euros). The mortality cost per pack of cigarettes is highly above its market price.

Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

Science.gov (United States)

DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

2016-01-01

Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

Characterization of a rhabdovirus isolated from carpione Salmo trutta carpio in Italy

Science.gov (United States)

Bovo, G.; Olesen, N.J.; Jorgensen, P.E.V.; Ahne, W.; Winton, J.R.

1995-01-01

A virus, strain 583, was isolated from carpione Salmo trutta carpio fry exhibiting high mortality. The virus was not neutralized by rabbit antisera against the fish rhabdoviruses viral haemorrhagic septicaemia virus (VHSV), infectious hematopoietic necrosis virus, eel rhabdovirus European X, spring viraemia of carp virus or pike fry rhabdovirus, or against the birnavirus infectious pancreatic necrosis virus. The virus replicated in several fish cell lines incubated at 20 to 25*C and grew optimally in the bluegill fry (BF-2) and fathead minnow (FHM) cell lines. Electron microscopy of infected BF-2 cell cultures revealed the presence of typical rhabdovirus particles, and immunofluorescent staining was observed using various polyclonal and monoclonal antibodies (MAbs) against Egtved virus, the causative agent of viral haemorrhagic septicaemia. The staining by a MAb against the nucleoprotein (N) of VHSV was particularly strong, a MAb against the glycoprotein (G) gave a moderate reaction, whereas a second MAb against the G protein and MAbs against the matrix proteins, M_(1) and M_(2), of VHSV did not react. Fluorescence titres using 3 rabbit antisera against whole Egtved virus varied between negative and moderately positive. Western blotting using polyclonal and monoclonal sera confirmed that both the N and G proteins of the carpione virus shared some epitopes with those of VHSV, but the M_(1) and M_(2) proteins did not. SDS-PAGE showed the structural proteins of the carpione virus produced a pattern typical of members of the Lyssavirus genus of the Rhabdoviridae and the molecular weights were very similar to those of VHSV, except for the M_(2) protein which was somewhat smaller. Infection trials showed the carpione virus induced high mortalities in carpione fry but not in rainbow trout Oncorhynchus mykiss fry. The carpione virus was clearly distinguishable from Egtved virus despite limited serological cross reaction. Since it was also easily distinguishable by

Risk factors for contrast-induced nephropathy and their association with mortality in patients with blunt splenic injuries.

Science.gov (United States)

Hsieh, Ting-Min; Tsai, Tzu-Hsien; Liu, Yueh-Wei; Hsieh, Ching-Hua

2016-11-01

Although angioembolization increases the success rate of non-operative management in patients with blunt splenic injuries (BSI), the issue of contrast-induced nephropathy (CIN) due to serial administration of contrast medium remains unclear. We aimed to examine the risk factors of CIN and their clinical effect on mortality in patients with BSI. We retrospectively studied the complete data on 377 trauma patients with BSI who survived more than 48 h between July 2003 and June 2015. CIN was defined as the relative (≥25%) or absolute (≥0.5 mg/dL) increase in serum creatinine within 48 h after contrast administration. A multivariate logistic regression analysis was conducted to identify the independent predictors of CIN and mortality. CIN was independently associated with body mass index (BMI) ≥ 30 kg/m 2 (odds ratio [OR]: 3.25, 95% confidence interval [CI]: 1.20-8.76), injury severity score (ISS) ≥ 25 (OR: 6.08, 95% CI: 2.76-13.53), and 24-h hemoglobin (Hb) < 10 g/dL (OR: 3.16, 95% CI: 1.46-6.81). CIN (OR: 19.04, 95% CI: 6.15-58.94) and diabetes (OR: 3.43, 95% CI: 1.04-11.26) were also identified as independent predictors for mortality. In this study, we found that BMI ≥ 30 kg/m 2 , ISS ≥ 25, and 24-h Hb < 10 g/dL were independent risk factors for the occurrence of CIN in patients with BSI. However, angioembolization was not identified to be an independent risk factor for CIN. In addition, CIN and diabetes mellitus were identified as independent risk factors for mortality in patients with BSI. Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Maternal mortality in Vietnam in 1994-95.

Science.gov (United States)

Hieu, D T; Hanenberg, R; Vach, T H; Vinh, D Q; Sokal, D

1999-12-01

This report presents the first population-based estimates of maternal mortality in Vietnam. All the deaths of women aged 15-49 in 1994-95 in three provinces of Vietnam were identified and classified by cause. Maternal mortality was the fifth most frequent cause of death. The maternal mortality ratio was 155 deaths per 100,000 live births. This ratio compares with the World Health Organization's estimates of 430 such deaths globally and 390 for Asia. The maternal mortality ratio in the delta regions of these provinces was half that of the mountainous and semimountainous regions. Because a larger proportion of the Vietnamese population live in delta regions than elsewhere, the maternal mortality ratio for Vietnam as a whole may be lower than that of the three provinces studied. Maternal mortality is low in Vietnam primarily because a relatively high proportion of deliveries take place in clinics and hospitals, where few women die in childbirth. Also, few women die of the consequences of induced abortion in Vietnam because the procedure is legal and easily available.

Tree regeneration following drought- and insect-induced mortality in piñon-juniper woodlands.

Science.gov (United States)

Redmond, Miranda D; Barger, Nichole N

2013-10-01

Widespread piñon (Pinus edulis) mortality occurred across the southwestern USA during 2002-2003 in response to drought and bark beetle infestations. Given the recent mortality and changes in regional climate over the past several decades, there is a keen interest in post-mortality regeneration dynamics in piñon-juniper woodlands. Here, we examined piñon and Utah juniper (Juniperus osteosperma) recruitment at 30 sites across southwestern Colorado, USA that spanned a gradient of adult piñon mortality levels (10-100%) to understand current regeneration dynamics. Piñon and juniper recruitment was greater at sites with more tree and shrub cover. Piñon recruitment was more strongly facilitated than juniper recruitment by trees and shrubs. New (post-mortality) piñon recruitment was negatively affected by recent mortality. However, mortality had no effect on piñon advanced regeneration (juveniles established pre-mortality) and did not shift juvenile piñon dominance. Our results highlight the importance of shrubs and juniper trees for the facilitation of piñon establishment and survival. Regardless of adult piñon mortality levels, areas with low tree and shrub cover may become increasingly juniper dominated as a result of the few suitable microsites for piñon establishment and survival. In areas with high piñon mortality and high tree and shrub cover, our results suggest that piñon is regenerating via advanced regeneration. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Effects of Extensive Beetle-Induced Forest Mortality on Aromatic Organic Carbon Loading and Disinfection Byproduct Formation Potential

Science.gov (United States)

Brouillard, B.; Mikkelson, K. M.; Dickenson, E.; Sharp, J.

2015-12-01

Recent drought and warmer temperatures associated with climate change have caused increased pest-induced forest mortality with impacts on biogeochemical and hydrologic processes. To better understand the seasonal impacts of bark beetle infestation on water quality, samples were collected regularly over two overlapping snow free seasons at surface water intakes of six water treatment facilities in the Rocky Mountain region of Colorado displaying varying levels of bark beetle infestation (high >40%, moderate 20-40%, and low <20%). Organic carbon concentrations were typically 3 to 6 times higher in waters sourced from high beetle-impacted watersheds compared to moderate and low impact watersheds, revealing elevated specific ultraviolet absorbance, fluorescence, and humic-like intensity indicative of elevated aromatic carbon signatures. Accordingly, an increase in disinfection byproduct (DBP) formation potential of 400 to 600% was quantified when contrasted with watersheds containing less tree mortality. Beetle impact exasperated seasonal increases in carbon loading and DBP formation potential following both runoff and precipitation events indicating windows when enhanced water treatment may be utilized by water providers in highly infested regions. Additionally, elevated carbon concentrations throughout the summer and fall along with peaks following precipitation events provide evidence of shifting hydrologic flow paths in areas experiencing high forest mortality from decreased tree water uptake and interception. Collectively, these results demonstrate the need for continued watershed protection and monitoring with a changing climate as the resultant perturbations can have adverse effects on biogeochemistry and water quality in heavily impacted areas.

Immunization of chickens with an agonistic monoclonal anti-chicken CD40 antibody-hapten complex: rapid and robust IgG response induced by a single subcutaneous injection.

Science.gov (United States)

Chen, Chang-Hsin; Abi-Ghanem, Daad; Waghela, Suryakant D; Chou, Wen-Ko; Farnell, Morgan B; Mwangi, Waithaka; Berghman, Luc R

2012-04-30

Producing diagnostic antibodies in chicken egg yolk represents an alternate animal system that offers many advantages including high productivity at low cost. Despite being an excellent counterpart to mammalian antibodies, chicken IgG from yolk still represents an underused resource. The potential of agonistic monoclonal anti-CD40 antibodies (mAb) as a powerful immunological adjuvant has been demonstrated in mammals, but not in chickens. We recently reported an agonistic anti-chicken CD40 mAb (designated mAb 2C5) and showed that it may have potential as an immunological adjuvant. In this study, we examined the efficacy of targeting a short peptide to chicken CD40 [expressed by the antigen-presenting cells (APCs)] in enhancing an effective IgG response in chickens. For this purpose, an immune complex consisting of one streptavidin molecule, two directionally biotinylated mAb 2C5 molecules, and two biotinylated peptide molecules was produced. Chickens were immunized subcutaneously with doses of this complex ranging from 10 to 90 μg per injection once, and relative quantification of the peptide-specific IgG response showed that the mAb 2C5-based complex was able to elicit a strong IgG response as early as four days post-immunization. This demonstrates that CD40-targeting antigen to chicken APCs can significantly enhance antibody responses and induce immunoglobulin isotype-switching. This immunization strategy holds promise for rapid production of hapten-specific IgG in chickens. Copyright © 2012 Elsevier B.V. All rights reserved.

Elucidating the weak protein-protein interaction mechanisms behind the liquid-liquid phase separation of a mAb solution by different types of additives.

Science.gov (United States)

Wu, Guoliang; Wang, Shujing; Tian, Zhou; Zhang, Ning; Sheng, Han; Dai, Weiguo; Qian, Feng

2017-11-01

Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering. The LLPS of JM2 was confirmed to be a thermodynamic equilibrium process with no structural changes or irreversible aggregation of proteins. Phase diagrams of various JM2 formulations were constructed, suggesting that the phase behavior of JM2 was dependent on the solution pH, ionic strength and the presence of other excipients such as glycine, alanine, sorbitol and sucrose. Furthermore, we demonstrated that for this mAb, the interaction parameter (k D ) determined at low protein concentration appeared to be a good predictor for the occurrence of LLPS at high concentration. Copyright © 2017 Elsevier B.V. All rights reserved.

Predominant antitumor effects by fully human anti-TRAIL-receptor2 (DR5) monoclonal antibodies in human glioma cells in vitro and in vivo

Science.gov (United States)

Nagane, Motoo; Shimizu, Saki; Mori, Eiji; Kataoka, Shiro; Shiokawa, Yoshiaki

2010-01-01

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/Apo2 L) preferentially induces apoptosis in human tumor cells through its cognate death receptors DR4 or DR5, thereby being investigated as a potential agent for cancer therapy. Here, we applied fully human anti-human TRAIL receptor monoclonal antibodies (mAbs) to specifically target one of death receptors for TRAIL in human glioma cells, which could also reduce potential TRAIL-induced toxicity in humans. Twelve human glioma cell lines treated with several fully human anti-human TRAIL receptor mAbs were sensitive to only anti-DR5 mAbs, whereas they were totally insensitive to anti-DR4 mAb. Treatment with anti-DR5 mAbs exerted rapid cytotoxicity and lead to apoptosis induction. The cellular sensitivity was closely associated with cell-surface expression of DR5. Expression of c-FLIPL, Akt, and Cyclin D1 significantly correlated with sensitivity to anti-DR5 mAbs. Primary cultures of glioma cells were also relatively resistant to anti-DR5 mAbs, exhibiting both lower DR5 and higher c-FLIPL expression. Downregulation of c-FLIPL expression resulted in the sensitization of human glioma cells to anti-DR5 mAbs, whereas overexpression of c-FLIPL conferred resistance to anti-DR5 mAb. Treatment of tumor-burden nude mice with the direct agonist anti-DR5 mAb KMTR2 significantly suppressed growth of subcutaneous glioma xenografts leading to complete regression. Similarly, treatment of nude mice bearing intracerebral glioma xenografts with KMTR2 significantly elongated lifespan without tumor recurrence. These results suggest that DR5 is the predominant TRAIL receptor mediating apoptotic signals in human glioma cells, and sensitivity to anti-DR5 mAbs was determined at least in part by the expression level of c-FLIPL and Akt. Specific targeting of death receptor pathway through DR5 using fully human mAbs might provide a novel therapeutic strategy for intractable malignant gliomas. PMID:20511188

Role of Crassicauda sp. in natural mortality of pantropical spotted dolphins Stenella attenuata: a reassessment.

Science.gov (United States)

Balbuena, Juan Antonio; Simpkin, Andrew

2014-02-04

Evaluating the effect of parasites on population size is essential for designing management and conservation plans of wild animal populations. Although knowledge in this area is scarce in cetaceans, current evidence suggests that species of the nematode genus Crassicauda may play an important regulatory role in some populations. In the present study, a semiparametric regression technique was applied to a previously published dataset to re-examine the role of Crassicauda sp. in natural mortality of pantropical spotted dolphins Stenella attenuata. The resulting model indicated parasite-induced mortality at ages between 6.5 and 9 yr and at roughly 12 yr. The maximum mortality estimates obtained could represent 2 to 4% of natural mortality in dolphins 6 to 8 yr old. This estimate is substantially smaller than previously published values, but in contrast with previous research, our model provides clear statistical evidence for parasite-induced mortality because the bootstrapped 95% confidence intervals of the estimated mortality rates excluded the 0 value. We also evaluated, through simulations, how potential sampling biases of infected dolphins could overestimate parasite-induced mortality. Small differences in sampling selectivity between infected and uninfected animals could substantially reduce the mortality estimates. However, the simulated models also supported the notion of statistically significant mortality in juvenile dolphins. Given that dolphins older than 16 yr were poorly represented in the dataset, further research is needed to establish whether Crassicauda sp. causes meaningful mortality for population dynamics among adult individuals.

The effect of college education on mortality.

Science.gov (United States)

Buckles, Kasey; Hagemann, Andreas; Malamud, Ofer; Morrill, Melinda; Wozniak, Abigail

2016-12-01

We exploit exogenous variation in years of completed college induced by draft-avoidance behavior during the Vietnam War to examine the impact of college on adult mortality. Our estimates imply that increasing college attainment from the level of the state at the 25th percentile of the education distribution to that of the state at the 75th percentile would decrease cumulative mortality for cohorts in our sample by 8 to 10 percent relative to the mean. Most of the reduction in mortality is from deaths due to cancer and heart disease. We also explore potential mechanisms, including differential earnings and health insurance. Copyright © 2016 Elsevier B.V. All rights reserved.

An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

Science.gov (United States)

Zhang, Yan; Fang, Lin; Zhang, Quan'an; Zheng, Qin; Tong, Jinlong; Fu, Xiaohui; Jiang, Xiaoqing; Su, Changqing; Zheng, Junnian

2013-06-01

Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Within- and among-family variation in parasite load and parasite-induced mortality in the land snail Arianta arbustorum, a host of parasitic mites.

Science.gov (United States)

Schüpbach, Hans Ulrich; Baur, Bruno

2010-08-01

Variation in host susceptibility and parasite-induced mortality are preconditions for parasite-related selection on host populations. In terrestrial gastropods, variation in resistance against ectoparasite infection is poorly understood. We examined the within- and among-family variation in parasite load in full-siblings of the land snail Arianta arbustorum experimentally infected with Riccardoella limacum , a mite living in the mantle cavity of helicid land snails. We also quantified the influence of family origin and host size on parasite load and calculated its heritability (h(2)). Furthermore, we examined the influence of parasite load, snail size, and family origin on host winter mortality, an important life-history trait of A. arbustorum . Parasite load was heritable (h(2) = 0.63). In infected snails, parasite load was affected by family origin and increased with increasing shell size. Host mortality during hibernation increased with increasing parasite load and differed among families, but was not affected by snail size. Our results show high among-family variation both in resistance against ectoparasite infection and in host winter mortality. Furthermore, we show that parasite load is linked to snail size, which suggests that the proliferation of R. limacum is limited by resources provided by A. arbustorum .

CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

OpenAIRE

Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P.; Morrione, Andrea; Scotlandi, Katia

2016-01-01

CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD9...

Rapid polyclonal desensitization with antibodies to IgE and FcεRIα.

Science.gov (United States)

Khodoun, Marat V; Kucuk, Zeynep Yesim; Strait, Richard T; Krishnamurthy, Durga; Janek, Kevin; Lewkowich, Ian; Morris, Suzanne C; Finkelman, Fred D

2013-06-01

Rapid desensitization, a procedure in which persons allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky, way to induce temporary tolerance. We wanted to determine whether this approach can be adapted to suppress all IgE-mediated allergies in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcεRIα. Active and passive models of antigen- and anti-IgE mAb-induced IgE-mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcεRIα mAb, or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux, and changes in cell number and FcεRI and IgE expression were evaluated. Rapid desensitization with anti-IgE mAb suppressed IgE-mediated immediate hypersensitivity; however, some mice developed mild anaphylaxis during desensitization. Rapid desensitization with anti-FcεRIα mAb that only binds FcεRI that is not occupied by IgE suppressed both active and passive IgE-mediated anaphylaxis without inducing disease. It quickly, but temporarily, suppressed IgE-mediated anaphylaxis by decreasing mast cell signaling through FcεRI, then slowly induced longer lasting mast cell unresponsiveness by removing membrane FcεRI. Rapid desensitization with anti-FcεRIα mAb was safer and longer lasting than rapid desensitization with antigen. A rapid desensitization approach with anti-FcεRIα mAb safely desensitizes mice to IgE-mediated anaphylaxis by inducing mast cell anergy and later removing all mast cell IgE. Rapid desensitization with an anti-human FcεRIα mAb may be able to prevent human IgE-mediated anaphylaxis. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

The Role of Biosphere Reserves in Environmental Education and Training = Le Role des reserves de la biosphere dans l'education et la formation environnementales. Report of the Unesco/MAB Symposium Held During the Unesco/UNEP International Congress on Environmental Education and Training (Moscow, USSR, August 17-21, 1987). Report 20.

Science.gov (United States)

Francis, George, Ed.

Environmental education and training have been key elements of Unesco's Program on Man and the Biosphere (MAB) since its inception in 1971. The MAB Program is an intergovernmental program of research, training, demonstration and distribution of information, aimed at providing the scientific background and the trained personnel to deal with…

A Conserved Epitope Mapped with a Monoclonal Antibody against the VP3 Protein of Goose Parvovirus by Using Peptide Screening and Phage Display Approaches.

Science.gov (United States)

Li, Chenxi; Liu, Hongyu; Li, Jinzhe; Liu, Dafei; Meng, Runze; Zhang, Qingshan; Shaozhou, Wulin; Bai, Xiaofei; Zhang, Tingting; Liu, Ming; Zhang, Yun

2016-01-01

Waterfowl parvovirus (WPV) infection causes high mortality and morbidity in both geese (Anser anser) and Muscovy ducks (Cairina moschata), resulting in significant losses to the waterfowl industries. The VP3 protein of WPV is a major structural protein that induces neutralizing antibodies in the waterfowl. However, B-cell epitopes on the VP3 protein of WPV have not been characterized. To understand the antigenic determinants of the VP3 protein, we used the monoclonal antibody (mAb) 4A6 to screen a set of eight partially expressed overlapping peptides spanning VP3. Using western blotting and an enzyme-linked immunosorbent assay (ELISA), we localized the VP3 epitope between amino acids (aa) 57 and 112. To identify the essential epitope residues, a phage library displaying 12-mer random peptides was screened with mAb 4A6. Phage clone peptides displayed a consensus sequence of YxRFHxH that mimicked the sequence 82Y/FNRFHCH88, which corresponded to amino acid residues 82 to 88 of VP3 protein of WPVs. mAb 4A6 binding to biotinylated fragments corresponding to amino acid residues 82 to 88 of the VP3 protein verified that the 82FxRFHxH88 was the VP3 epitope and that amino acids 82F is necessary to retain maximal binding to mAb 4A6. Parvovirus-positive goose and duck sera reacted with the epitope peptide by dot blotting assay, revealing the importance of these amino acids of the epitope in antibody-epitope binding reactivity. We identified the motif FxRFHxH as a VP3-specific B-cell epitope that is recognized by the neutralizing mAb 4A6. This finding might be valuable in understanding of the antigenic topology of VP3 of WPV.

Role of tumor necrosis factor-alpha and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis.

Science.gov (United States)

Lupia, E; Montrucchio, G; Battaglia, E; Modena, V; Camussi, G

1996-08-01

The aim of the present study was to investigate in vivo in a mouse model the stimulation of neoangiogenesis by synovial fluids of patients with rheumatoid arthritis (RA) and to determine the role of tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) in the formation of new vessels. Angiogenesis was studied in a mouse model in which Matrigel, injected subcutaneously, was used as a vehicle for the delivery of potential angiogenic stimuli. Synovial fluids of patients with RA but not with osteoarthritis (OA) were shown to induce neoangiogenesis. Since synovial fluid of patients with RA contained significantly higher levels of TNF-alpha-like bioactivity and of PAF than that of patients with OA, the role of these mediators was evaluated by using an anti-TNF-alpha neutralizing monoclonal antibody (mAb) and a PAF receptor antagonist, WEB 2170. When added to Matrigel, anti-TNF-alpha mAb and particularly WEB 2170 significantly reduced neoangiogenesis induced by synovial fluids of RA patients. Moreover, PAF extracted and purified from synovial fluid induced angiogenesis. These results suggest that the neoangiogenesis observed in rheumatoid synovitis may be due, at least in part, to the angiogenic effect of locally produced TNF-alpha and PAF.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies

DEFF Research Database (Denmark)

Monforte, Antonella d'Arminio; Abrams, Donald; Pradier, Christian

2008-01-01

OBJECTIVE: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. DESIGN: Observational cohort study. METHODS: Patients (23 437) were followed prospectively......-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality...

Viruses and Protists Induced-mortality of Prokaryotes around the Antarctic Peninsula during the Austral Summer

KAUST Repository

Vaque, Dolors; Boras, Julia A.; Torrent-Llagostera, Francesc; Agusti, Susana; Arrieta, J M; Lara, Elena; Castillo, Yaiza M.; Duarte, Carlos M.; Sala, Maria M.

2017-01-01

During the Austral summer 2009 we studied three areas surrounding the Antarctic Peninsula: the Bellingshausen Sea, the Bransfield Strait and the Weddell Sea. We aimed to investigate, whether viruses or protists were the main agents inducing prokaryotic mortality rates, and the sensitivity to temperature of prokaryotic heterotrophic production and mortality based on the activation energy (Ea) for each process. Seawater samples were taken at seven depths (0.1-100 m) to quantify viruses, prokaryotes and protists abundances, and heterotrophic prokaryotic production (PHP). Viral lytic production, lysogeny, and mortality rates of prokaryotes due to viruses and protists were estimated at surface (0.1-1 m) and at the Deep Fluorescence Maximum (DFM, 12-55 m) at eight representative stations of the three areas. The average viral lytic production ranged from 1.0 +/- 0.3 x 10(7) viruses ml(-1) d(-1) in the Bellingshausen Sea to1.3 +/- 0.7 x 10(7) viruses ml(-1) d(-1) in the Bransfield Strait, while lysogeny, when detectable, recorded the lowest value in the Bellingshausen Sea (0.05 +/- 0.05 x 10(7) viruses ml(-1) d(-1)) and the highest in the Weddell Sea (4.3 +/- 3.5 x 10(7) viruses ml(-1) d(-1)). Average mortality rates due to viruses ranged from 9.7 +/- 6.1 x 10(4) cells ml(-1) d(-1) in the Weddell Sea to 14.3 +/- 4.0 x 10(4) cells ml(-1) d(-1) in the Bellingshausen Sea, and were higher than averaged grazing rates in the Weddell Sea (5.9 +/- 1.1 x 10(4) cells ml(-1) d(-1)) and in the Bellingshausen Sea (6.8 +/- 0.9 x 10(4) cells ml-1 d(-1)). The highest impact on prokaryotes by viruses and main differences between viral and protists activities were observed in surface samples: 17.8 +/- 6.8 x 10(4) cells ml(-1) d(-1) and 6.5 +/- 3.9 x 10(4) cells ml(-1) d(-1) in the Weddell Sea; 22.1 +/- 9.6 x 10(4) cells ml(-1) d(-1) and 11.6 +/- 1.4 x 10(4) cells ml(-1) d(-1) in the Bransfield Strait; and 16.1 +/- 5.7 x 10(4) cells ml(-1) d(-1) and 7.9 +/- 2.6 x 10(4) cells ml(-1) d(-1) in

Viruses and Protists Induced-mortality of Prokaryotes around the Antarctic Peninsula during the Austral Summer

KAUST Repository

Vaque, Dolors

2017-03-27

During the Austral summer 2009 we studied three areas surrounding the Antarctic Peninsula: the Bellingshausen Sea, the Bransfield Strait and the Weddell Sea. We aimed to investigate, whether viruses or protists were the main agents inducing prokaryotic mortality rates, and the sensitivity to temperature of prokaryotic heterotrophic production and mortality based on the activation energy (Ea) for each process. Seawater samples were taken at seven depths (0.1-100 m) to quantify viruses, prokaryotes and protists abundances, and heterotrophic prokaryotic production (PHP). Viral lytic production, lysogeny, and mortality rates of prokaryotes due to viruses and protists were estimated at surface (0.1-1 m) and at the Deep Fluorescence Maximum (DFM, 12-55 m) at eight representative stations of the three areas. The average viral lytic production ranged from 1.0 +/- 0.3 x 10(7) viruses ml(-1) d(-1) in the Bellingshausen Sea to1.3 +/- 0.7 x 10(7) viruses ml(-1) d(-1) in the Bransfield Strait, while lysogeny, when detectable, recorded the lowest value in the Bellingshausen Sea (0.05 +/- 0.05 x 10(7) viruses ml(-1) d(-1)) and the highest in the Weddell Sea (4.3 +/- 3.5 x 10(7) viruses ml(-1) d(-1)). Average mortality rates due to viruses ranged from 9.7 +/- 6.1 x 10(4) cells ml(-1) d(-1) in the Weddell Sea to 14.3 +/- 4.0 x 10(4) cells ml(-1) d(-1) in the Bellingshausen Sea, and were higher than averaged grazing rates in the Weddell Sea (5.9 +/- 1.1 x 10(4) cells ml(-1) d(-1)) and in the Bellingshausen Sea (6.8 +/- 0.9 x 10(4) cells ml-1 d(-1)). The highest impact on prokaryotes by viruses and main differences between viral and protists activities were observed in surface samples: 17.8 +/- 6.8 x 10(4) cells ml(-1) d(-1) and 6.5 +/- 3.9 x 10(4) cells ml(-1) d(-1) in the Weddell Sea; 22.1 +/- 9.6 x 10(4) cells ml(-1) d(-1) and 11.6 +/- 1.4 x 10(4) cells ml(-1) d(-1) in the Bransfield Strait; and 16.1 +/- 5.7 x 10(4) cells ml(-1) d(-1) and 7.9 +/- 2.6 x 10(4) cells ml(-1) d(-1) in

Retrospective look at Rn-induced lung cancer mortality from the viewpoint of a relative risk model

International Nuclear Information System (INIS)

Puskin, J.S.; Yang, Y.

1988-01-01

The potential contribution to U.S. lung cancer deaths from 1930 to 1987 from indoor 222 Rn exposures is investigated from the standpoint of a constant relative risk model. Based on this model, which assumes a Rn risk proportional to the baseline lung cancer risk from other causes, the rate of Rn-induced lung cancer mortality has been increasing sharply since 1930. However, the estimated proportion of lung cancer deaths attributable to Rn has remained fairly constant. Applying the range of coefficients the U.S. Environmental Protection Agency employs in assessing the risk from indoor Rn, it is estimated that 8-25% of all current lung cancer deaths are attributable to past Rn exposures. The major sources of uncertainty in the estimates are discussed

Establishment of novel mAb to human ERC/mesothelin useful for study and diagnosis of ERC/mesothelin-expressing cancers.

Science.gov (United States)

Ishikawa, Kiyoshi; Segawa, Tatsuya; Hagiwara, Yoshiaki; Maeda, Masahiro; Abe, Masaaki; Hino, Okio

2009-03-01

Malignant mesothelioma is a highly aggressive tumor of the serosal cavity that arises from the mesothelial cells of the pleura, peritoneum, or pericardium. The immunohistochemical diagnosis of epithelioid mesothelioma from biopsy or surgically resected specimens has been actively pursued, using markers such as mesothelin. Several markers have indeed been helpful for confirming the diagnosis of mesothelioma and distinguishing between mesothelioma and adenocarcinoma. The authors have developed a novel mAb to human C-ERC/mesothelin, which performed well when used in western blotting, fluorescence-activated cell sorting, immunocytochemistry and immunohistochemistry, and which therefore will be useful in studying the molecular biology of mesothelin, in addition to improving the diagnosis and therapy of mesothelin-expressing cancers.

Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy.

Science.gov (United States)

Zhao, Junli; Wang, Yi; Xu, Cenglin; Liu, Keyue; Wang, Ying; Chen, Liying; Wu, Xiaohua; Gao, Feng; Guo, Yi; Zhu, Junming; Wang, Shuang; Nishibori, Masahiro; Chen, Zhong

2017-08-01

Brain inflammation is a major factor in epilepsy, and the high mobility group box-1 (HMGB1) protein is known to contribute significantly to the generation of seizures. Here, we investigated the therapeutic potential of an anti-HMGB1 monoclonal antibody (mAb) in epilepsy. anti-HMGB1 mAb attenuated both acute seizure models (maximal electroshock seizure, pentylenetetrazole-induced and kindling-induced), and chronic epilepsy model (kainic acid-induced) in a dose-dependent manner. Meanwhile, the anti-HMGB1 mAb also attenuated seizure activities of human brain slices obtained from surgical resection from drug-resistant epilepsy patients. The mAb showed an anti-seizure effect with a long-term manner and appeared to be minimal side effects at even very high dose (no disrupted physical EEG rhythm and no impaired basic physical functions, such as body growth rate and thermoregulation). This anti-seizure effect of mAb results from its inhibition of translocated HMGB1 from nuclei following seizures, and the anti-seizure effect was absent in toll-like receptor 4 knockout (TLR4 -/- ) mice. Interestingly, the anti-HMGB1 mAb also showed a disease-modifying anti-epileptogenetic effect on epileptogenesis after status epileptics, which is indicated by reducing seizure frequency and improving the impaired cognitive function. These results indicate that the anti-HMGB1 mAb should be viewed as a very promising approach for the development of novel therapies to treat refractory epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute Ethanol Intake Induces NAD(P)H Oxidase Activation and Rhoa Translocation in Resistance Arteries.

Science.gov (United States)

Simplicio, Janaina A; Hipólito, Ulisses Vilela; Vale, Gabriel Tavares do; Callera, Glaucia Elena; Pereira, Camila André; Touyz, Rhian M; Tostes, Rita de Cássia; Tirapelli, Carlos R

2016-11-01

The mechanism underlying the vascular dysfunction induced by ethanol is not totally understood. Identification of biochemical/molecular mechanisms that could explain such effects is warranted. To investigate whether acute ethanol intake activates the vascular RhoA/Rho kinase pathway in resistance arteries and the role of NAD(P)H oxidase-derived reactive oxygen species (ROS) on such response. We also evaluated the requirement of p47phox translocation for ethanol-induced NAD(P)H oxidase activation. Male Wistar rats were orally treated with ethanol (1g/kg, p.o. gavage) or water (control). Some rats were treated with vitamin C (250 mg/kg, p.o. gavage, 5 days) before administration of water or ethanol. The mesenteric arterial bed (MAB) was collected 30 min after ethanol administration. Vitamin C prevented ethanol-induced increase in superoxide anion (O2-) generation and lipoperoxidation in the MAB. Catalase and superoxide dismutase activities and the reduced glutathione, nitrate and hydrogen peroxide (H2O2) levels were not affected by ethanol. Vitamin C and 4-methylpyrazole prevented the increase on O2- generation induced by ethanol in cultured MAB vascular smooth muscle cells. Ethanol had no effect on phosphorylation levels of protein kinase B (Akt) and eNOS (Ser1177 or Thr495 residues) or MAB vascular reactivity. Vitamin C prevented ethanol-induced increase in the membrane: cytosol fraction ratio of p47phox and RhoA expression in the rat MAB. Acute ethanol intake induces activation of the RhoA/Rho kinase pathway by a mechanism that involves ROS generation. In resistance arteries, ethanol activates NAD(P)H oxidase by inducing p47phox translocation by a redox-sensitive mechanism. O mecanismo da disfunção vascular induzido pelo consumo de etanol não é totalmente compreendido. Justifica-se, assim a identificação de mecanismos bioquímicos e moleculares que poderiam explicar tais efeitos. Investigar se a ingestão aguda de etanol ativa a via vascular RhoA/Rho quinase

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

OpenAIRE

Luo, Min; Guan, Xiaoqun; Luczak, Elizabeth D.; Lang, Di; Kutschke, William; Gao, Zhan; Yang, Jinying; Glynn, Patric; Sossalla, Samuel; Swaminathan, Paari D.; Weiss, Robert M.; Yang, Baoli; Rokita, Adam G.; Maier, Lars S.; Efimov, Igor R.

2013-01-01

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabeti...

Mapping of Lol p I allergenic epitopes by using murine monoclonal antibodies.

Science.gov (United States)

Mourad, W; Bernier, D; Jobin, M; Hébert, J

1989-11-01

Murine monoclonal antibodies (MAbs) against three non-overlapping epitopes of Lol p I allergen were previously produced and subsequently used for purification of the allergen. In the present study, these MAbs were further characterized, and the biological activity of the purified allergen assessed. The three MAbs were of the IgG isotype and carried a kappa light chain. Their affinity constants were in the range of 7.4-15.1 x 10(-9) mol/l. Purified Lol p I kept its biological activity, as shown by its ability to induce histamine release by basophils of Lol p I-sensitive patients. The profiles of histamine release induced by either Lol p I or crude Lolium perenne extracts were comparable. This observation suggests that human IgE bound to basophils are polyspecific which has been confirmed by immunoblot and inhibition assay. Our data indicated also that Lol p I possesses a major allergenic epitope recognized by all human serum IgE tested. This epitope seems to be partially shared by those recognized by the three MAbs. Finally, preincubation of Lol p I with either one of the Mabs did not affect significantly the basophil-histamine release induced by the purified allergen. This suggests that Lol p I possesses allergenic sites other than the one shared by MAbs and IgE Abs.

Viruses and Protists Induced-mortality of Prokaryotes around the Antarctic Peninsula during the Austral Summer.

Science.gov (United States)

Vaqué, Dolors; Boras, Julia A; Torrent-Llagostera, Francesc; Agustí, Susana; Arrieta, Jesús M; Lara, Elena; Castillo, Yaiza M; Duarte, Carlos M; Sala, Maria M

2017-01-01

During the Austral summer 2009 we studied three areas surrounding the Antarctic Peninsula: the Bellingshausen Sea, the Bransfield Strait and the Weddell Sea. We aimed to investigate, whether viruses or protists were the main agents inducing prokaryotic mortality rates, and the sensitivity to temperature of prokaryotic heterotrophic production and mortality based on the activation energy (Ea) for each process. Seawater samples were taken at seven depths (0.1-100 m) to quantify viruses, prokaryotes and protists abundances, and heterotrophic prokaryotic production (PHP). Viral lytic production, lysogeny, and mortality rates of prokaryotes due to viruses and protists were estimated at surface (0.1-1 m) and at the Deep Fluorescence Maximum (DFM, 12-55 m) at eight representative stations of the three areas. The average viral lytic production ranged from 1.0 ± 0.3 × 10 7 viruses ml -1 d -1 in the Bellingshausen Sea to1.3 ± 0.7 × 10 7 viruses ml -1 d -1 in the Bransfield Strait, while lysogeny, when detectable, recorded the lowest value in the Bellingshausen Sea (0.05 ± 0.05 × 10 7 viruses ml -1 d -1 ) and the highest in the Weddell Sea (4.3 ± 3.5 × 10 7 viruses ml -1 d -1 ). Average mortality rates due to viruses ranged from 9.7 ± 6.1 × 10 4 cells ml -1 d -1 in the Weddell Sea to 14.3 ± 4.0 × 10 4 cells ml -1 d -1 in the Bellingshausen Sea, and were higher than averaged grazing rates in the Weddell Sea (5.9 ± 1.1 × 10 4 cells ml -1 d -1 ) and in the Bellingshausen Sea (6.8 ± 0.9 × 10 4 cells ml -1 d -1 ). The highest impact on prokaryotes by viruses and main differences between viral and protists activities were observed in surface samples: 17.8 ± 6.8 × 10 4 cells ml -1 d -1 and 6.5 ± 3.9 × 10 4 cells ml -1 d -1 in the Weddell Sea; 22.1 ± 9.6 × 10 4 cells ml -1 d -1 and 11.6 ± 1.4 × 10 4 cells ml -1 d -1 in the Bransfield Strait; and 16.1 ± 5.7 × 10 4 cells ml -1 d -1 and 7.9 ± 2.6 × 10 4 cells ml -1 d -1 in the Bellingshausen Sea, respectively

Rest in peace? Brand-induced mortality salience and consumer behavior

NARCIS (Netherlands)

Fransen, M.L.; Fennis, B.M.; Pruyn, A.Th.; Das, E.

2008-01-01

The present research examines the hypothesis that brands can automatically activate mortality-related thoughts and, in turn, affect consumer behavior. Terror Management Theory (TMT; [Greenberg Jeff, Pyszczynski Tom, Solomon Sheldon. The Causes and Consequences of a Need for Self-esteem: A Terror

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents.

Science.gov (United States)

Qiu, Ao-Wang; Liu, Qing-Huai; Wang, Jun-Ling

2017-01-01

Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR. © 2017 The Author(s)Published by S. Karger AG, Basel.

Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis.

OpenAIRE

Braley-Mullen, H.; Sharp, G. C.; Tang, H.; Chen, K.; Kyriakos, M.; Bickel, J. T.

1998-01-01

Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T...

Use of risk projection models to estimate mortality and incidence from radiation-induced breast cancer in screening programs

International Nuclear Information System (INIS)

Ramos, M; Ferrer, S; Villaescusa, J I; Verdu, G; Salas, M D; Cuevas, M D

2005-01-01

The authors report on a method to calculate radiological risks, applicable to breast screening programs and other controlled medical exposures to ionizing radiation. In particular, it has been applied to make a risk assessment in the Valencian Breast Cancer Early Detection Program (VBCEDP) in Spain. This method is based on a parametric approach, through Markov processes, of hazard functions for radio-induced breast cancer incidence and mortality, with mean glandular breast dose, attained age and age-at-exposure as covariates. Excess relative risk functions of breast cancer mortality have been obtained from two different case-control studies exposed to ionizing radiation, with different follow-up time: the Canadian Fluoroscopy Cohort Study (1950-1987) and the Life Span Study (1950-1985 and 1950-1990), whereas relative risk functions for incidence have been obtained from the Life Span Study (1958-1993), the Massachusetts tuberculosis cohorts (1926-1985 and 1970-1985), the New York post-partum mastitis patients (1930-1981) and the Swedish benign breast disease cohort (1958-1987). Relative risks from these cohorts have been transported to the target population undergoing screening in the Valencian Community, a region in Spain with about four and a half million inhabitants. The SCREENRISK software has been developed to estimate radiological detriments in breast screening. Some hypotheses corresponding to different screening conditions have been considered in order to estimate the total risk associated with a woman who takes part in all screening rounds. In the case of the VBCEDP, the total radio-induced risk probability for fatal breast cancer is in a range between [5 x 10 -6 , 6 x 10 -4 ] versus the natural rate of dying from breast cancer in the Valencian Community which is 9.2 x 10 -3 . The results show that these indicators could be included in quality control tests and could be adequate for making comparisons between several screening programs

Acemannan (a polysaccharides of Aloe vera gel) protects against radiation induced mortality by modulation of immunosuppression

International Nuclear Information System (INIS)

Kumar, Sumit; Tiku, Ashu Bhan

2014-01-01

Acemannan (poly-acetylated mannose) is an active component of Aloe vera gel and has been reported to have anticancerous, antimicrobial and shown to stimulate the development and proliferation of the hematopoietic cells. The anticancerous properties of acemannan have been attributed to the modulation of immune system rather then cytotoxicity. Therefore objective of the present study was to evaluate radioprotective efficacy of acemannan against radiation induced immune suppression using Swiss albino mice as a model system. For In-vivo studies mice were treated for 7 days orally prior to irradiation (5 Gy). Animals were sacrificed at different time point to study the effect on cellular proliferation, DNA damage, apoptosis and ROS level, cytokines level, antioxidant enzymes, nitric oxide and protein expression. For survival studies mice were treated with acemannan for 7 days pre or post irradiation and survival was monitored for 30 days. Acemannan showed a significant induction of proliferation of splenocytes in radiation treated groups. Beside a decrease in radiation induced ROS and DNA damage resulted in the reduction of apoptosis in murine splenocytes. Acemannan restored the antioxidant enzyme level (catalase, SOD, DTD and GST) and maintained the proper redox status via GSH, in irradiated mice. Further acemannan was shown to induce the hematopoiesis (peripheral lymphocytes cells, spleen colony cells, spleen index) by increasing the level of the pro-hematopoiesis cytokines (IL-1, TNF-α). Being an immunomodulator, acemannan reduced the level of the inflammation (IL-6, nitric oxide). Also the multiple mechanisms operational at cellular and molecule levelled to the reduction of radiation induced mortality of mice in both pre and post-irradiation studies. On the basis of the above results it can be concluded that radioprotective effects of the acemannan was due to its immunomodulatory activity and could have application for radio-therapeutic purposes. (author)

System visualization of integrated biofuels and high value chemicals developed within the MacroAlgaeBiorefinery (MAB3) project

DEFF Research Database (Denmark)

Seghetta, Michele; Hasler, Berit; Bastianoni, Simone

MacroAlgaeBiorefinery (MAB3) may functions as production platform and raw material supplier for future sustainable production chains of biofuels and high value chemicals. Biofuels are interesting energy source but challenges in terms of the composition of the biomass and resulting energy...... efficiencies has to be compensated for to make the biofuel prices competitive in replacing fossil fuel. Since it is difficult to increase the yield of the single biorefinery, the overall system productivity can be improved integrating different sub-systems. In this study, macroalgae cultivation in Denmark...... is integrated with a biogas biorefinery, a bioethanol biorefinery and a fish feed industry. The modeled system is able to adapt itself to different amount and quality of feedstock and to maximize valuable outputs (e.g. bio-fuels and chemical). Macroalgae are harvested and utilized as feedstock in bioethanol...

3β-Hydroxysterol Δ24-Reductase on the Surface of Hepatitis C Virus-Related Hepatocellular Carcinoma Cells Can Be a Target for Molecular Targeting Therapy

Science.gov (United States)

Saito, Makoto; Takano, Takashi; Nishimura, Tomohiro; Kohara, Michinori; Tsukiyama-Kohara, Kyoko

2015-01-01

In our previous study, we demonstrated that 3β-hydroxysterol Δ24-reductase (DHCR24) was overexpressed in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), and that its expression was induced by HCV. Using a monoclonal antibody against DHCR24 (2-152a MAb), we found that DHCR24 was specifically expressed on the surface of HCC cell lines. Based on these findings, we aimed to establish a novel targeting strategy using 2-152a MAb to treat HCV-related HCC. In the present study, we examined the antitumor activity of 2-152a MAb. In the presence of complement, HCC-derived HuH-7 cells were killed by treatment with 2-152a MAb, which was mediated by complement-dependent cytotoxicity (CDC). In addition, the antigen recognition domain of 2-152a MAb was responsible for the unique anti-HCV activity. These findings demonstrate the feasibility of using 2-152a MAb for antibody therapy against HCV-related HCC. In addition, surface DHCR24 on HCC cells exhibited a functional property, agonist-induced internalization. We showed that 2-152a MAb-mediated binding of a cytotoxic agent (a saponin-conjugated secondary antibody) to surface DHCR24 led to significant cytotoxicity. This suggests that surface DHCR24 on HCC cells can function as a carrier for internalization. Therefore, surface DHCR24 could be a valuable target for HCV-related HCC therapy, and 2-152a MAb appears to be useful for this targeted therapy. PMID:25875901

Impact of mountain pine beetle induced mortality on forest carbon and water fluxes

International Nuclear Information System (INIS)

E Reed, David; Ewers, Brent E; Pendall, Elise

2014-01-01

Quantifying impacts of ecological disturbance on ecosystem carbon and water fluxes will improve predictive understanding of biosphere—atmosphere feedbacks. Tree mortality caused by mountain pine bark beetles (Dendroctonus ponderosae) is hypothesized to decrease photosynthesis and water flux to the atmosphere while increasing respiration at a rate proportional to mortality. This work uses data from an eddy-covariance flux tower in a bark beetle infested lodgepole pine (Pinus contorta) forest to test ecosystem responses during the outbreak. Analyses were conducted on components of carbon (C) and water fluxes in response to disturbance and environmental factors (solar radiation, soil water content and vapor pressure deficit). Maximum CO 2 uptake did not change as tree basal area mortality increased from 30 to 78% over three years of beetle disturbance. Growing season evapotranspiration varied among years while ecosystem water use efficiency (the ratio of net CO 2 uptake to water vapor loss) did not change. Between 2009 and 2011, canopy water conductance increased from 98.6 to 151.7 mmol H 2 O m −2 s −1 . Ecosystem light use efficiency of photosynthesis increased, with quantum yield increasing by 16% during the outbreak as light increased below the mature tree canopy and illuminated remaining vegetation more. Overall net ecosystem productivity was correlated with water flux and hence water availability. Average weekly ecosystem respiration, derived from light response curves and standard Ameriflux protocols for CO 2 flux partitioning into respiration and gross ecosystem productivity, did not change as mortality increased. Separate effects of increased respiration and photosynthesis efficiency largely canceled one another out, presumably due to increased diffuse light in the canopy and soil organic matter decomposition resulting in no change in net CO 2 exchange. These results agree with an emerging consensus in the literature demonstrating CO 2 and H 2 O dynamics

Soil Respiration Declines Following Beetle - Induced Forest Mortality in a Lodgepole Pine Forest

Science.gov (United States)

Borkhuu, B.; Peckham, S. D.; Norton, U.; Ewers, B. E.; Pendall, E.

2014-12-01

Lodgepole pine (Pinus contorta var. latifolia) forests in northern Colorado and southeast Wyoming have been undergoing a major mortality event owing to mountain pine beetle (Dendroctonus ponderosae) infestation since 2007. We studied biotic and abiotic drivers of growing season soil respiration in four mature stands experiencing different levels of mortality between 2008 and 2012 in the Medicine Bow Mountains, southeastern Wyoming, USA. For five years, beetle infestation significantly altered forest structure. Stand mortality was 30% and more than 80% in stands with the lowest and highest mortality, respectively. Understory vegetation cover increased by 50% for five years following beetle infestation. Needlefall was increased by more than 50% during first two years of beetle infestation compared to the pre-disturbance period. We did not observe an immediate increase in soil respiration following beetle infestation as suggested by some researchers. Soil respiration rates in midsummer ranged from 1.4 ± 0.1 μmol m-2 s-1 in stands with highest mortality to 3.1 ± 0.2 μmol m-2s-1 in uninfested stand. Live tree basal area was the dominant factor controlling soil respiration, explaining more than 60% of the interannual and spatial variations in response to the disturbance. In addition, soil respiration was significantly correlated with fine root biomass, which explained 55% of variations, providing strong evidence that autotrophic respiration dominated the forest soil respiration flux. Furthermore, the seasonality of soil respiration was controlled mainly by mean monthly precipitation and mid-day photosynthetically active radiation. Each factor predicted from 30% to 50% of seasonal soil respiration variability with the highest correlation coefficients in stand with the lowest mortality. Our results clearly indicate that the reduction of photosynthesis in trees over the infestation period significantly reduced soil respiration. The remaining activity in dead stands may

Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine.

Science.gov (United States)

Boelaert, Kristien; Maisonneuve, Patrick; Torlinska, Barbara; Franklyn, Jayne A

2013-05-01

Hyperthyroidism is common, but opinions regarding optimal therapy with antithyroid drugs or radioiodine (131-I) differ. There are no randomized trials comparing these options in terms of mortality. The aim of the study was to determine whether mortality associated with hyperthyroidism varies with treatment administered or other factors. We conducted a prospective observational population-based study of 1036 subjects aged ≥ 40 years presenting to a single specialist clinic from 1989-2003 with a first episode of hyperthyroidism who were followed until June 2012. Antithyroid drugs or radioiodine (131-I) were administered. We compared causes of death with age-, sex-, and period-specific mortality in England and Wales and used within-cohort analysis of influence of treatment modality, outcome, disease etiology, severity and control, and comorbidities. In 12 868 person-years of follow-up, 334 died vs 290.6 expected (standardized mortality ratio [SMR], 1.15 [95% confidence interval (CI),1.03-1.28]; P = .01). Increased all-cause mortality largely reflected increased circulatory deaths (SMR, 1.20 [95% CI, 1.01-1.43]; P = .04). All-cause mortality was increased for the person-years accumulated during thionamide treatment (SMR, 1.30 [95% CI, 1.05-1.61]; P = .02) and after 131-I not associated with hypothyroidism (SMR, 1.24 [95% CI, 1.04-1.46]; P = .01) but not during T₄ replacement for 131-I-induced hypothyroidism (SMR, 0.98 [95% CI, 0.82-1.18]; P = .85). Within-cohort analysis comparing mortality during thionamide treatment showed a similar hazard ratio (HR) for all-cause mortality when 131-I did not result in hypothyroidism (HR, 0.95 [95% CI, 0.70-1.29]), but reduced mortality with 131-I-induced hypothyroidism (HR, 0.70 [95% CI, 0.51-0.96]). Reduced mortality associated with hypothyroidism was seen only in those without significant comorbidities and not in those with other serious diseases. Atrial fibrillation at presentation (P = .02) and an increment of 10 pmol/L in

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

NARCIS (Netherlands)

Hoefnagel, C. A.; Rutgers, M.; Buitenhuis, C. K.; Smets, L. A.; de Kraker, J.; Meli, M.; Carrel, F.; Amstutz, H.; Schubiger, P. A.; Novak-Hofer, I.

2001-01-01

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in

The mortality of Oryzaephilus surinamensis Linnaeus, 1758 (Coleoptera: Silvanidae induced by powdered plants

Directory of Open Access Journals (Sweden)

Kłyś Małgorzata

2015-01-01

Full Text Available The aim of this study was to investigate whether powdered plants of different species namely: peppermint Mentha piperita (L. (Lamiaceae, wormwood Artemisia absinthium (L. (Asteraceae, common sage Salvia officinalis (L. (Lamiaceae, allspice Pimenta dioica (Linnaeus et Merrill (Myrtaceae and common garlic Allium sativum (L. (Amaryllidaceae, added to semolina using concentrations of 1.23, 3.61, and 5.88%, influence the mortality rate in the saw-toothed grain beetle Oryzaephilus surinamensis Linnaeus, 1758 (Coleoptera: Silvanidae. Experiments were conducted in a laboratory at 28°C and relative humidity 60±5%. At the concentration of 1.23%, allspice seeds caused the highest mortality amongst the saw-toothed grain beetle. When concentrations of 3.61 and 5.88% were used, sage, peppermint and wormwood caused the highest statistically significant mortality of O. surinamensis

Occupational radiation exposure and mortality study

International Nuclear Information System (INIS)

Coppock, E.; Dobson, D.; Fair, M.

1992-06-01

An epidemiological cohort study of some 300,000 Canadians enrolled in the National Dose Registry (NDR) is being undertaken to determine if there is excess cancer or other causes of mortality among those workers who are occupationally exposed to low levels of ionizing radiation. The results of this study may provide better understanding of the dose-response relationship for low doses of ionizing radiation and aid in the verification of risk estimates for radiation-induced cancer mortality. The Department of National Health and Welfare (DNHW) is responsible for the Registry; this study is being carried out by the Bureau of Radiation and Medical Devices (BRMD) with financial assistance and co-operation of various agencies including Statistics Canada and the Atomic Energy Control Board

The Preinterventional Cystatin-Creatinine-Ratio: A Prognostic Marker for Contrast Medium-Induced Acute Kidney Injury and Long-Term All-Cause Mortality.

Science.gov (United States)

Lüders, Florian; Meyborg, Matthias; Malyar, Nasser; Reinecke, Holger

2015-01-01

Contrast medium-induced acute kidney injury (CI-AKI) is an important iatrogenic complication following the injection of iodinated contrast media. The level of serum creatinine (SCr) is the currently accepted 'gold standard' to diagnose CI-AKI. Cystatin C (CyC) has been detected as a more sensitive marker for renal dysfunction. Both have their limitations. The role of the preinterventional CyC-SCr ratio for evaluating the risk for CI-AKI and long-term all-cause mortality was retrospectively analyzed in the prospective single-center 'Dialysis-versus-Diuresis trial'. CI-AKI was defined and staged according to the Acute Kidney Injury Network classification. Three hundred and seventy-three patients were included (average age 67.4 ± 10.2 years, 16.4% women, 29.2% with diabetes mellitus, mean baseline glomerular filtration rate 56.3 ± 20.2 ml/min/1.73 m(2) [as estimated by Chronic Kidney Disease Epidemiology Collaboration Serum Creatinine Cystatin C equation], 5.1% ejection fraction high significant association between preinterventional CyC-SCr ratio and long-term all-cause mortality (mean follow-up 649 days, hazards ratio 4.096, 95% CI 1.625-10.329, p = 0.003). The preinterventional CyC-SCr ratio is independently associated with CI-AKI and highly significant associated with long-term mortality after heart catheterization. © 2015 S. Karger AG, Basel.

Detecting Drought-Induced Tree Mortality in Sierra Nevada Forests with Time Series of Satellite Data

Directory of Open Access Journals (Sweden)

Sarah Byer

2017-09-01

Full Text Available A five-year drought in California led to a significant increase in tree mortality in the Sierra Nevada forests from 2012 to 2016. Landscape level monitoring of forest health and tree dieback is critical for vegetation and disaster management strategies. We examined the capability of multispectral imagery from the Moderate Resolution Imaging Spectroradiometer (MODIS in detecting and explaining the impacts of the recent severe drought in Sierra Nevada forests. Remote sensing metrics were developed to represent baseline forest health conditions and drought stress using time series of MODIS vegetation indices (VIs and a water index. We used Random Forest algorithms, trained with forest aerial detection surveys data, to detect tree mortality based on the remote sensing metrics and topographical variables. Map estimates of tree mortality demonstrated that our two-stage Random Forest models were capable of detecting the spatial patterns and severity of tree mortality, with an overall producer’s accuracy of 96.3% for the classification Random Forest (CRF and a RMSE of 7.19 dead trees per acre for the regression Random Forest (RRF. The overall omission errors of the CRF ranged from 19% for the severe mortality class to 27% for the low mortality class. Interpretations of the models revealed that forests with higher productivity preceding the onset of drought were more vulnerable to drought stress and, consequently, more likely to experience tree mortality. This method highlights the importance of incorporating baseline forest health data and measurements of drought stress in understanding forest response to severe drought.

Anti-human tissue factor antibody ameliorated intestinal ischemia reperfusion-induced acute lung injury in human tissue factor knock-in mice.

Directory of Open Access Journals (Sweden)

Xiaolin He

Full Text Available BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS. Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859 were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v. attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies.

Anti-high mobility group box-1 antibody therapy for traumatic brain injury.

Science.gov (United States)

Okuma, Yu; Liu, Keyue; Wake, Hidenori; Zhang, Jiyong; Maruo, Tomoko; Date, Isao; Yoshino, Tadashi; Ohtsuka, Aiji; Otani, Naoki; Tomura, Satoshi; Shima, Katsuji; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Takahashi, Hideo K; Mori, Shuji; Nishibori, Masahiro

2012-09-01

High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury. Traumatic brain injury was induced in rats or mice by fluid percussion. Anti-HMGB1 mAb or control mAb was administered intravenously after TBI. Anti-HMGB1 mAb remarkably inhibited fluid percussion-induced brain edema in rats, as detected by T2-weighted magnetic resonance imaging; this was associated with inhibition of HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression, and improvement of motor function. In contrast, intravenous injection of recombinant HMGB1 dose-dependently produced the opposite effects. Experiments using receptor for advanced glycation end product (RAGE)(-/-) , toll-like receptor-4 (TLR4)(-/-) , and TLR2(-/-) mice suggested the involvement of RAGE as the predominant receptor for HMGB1. Anti-HMGB1 mAb may provide a novel and effective therapy for TBI by protecting against BBB disruption and reducing the inflammatory responses induced by HMGB1. Copyright © 2012 American Neurological Association.

Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes

DEFF Research Database (Denmark)

Nielsen, M; Svejgaard, A; Skov, S

1994-01-01

that stimulation through the IL-2R induced tyrosine phosphorylation and subsequent nuclear translocation of stat3, a newly identified member of the signal transducers and activators of transcription (STAT) family of proteins. In contrast, stat1 proteins were not tyrosine phosphorylated after IL-2 ligation, whereas...... an apparent molecular mass of 84 kDa and was not recognized by stat3 or stat1 mAb or antisera. Since IL-2 induced nuclear translocation of the 84 kDa protein and stat3 followed identical kinetics, p84 is a candidate for a new, yet undefined, member of the STAT family. Taken together, we report that IL-2...... induces tyrosine phosphorylation and subsequent nuclear translocation of stat3 and an as yet undefined 84-kDa protein in antigen-specific human T cell lines....

Climatic correlates of tree mortality in water- and energy-limited forests.

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Adrian J Das

Full Text Available Recent increases in tree mortality rates across the western USA are correlated with increasing temperatures, but mechanisms remain unresolved. Specifically, increasing mortality could predominantly be a consequence of temperature-induced increases in either (1 drought stress, or (2 the effectiveness of tree-killing insects and pathogens. Using long-term data from California's Sierra Nevada mountain range, we found that in water-limited (low-elevation forests mortality was unambiguously best modeled by climatic water deficit, consistent with the first mechanism. In energy-limited (high-elevation forests deficit models were only equivocally better than temperature models, suggesting that the second mechanism is increasingly important in these forests. We could not distinguish between models predicting mortality using absolute versus relative changes in water deficit, and these two model types led to different forecasts of mortality vulnerability under future climate scenarios. Our results provide evidence for differing climatic controls of tree mortality in water- and energy-limited forests, while highlighting the need for an improved understanding of tree mortality processes.

An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.

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Motamedi-Shad, Neda; Jagger, Alistair M; Liedtke, Maximilian; Faull, Sarah V; Nanda, Arjun Scott; Salvadori, Enrico; Wort, Joshua L; Kay, Christopher W M; Heyer-Chauhan, Narinder; Miranda, Elena; Perez, Juan; Ordóñez, Adriana; Haq, Imran; Irving, James A; Lomas, David A

2016-10-01

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation. © 2016 The Author(s).

Maternal mortality ratio in Lebanon in 2008: a hospital-based reproductive age mortality study (RAMOS).

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Hobeika, Elie; Abi Chaker, Samer; Harb, Hilda; Rahbany Saad, Rita; Ammar, Walid; Adib, Salim

2014-01-01

International agencies have recently assigned Lebanon to the group H of countries with "no national data on maternal mortality," and estimated a corresponding maternal mortality ratio (MMR) of 150 per 100,000 live births. The Ministry of Public Health addressed the discrepancy perceived between the reality of the maternal mortality ratio experience in Lebanon and the international report by facilitating a hospital-based reproductive age mortality study, sponsored by the World Health Organization Representative Office in Lebanon, aiming at providing an accurate estimate of a maternal mortality ratio for 2008. The survey allowed a detailed analysis of maternal causes of deaths. Reproductive age deaths (15-49 years) were initially identified through hospital records. A trained MD traveled to each hospital to ascertain whether recorded deaths were in fact maternal deaths or not. ICD10 codes were provided by the medical controller for each confirmed maternal deaths. There were 384 RA death cases, of which 13 were confirmed maternal deaths (339%) (numerator). In 2008, there were 84823 live births in Lebanon (denominator). The MMR in Lebanon in 2008 was thus officially estimated at 23/100,000 live births, with an "uncertainty range" from 153 to 30.6. Hemorrhage was the leading cause of death, with double the frequency of all other causes (pregnancy-induced hypertension, eclampsia, infection, and embolism). This specific enquiry responded to a punctual need to correct a clearly inadequate report, and it should be relayed by an on-going valid surveillance system. Results indicate that special attention has to be devoted to the management of peri-partum hemorrhage cases. Arab, postpartum hemorrhage, development, pregnancy management, verbal autopsy

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein.

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Leemans, A; De Schryver, M; Van der Gucht, W; Heykers, A; Pintelon, I; Hotard, A L; Moore, M L; Melero, J A; McLellan, J S; Graham, B S; Broadbent, L; Power, U F; Caljon, G; Cos, P; Maes, L; Delputte, P

2017-07-15

Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs in vivo and how this might impact RSV replication. IMPORTANCE Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are

Therapeutic effect of anti-feline TNF-alpha monoclonal antibody for feline infectious peritonitis.

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Doki, Tomoyoshi; Takano, Tomomi; Kawagoe, Kohei; Kito, Akihiko; Hohdatsu, Tsutomu

2016-02-01

Feline infectious peritonitis virus (FIPV) replication in macrophages/monocytes induced tumor necrosis factor (TNF)-alpha production, and that the TNF-alpha produced was involved in aggravating the pathology of FIP. We previously reported the preparation of a feline TNF-alpha (fTNF-alpha)-neutralizing mouse monoclonal antibody (anti-fTNF-alpha mAb). This anti-fTNF-alpha mAb 2-4 was confirmed to inhibit the following fTNF-alpha-induced conditions in vitro. In the present study, we investigated whether mAb 2-4 improved the FIP symptoms and survival rate of experimentally FIPV-inoculated SPF cats. Progression to FIP was prevented in 2 out of 3 cats treated with mAb 2-4, whereas all 3 cats developed FIP in the placebo control group. Plasma alpha1-glycoprotein and vascular endothelial growth factor levels were improved by the administration of mAb 2-4, and the peripheral lymphocyte count also recovered. These results strongly suggested that the anti-fTNF-alpha antibody is effective for the treatment of FIP. Copyright © 2015 Elsevier Ltd. All rights reserved.

DNA fragmentation and cell death mediated by T cell antigen receptor/CD3 complex on a leukemia T cell line.

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Takahashi, S; Maecker, H T; Levy, R

1989-10-01

An anti-T cell receptor (TcR) monoclonal antibody (mAb), LC4, directed against a human leukemic T cell line, SUP-T13, caused DNA fragmentation ("apoptosis") and cell death upon binding to this cell line. Cross-linking of receptor molecules was necessary for this effect since F(ab')2, but not Fab', fragments of LC4 could induce cell death. Five anti-CD3 mAb tested also caused apoptosis, but only when they were presented on a solid phase. Interestingly, soluble anti-CD3 mAb induced calcium flux and had an additive effect on the calcium flux and interleukin 2 receptor expression induced by LC4, but these anti-CD3 mAb reversed the growth inhibition and apoptosis caused by LC4. The calcium ionophore A23187, but not the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), also induced apoptosis, suggesting that protein kinase C activation alone does not cause apoptosis, although PMA is growth inhibitory. These results suggest that two distinct biological phenomena can accompany stimulation of the TcR/CD3 complex. In both cases, calcium flux and interleukin 2 receptor expression is induced, but only in one case is apoptosis and cell death seen. The signal initiating apoptosis can be selectively prevented by binding CD3 portion of the receptor in this cell line. This difference in signals mediated by the TcR/CD3 complex may be important in explaining the process of thymic selection, as well as in choosing anti-TcR mAb for therapeutic use.

Siberian Pine Decline and Mortality in Southern Siberian Mountains

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Kharuk, V. I.; Im, S. T.; Oskorbin, P. A.; Petrov, I. A.; Ranson, K. J.

2013-01-01

The causes and resulting spatial patterns of Siberian pine mortality in eastern Kuznetzky Alatau Mountains, Siberia were analyzed based on satellite (Landsat, MODIS) and dendrochronology data. Climate variables studied included temperature, precipitation and Standardized Precipitation-Evapotranspiration Index (SPEI) drought index. Landsat data analysis showed that stand mortality was first detected in the year 2006 at an elevation of 650 m, and extended up to 900 m by the year 2012. Mortality was accompanied by a decrease in MODIS derived vegetation index (EVI).. The area of dead stands and the upper mortality line were correlated with increased drought. The uphill margin of mortality was limited by elevational precipitation gradients. Dead stands (i.e., >75% tree mortality) were located mainly on southern slopes. With respect to slope, mortality was observed within a 7 deg - 20 deg range with greatest mortality occurring on convex terrain. Tree radial incrementmeasurements correlate and were synchronous with SPEI (r sq = 0.37, r(sub s) = 80). Increasing synchrony between tree ring growth and SPEI indicates that drought has reduced the ecological niche of Siberian pine. The results also showed the primary role of drought stress on Siberian pine mortality. A secondary role may be played by bark beetles and root fungi attacks. The observed Siberian pine mortality is part of a broader phenomenon of "dark needle conifers" (DNC, i.e., Siberian pine, fir and spruce) decline and mortality in European Russia, Siberia, and the Russian Far East. All locations of DNC decline coincided with areas of observed drought increase. The results obtained are one of the first observations of drought-induced decline and mortality of DNC at the southern border of boreal forests. Meanwhile if model projections of increased aridity are correct DNC, within the southern part of its range may be replaced by drought-resistant Pinus silvestris and Larix sibirica.

Tsuga canadensis (L.) Carr, mortality will impact hydrologic processes in southern Appalachian forest ecosystems

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Chelcy R. Ford; James M. Vose

2007-01-01

Eastern hemlock (Tsuga canadensis (L.) Carr.) is one of the principal riparian and cove canopy species in the southern Appalachian Mountains. Throughout its range, eastern hemlock is facing potential widespread mortality from the hemlock woolly adelgid (HWA). If HWA-induced eastern hemlock mortality alters hydrologic function, land managers...

Detection of early warning signals of forest mortality in California

Science.gov (United States)

Liu, Y.; Kumar, M.; Katul, G. G.; Porporato, A. M.

2017-12-01

Massive forest mortality was observed in California during the most recent drought. Owing to complex interactions of physiological mechanisms under stress, prediction of climate-induced forest mortality using dynamic global vegetation models remains fraught with uncertainty. Given that forest ecosystems approaching mortality tend to exhibit reduction in resilience, we evaluate the time-varying resilience from time series of satellite images to detect early warning signals (EWSs) of mortality. Four metrics of EWSs are used: (1) low greenness, (2) high empirical autocorrelation of greenness, (3) high autocorrelation inferred using a Bayesian dynamic linear model considering the influence of seasonality and climate conditions, and (4) low recovery rate inferred from the drift term in the Langevin equation describing stochastic dynamics. Spatial accuracy and lead-time of these EWSs are evaluated by comparing the EWSs against observed mortality from aerial surveys conducted by the US Forest Service. Our results show that most forested areas in California that underwent mortality exhibit a EWS with a lead time of three months to two years ahead of observed mortality. Notably, EWS is also detected in some areas without mortality, suggesting reduced resilience during drought. Furthermore, the influence of the previous drought (2007-2009) may have propagated into the recent drought (2012-2016) through reduced resilience, hence contributing to the massive forest mortality observed recently. Methodologies developed in this study for detection of EWS will improve the near-term predictability of forest mortality, thus providing crucial information for forest and water resource management.

3β-hydroxysterol δ24-reductase on the surface of hepatitis C virus-related hepatocellular carcinoma cells can be a target for molecular targeting therapy.

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Makoto Saito

Full Text Available In our previous study, we demonstrated that 3β-hydroxysterol Δ24-reductase (DHCR24 was overexpressed in hepatitis C virus (HCV-related hepatocellular carcinoma (HCC, and that its expression was induced by HCV. Using a monoclonal antibody against DHCR24 (2-152a MAb, we found that DHCR24 was specifically expressed on the surface of HCC cell lines. Based on these findings, we aimed to establish a novel targeting strategy using 2-152a MAb to treat HCV-related HCC. In the present study, we examined the antitumor activity of 2-152a MAb. In the presence of complement, HCC-derived HuH-7 cells were killed by treatment with 2-152a MAb, which was mediated by complement-dependent cytotoxicity (CDC. In addition, the antigen recognition domain of 2-152a MAb was responsible for the unique anti-HCV activity. These findings demonstrate the feasibility of using 2-152a MAb for antibody therapy against HCV-related HCC. In addition, surface DHCR24 on HCC cells exhibited a functional property, agonist-induced internalization. We showed that 2-152a MAb-mediated binding of a cytotoxic agent (a saponin-conjugated secondary antibody to surface DHCR24 led to significant cytotoxicity. This suggests that surface DHCR24 on HCC cells can function as a carrier for internalization. Therefore, surface DHCR24 could be a valuable target for HCV-related HCC therapy, and 2-152a MAb appears to be useful for this targeted therapy.

Antibody-Based Therapies in Multiple Myeloma

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Yu-Tzu Tai

2011-01-01

Full Text Available The unmet need for improved multiple myeloma (MM therapy has stimulated clinical development of monoclonal antibodies (mAbs targeting either MM cells or cells of the bone marrow (BM microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA approval of therapeutic Abs for cancer and other diseases.

Factors affecting fungus-induced larval mortality in Anopheles gambiae and Anopheles stephensi

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Takken Willem

2010-01-01

Full Text Available Abstract Background Entomopathogenic fungi have shown great potential for the control of adult malaria vectors. However, their ability to control aquatic stages of anopheline vectors remains largely unexplored. Therefore, how larval characteristics (Anopheles species, age and larval density, fungus (species and concentration and environmental effects (exposure duration and food availability influence larval mortality caused by fungus, was studied. Methods Laboratory bioassays were performed on the larval stages of Anopheles gambiae and Anopheles stephensi with spores of two fungus species, Metarhizium anisopliae and Beauveria bassiana. For various larval and fungal characteristics and environmental effects the time to death was determined and survival curves established. These curves were compared by Kaplan Meier and Cox regression analyses. Results Beauveria bassiana and Metarhizium anisopliae caused high mortality of An. gambiae and An. stephensi larvae. However, Beauveria bassiana was less effective (Hazard ratio (HR Metarhizium anisopliae. Anopheles stephensi and An. gambiae were equally susceptible to each fungus. Older larvae were less likely to die than young larvae (HR Conclusions This study shows that both fungus species have potential to kill mosquitoes in the larval stage, and that mortality rate depends on fungus species itself, larval stage targeted, larval density and amount of nutrients available to the larvae. Increasing the concentration of fungal spores or reducing the exposure time to spores did not show a proportional increase and decrease in mortality rate, respectively, because the spores clumped together. As a result spores did not provide uniform coverage over space and time. It is, therefore, necessary to develop a formulation that allows the spores to spread over the water surface. Apart from formulation appropriate delivery methods are also necessary to avoid exposing non-target organisms to fungus.

Precipitation thresholds and drought-induced tree die-off: insights from patterns of Pinus edulis mortality along an environmental stress gradient.

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Clifford, Michael J; Royer, Patrick D; Cobb, Neil S; Breshears, David D; Ford, Paulette L

2013-10-01

Recent regional tree die-off events appear to have been triggered by a combination of drought and heat - referred to as 'global-change-type drought'. To complement experiments focused on resolving mechanisms of drought-induced tree mortality, an evaluation of how patterns of tree die-off relate to highly spatially variable precipitation is needed. Here, we explore precipitation relationships with a die-off event of pinyon pine (Pinus edulis Engelm.) in southwestern North America during the 2002-2003 global-change-type drought. Pinyon die-off and its relationship with precipitation was quantified spatially along a precipitation gradient in north-central New Mexico with standard field plot measurements of die-off combined with canopy cover derived from normalized burn ratio (NBR) from Landsat imagery. Pinyon die-off patterns revealed threshold responses to precipitation (cumulative 2002-2003) and vapor pressure deficit (VPD), with little to no mortality (< 10%) above 600 mm and below warm season VPD of c. 1.7 kPa. [Correction added after online publication 17 June 2013; in the preceding sentence, the word 'below' has been inserted.] Our results refine how precipitation patterns within a region influence pinyon die-off, revealing a precipitation and VPD threshold for tree mortality and its uncertainty band where other factors probably come into play - a response type that influences stand demography and landscape heterogeneity and is of general interest, yet has not been documented. © 2013 No claim to US Government works. New Phytologist © 2013 New Phytologist Trust.

Oral delivery of double-stranded RNAs induces mortality in nymphs and adults of the Asian citrus psyllid, Diaphorina citri.

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Galdeano, Diogo Manzano; Breton, Michèle Claire; Lopes, João Roberto Spotti; Falk, Bryce W; Machado, Marcos Antonio

2017-01-01

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama, is one of the most important citrus pests. ACP is the vector of the phloem-limited bacteria Candidatus Liberibacter americanus and Candidatus Liberibacter asiaticus, the causal agents of the devastating citrus disease huanglongbing (HLB). The management of HLB is based on the use of healthy young plants, eradication of infected plants and chemical control of the vector. RNA interference (RNAi) has proven to be a promising tool to control pests and explore gene functions. Recently, studies have reported that target mRNA knockdown in many insects can be induced through feeding with double-stranded RNA (dsRNA). In the current study, we targeted the cathepsin D, chitin synthase and inhibitor of apoptosis genes of adult and nymph ACP by feeding artificial diets mixed with dsRNAs and Murraya paniculata leaves placed in dsRNAs solutions, respectively. Adult ACP mortality was positively correlated with the amount of dsRNA used. Both nymphs and adult ACP fed dsRNAs exhibited significantly increased mortality over time compared with that of the controls. Moreover, qRT-PCR analysis confirmed the dsRNA-mediated RNAi effects on target mRNAs. These results showed that RNAi can be a powerful tool for gene function studies in ACP and perhaps for HLB control.

Frequency and mortality associated with hyperglycemia in critically III children

International Nuclear Information System (INIS)

Khan, S.A.; Haq, A.U.

2015-01-01

Objective: To determine the frequency of hyperglycemia in critically ill children admitted in PICU of a tertiary care hospital of Karachi and to compare the mortality of critically ill children with and without hyperglycemia. Study Design: Cross-sectional study. Place and Duration of Study: Paediatrics Intensive Care Unit (PICU) of National Institute of Child Health (NICH), Karachi, from November 2011 to April 2012. Methodology: One hundred fifty critically ill children admitted to PICU were included. Patients who had fasting blood sugar levels more than 126 mg/dl within 48 hours of admission were included in the hyperglycemic group. The normoglycemic and hyperglycemic groups were followed till 10 days to determine the mortality associated with hyperglycemia. Results: Out of 150 patients, 82 (54.7%) had hyperglycemia. Mortality rate was 48.7% (n=73/150). However, mortality rate was significantly high 57.3% (n=47) in hyperglycemic patients than non-hyperglycemic patients (p=0.019). Conclusion: The presence of stress-induced hyperglycemia in critically ill patients is a well established marker of poor outcome, and a very high mortality rate. Normoglycemia was associated with favorable outcomes in terms of hospital stay and mortality. (author)

Lung, liver and bone cancer mortality after plutonium exposure in beagle dogs and nuclear workers.

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Wilson, Dulaney A; Mohr, Lawrence C; Frey, G Donald; Lackland, Daniel; Hoel, David G

2010-01-01

The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

Weather radar data correlate to hail-induced mortality in grassland birds

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Large hail can kill animals, but its contribution to annual mortality is under-studied and difficult to quantify. Hail events are challenging to predict, and they often occur in locations where populations are not being studied. Small-bodied terrestrial animals such as songbirds (Order Passeriformes...

Mortality table construction

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Sutawanir

2015-12-01

Mortality tables play important role in actuarial studies such as life annuities, premium determination, premium reserve, valuation pension plan, pension funding. Some known mortality tables are CSO mortality table, Indonesian Mortality Table, Bowers mortality table, Japan Mortality table. For actuary applications some tables are constructed with different environment such as single decrement, double decrement, and multiple decrement. There exist two approaches in mortality table construction : mathematics approach and statistical approach. Distribution model and estimation theory are the statistical concepts that are used in mortality table construction. This article aims to discuss the statistical approach in mortality table construction. The distributional assumptions are uniform death distribution (UDD) and constant force (exponential). Moment estimation and maximum likelihood are used to estimate the mortality parameter. Moment estimation methods are easier to manipulate compared to maximum likelihood estimation (mle). However, the complete mortality data are not used in moment estimation method. Maximum likelihood exploited all available information in mortality estimation. Some mle equations are complicated and solved using numerical methods. The article focus on single decrement estimation using moment and maximum likelihood estimation. Some extension to double decrement will introduced. Simple dataset will be used to illustrated the mortality estimation, and mortality table.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

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Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

2009-12-01

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with

Abortion-Related Mortality in the United States 1998–2010

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Zane, Suzanne; Creanga, Andreea A.; Berg, Cynthia J.; Pazol, Karen; Suchdev, Danielle B.; Jamieson, Denise J.; Callaghan, William M.

2015-01-01

OBJECTIVE To examine characteristics and causes of legal induced abortion–related deaths in the United States between 1998 and 2010. METHODS Abortion-related deaths were identified through the national Pregnancy Mortality Surveillance System with enhanced case-finding. We calculated the abortion mortality rate by race, maternal age, and gestational age and the distribution of causes of death by gestational age and procedure. RESULTS During the period from 1998–2010, of approximately 16.1 million abortion procedures, 108 women died, for a mortality rate of 0.7 deaths per 100,000 procedures overall, 0.4 deaths for non-Hispanic white women, 0.5 deaths for Hispanic women, and 1.1 deaths for black women. The mortality rate increased with gestational age, from 0.3 to 6.7 deaths for procedures performed at 8 weeks or less and at 18 weeks or greater, respectively. A majority of abortion-related deaths at 13 weeks of gestation or less were associated with anesthesia complications and infection, whereas a majority of abortion-related deaths at more than 13 weeks of gestation were associated with infection and hemorrhage. In 20 of the 108 cases, the abortion was performed as a result of a severe medical condition where continuation of the pregnancy threatened the woman’s life. CONCLUSION Deaths associated with legal induced abortion continue to be rare events—less than 1 per 100,000 procedures. Primary prevention of unintended pregnancy, including those in women with serious pre-existing medical conditions, and increased access to abortion services at early gestational ages may help to further decrease abortion-related mortality in the United States. PMID:26241413

Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection.

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Wan, Shu-Wen; Chen, Pei-Wei; Chen, Chin-Yu; Lai, Yen-Chung; Chu, Ya-Ting; Hung, Chia-Yi; Lee, Han; Wu, Hsuan Franziska; Chuang, Yung-Chun; Lin, Jessica; Chang, Chih-Peng; Wang, Shuying; Liu, Ching-Chuan; Ho, Tzong-Shiann; Lin, Chiou-Feng; Lee, Chien-Kuo; Wu-Hsieh, Betty A; Anderson, Robert; Yeh, Trai-Ming; Lin, Yee-Shin

2017-10-15

Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease. Copyright © 2017 by The American Association of Immunologists, Inc.

The impact of heat waves and cold spells on mortality rates in the Dutch population

NARCIS (Netherlands)

Huynen, M. M.; Martens, P.; Schram, D.; Weijenberg, M. P.; Kunst, A. E.

2001-01-01

We conducted the study described in this paper to investigate the impact of ambient temperature on mortality in the Netherlands during 1979-1997, the impact of heat waves and cold spells on mortality in particular, and the possibility of any heat wave- or cold spell-induced forward displacement of

An analysis of radiation-induced damage in the spider mite. Relationship between mortality of haploid and diploid eggs in two successive generations

International Nuclear Information System (INIS)

Leenhouts, H.P.; Chadwick, K.H.

1976-01-01

Unfertilized females of the spider mite (Tetranychus urticae) produce only haploid eggs which develop into a haploid male. Fertilized females produce both haploid eggs (unfertilized), which develop into males, and diploid eggs (fertilized), which develop into females. Radiobiological experiments performed by A.M. Feldmann (Association Euratom-ITAL) made data available on the radiation-induced mortality of haploid and diploid eggs in the F 1 and F 2 generation following irradiation of either males or females with X rays or fast neutrons. The data have been analysed using the molecular theory of cell survival where it is assumed that DNA double strand breaks, induced randomly in the cell, are the critical radiation-induced lesions, which lead to cell death. Theoretical relationships are derived for the dose dependence of hatchability in haploid and diploid eggs in the first and second generations expressed as a function of the radiation damage in the parental genome. These theoretical relationships can be used to derive the inter-relationship between the different hatchabilities, and the results from the spider mite have been analysed using these considerations. It is concluded that the radiation-induced genetic damage arises from one type of initial lesion. The eventual radiobiological implications of this analysis are discussed, expecially with respect to the transmittance of radiation-induced genetic damage after low-level radiation. (author)

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

Science.gov (United States)

Burastero, Samuele E; Frigerio, Barbara; Lopalco, Lucia; Sironi, Francesca; Breda, Daniela; Longhi, Renato; Scarlatti, Gabriella; Canevari, Silvana; Figini, Mariangela; Lusso, Paolo

2011-01-01

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

Directory of Open Access Journals (Sweden)

Samuele E Burastero

Full Text Available To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

Tree Mortality

Science.gov (United States)

Mark J. Ambrose

2012-01-01

Tree mortality is a natural process in all forest ecosystems. However, extremely high mortality also can be an indicator of forest health issues. On a regional scale, high mortality levels may indicate widespread insect or disease problems. High mortality may also occur if a large proportion of the forest in a particular region is made up of older, senescent stands....

Estimating drought induced tree mortality in the Amazon rainforest: A simulation study with a focus on plant hydraulic processes

Science.gov (United States)

Papastefanou, P.; Fleischer, K.; Hickler, T.; Grams, T.; Lapola, D.; Quesada, C. A.; Zang, C.; Rammig, A.

2017-12-01

The Amazon basin was recently hit by severe drought events that were unprecedented in their severity and spatial extent, e.g. during 2005, 2010 and 2015/2016. Significant amounts of biomass were lost, turning large parts of the rainforest from a carbon sink into a carbon source. It is assumed that drought-induced tree mortality from hydraulic failure played an important role during these events and may become more frequent in the Amazon region in the future. Many state-of-the-art dynamic vegetation models do not include plant hydraulic processes and fail to reproduce observed rainforest responses to drought events, such as e.g. increased tree mortality. We address this research gap by developing a simple plant-hydraulic module for the dynamic vegetation model LPJ-GUESS. This plant-hydraulic module uses leaf water potential and cavitation as baseline processes to simulate tree mortality under drought stress. Furthermore, we introduce different plant strategies in the model, which describe e.g. differences in the stomatal regulation under drought stress. To parameterize and evaluate our hydraulic module, we use a set of available observational data from the Amazon region. We apply our model to the Amazon Basin and highlight similarities and differences across other measured and predicted drought responses, e.g. extrapolated observations and data derived from satellite measurements. Our results highlight the importance of including plant hydraulic processes in dynamic vegetation models to correctly predict vegetation dynamics under drought stress and show major differences on the vegetation dynamics depending on the selected plant strategies. We also identify gaps in process understanding of the triggering factors, the extent and the consequences of drought responses that hampers our ability to predict potential impact of future drought events on the Amazon rainforest.

Infant Mortality

Science.gov (United States)

... After hours (404) 639-2888 Contact Media Infant Mortality Recommend on Facebook Tweet Share Compartir On This ... differences in rates among population groups. About Infant Mortality Infant mortality is the death of an infant ...

Risk factors of neonatal mortality and child mortality in Bangladesh.

Science.gov (United States)

Maniruzzaman, Md; Suri, Harman S; Kumar, Nishith; Abedin, Md Menhazul; Rahman, Md Jahanur; El-Baz, Ayman; Bhoot, Makrand; Teji, Jagjit S; Suri, Jasjit S

2018-06-01

Child and neonatal mortality is a serious problem in Bangladesh. The main objective of this study was to determine the most significant socio-economic factors (covariates) between the years 2011 and 2014 that influences on neonatal and child mortality and to further suggest the plausible policy proposals. We modeled the neonatal and child mortality as categorical dependent variable (alive vs death of the child) while 16 covariates are used as independent variables using χ 2 statistic and multiple logistic regression (MLR) based on maximum likelihood estimate. Using the MLR, for neonatal mortality, diarrhea showed the highest positive coefficient (β = 1.130; P  economic conditions for neonatal mortality. For child mortality, birth order between 2-6 years and 7 and above years showed the highest positive coefficients (β = 1.042; P  economic conditions for child mortality. This study allows policy makers to make appropriate decisions to reduce neonatal and child mortality in Bangladesh. In 2014, mother's age and father's education were also still significant covariates for child mortality. This study allows policy makers to make appropriate decisions to reduce neonatal and child mortality in Bangladesh.

Compensatory vapor loss and biogeochemical attenuation along flowpaths mute the water resources impacts of insect-induced forest mortality

Science.gov (United States)

Biederman, J. A.; Brooks, P. D.; Harpold, A. A.; Gochis, D. J.; Ewers, B. E.; Reed, D. E.; Gutmann, E. D.

2013-12-01

-impacted zero-order channel, DOC and DON were reduced by ~50 % within 5 km downstream in a 700-ha catchment with similar MPB forest mortality. Soil water NO3 up to 500 μeq l-1 during the snowmelt flush was attenuated by an order of magnitude in the riparian groundwater and was usually below detection limit in the adjacent zero-order channel. These observations demonstrate that water resources impacts of insect-induced forest mortality may be muted because 1) compensatory vapor loss can offset expected water yield increases and 2) processing of carbon and nitrogen along both hillslope flowpaths and within headwater streams can rapidly attenuate biogeochemical fluxes.

Pattern of mortality among Danish thorotrast patients

DEFF Research Database (Denmark)

Andersson, Michael; Juel, K; Storm, Hans Henrik

1993-01-01

by 3-4 fold even for the follow up period after the first 3 years. The increase in mortality was evident for all categories of cause of death, the SMR being 11.1 (95% confidence interval (CI) 7.1-16.4) for cirrhosis of the liver, 4.7 (4.1-5.3) for cancer, 1.6 (1.3-1.9) for cardiac disease, 3.3 (2...... neurological conditions and by diseases known to be induced by Thorotrast (cirrhosis and cancer of the liver, leukaemia and other haematological diseases), and it is suggested that unspecific effects induced by the alpha-radiation of Thorotrast may have contributed....

Biocontrol Potential of Lariophagus distinguendus (Hymenoptera: Pteromalidae) Against Sitophilus granarius (Coleoptera: Curculionidae) at Low Temperatures: Reproduction and Parasitoid-Induced Mortality

DEFF Research Database (Denmark)

Hansen, Lise Stengård

2007-01-01

Lariophagus distinguendus Förster (Hymenoptera: Pteromalidae) has been suggested as a biological control agent against the granary weevil, Sitophilus granarius (L.), in grain stores. Information on the effect of low temperatures prevailing in grain stores is necessary to be able to predict...... the potential of this parasitoid against S. granarius in temperate regions, where grain is cooled with ambient air to achieve safe storage conditions. The influence of constant temperatures of 16, 18, and 20°C on life table parameters and parasitoid-induced mortality (PIM) was investigated in the laboratory. L...... is quicker than that of its host, estimated from the literature; and it kills many hosts in addition to those used for reproduction....

Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway.

Science.gov (United States)

Kuo, Yung-Chih; Shih-Huang, Chun-Yuan

2013-09-01

Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83-14 monoclonal antibody (MAb) (83-14 MAb/BCNU-SLNs) and applied to the brain-targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83-14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83-14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4 °C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83-14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83-14 MAb/BCNU-SLNs across the blood-brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83-14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83-14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain.

Perceived Mortality and Perceived Morality: Perceptions of Value-Orientation Are More Likely When a Decision Is Preceded by a Mortality Reminder.

Science.gov (United States)

Nordmo, Mads; Norman, Elisabeth

2016-01-01

The questions addressed in this paper are whether and how reported mortality reminders can function as an indication of sincerity when communicating ambiguously motivated decisions. In two experiments, participants were exposed to a fictitious CEO who announced a decision to implement new organizational measures that were both environmentally and financially beneficial. In the experimental condition, the CEO attributed her new ideas to a recent mortality reminder. In the active control condition, the CEO attributed her decision to a non-lethal dentistry health scare, and in the passive control condition the CEO did not give any account of events preceding her decision. When a CEO implemented new corporate initiatives after a mortality reminder, her motivation for doing so was perceived as somewhat more motivated by intrinsic values, and significantly less motivated by financial gains. This change in attribution patterns was demonstrated to be indirectly related to a positive evaluation of the CEO, as well as an increased willingness to pay for the organization's services. The second experiment further demonstrated that the reduced attribution to financial motivation associated with mortality awareness persisted even when the CEO in question was known for placing a high personal priority on financial goal attainment. The findings underscore the importance of perceived value-oriented motivation when communicating climate change mitigating policies, and the role of mortality awareness as one of many ways to induce such attributions.

Imiquimod induced ApoE-deficient mice might be a composite animal model for the study of psoriasis and dyslipideamia comorbidity.

Science.gov (United States)

Xie, Xinran; Zhang, Lei; Lin, Yan; Wang, Yan; Liu, Weihong; Li, Xue; Li, Ping

2017-10-01

Psoriasis patients are at increased risk of developing lipid metabolism disturbances. Both psoriasis and dyslipideamia not only closely interact in disease development, but occur as mutual side effects in some medicine treatment. The interactive mechanism of the two diseases is complicated and still unclear. Here, we proposed applying imiquimod on the dorsal skin of ApoE -/- mice to establish a composite animal model which formed psoriasiform skin lesions under hyperlipidemic condition. By comparison with corresponding wild-type(C57BL/6) mice, the composite mice model was evaluated by skin pathological features, lipid levels, immune inflammatory factors in order to clarify the diseases interplay mechanism. In addition, IL-17 mAb treatment was applied to observe the effect of IL-17 antibody on the composite animal model. The results verified that imiquimod-induced ApoE -/- mice model presented keratinocyte hyperplasia, parakeratosis, inflammatory cells infiltration and elevated serum lipid levels, and also reflected the complex interaction between inflammation and lipid metabolism. IL-17 mAb could inhibit psoriasis skin lesions with lipid accumulation via STAT3 pathway, but no influence on elevated serum cholesterol. Imiquimod-induced ApoE -/- mice model presented the pathological features of psoriasis and dyslipideamia, which could be an ideal composite animal model for the study of pathogenesis and pharmacotherapeutics of psoriasis and dyslipideamia comorbidity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Polysome profiling of mAb producing CHO cell lines links translational control of cell proliferation and recombinant mRNA loading onto ribosomes with global and recombinant protein synthesis.

Science.gov (United States)

Godfrey, Charlotte L; Mead, Emma J; Daramola, Olalekan; Dunn, Sarah; Hatton, Diane; Field, Ray; Pettman, Gary; Smales, C Mark

2017-08-01

mRNA translation is a key process determining growth, proliferation and duration of a Chinese hamster ovary (CHO) cell culture and influences recombinant protein synthesis rate. During bioprocessing, CHO cells can experience stresses leading to reprogramming of translation and decreased global protein synthesis. Here we apply polysome profiling to determine reprogramming and translational capabilities in host and recombinant monoclonal antibody-producing (mAb) CHO cell lines during batch culture. Recombinant cell lines with the fastest cell specific growth rates were those with the highest global translational efficiency. However, total ribosomal capacity, determined from polysome profiles, did not relate to the fastest growing or highest producing mAb cell line, suggesting it is the ability to utilise available machinery that determines protein synthetic capacity. Cell lines with higher cell specific productivities tended to have elevated recombinant heavy chain transcript copy numbers, localised to the translationally active heavy polysomes. The highest titre cell line was that which sustained recombinant protein synthesis and maintained high recombinant transcript copy numbers in polysomes. Investigation of specific endogenous transcripts revealed a number that maintained or reprogrammed into heavy polysomes, identifying targets for potential cell engineering or those with 5' untranslated regions that might be utilised to enhance recombinant transcript translation. © 2017 The Authors. Biotechnology Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Trends in the Pattern of Induced Abortions in Ilorin | Adeleke ...

African Journals Online (AJOL)

Context: Induced abortion remains a major cause of maternal mortality in developing countries. Reports from Nigeria put it's contribution to maternal death at between 15-40%. Prevention of maternal mortality project (Which trys to eliminate hospital delay in the treatment of complication of induced abortion) was introduced ...

Alcohol use disorder-related sick leave and mortality: a cohort study.

Science.gov (United States)

Wedegaertner, Felix; Geyer, Siegfried; Arnhold-Kerri, Sonja; Sittaro, Nicola-Alexander; te Wildt, Bert

2013-01-30

Alcohol use disorders (AUDs) are associated with the highest all-cause mortality rates of all mental disorders. The majority of patients with AUDs never receive inpatient treatment for their AUD, and there is lack of data about their mortality risks despite their constituting the majority of those affected. Absenteeism from work (sick leave) due to an AUD likely signals worsening. In this study, we assessed whether AUD-related sick leave was associated with mortality in a cohort of workers in Germany. 128,001 workers with health insurance were followed for a mean of 6.4 years. We examined the associations between 1) AUD-related sick leave managed on an outpatient basis and 2) AUD-related psychiatric inpatient treatment, and mortality using survival analysis, and Cox proportional hazard regression models (separately by sex) adjusted for age, education, and job code classification. We also stratified analyses by sick leave related to three groups of alcohol-related conditions (all determined by International Classification of Diseases 9th ed. (ICD-9) codes): alcohol abuse and dependence; alcohol-induced mental disorder; and alcohol-induced medical conditions. Outpatient-managed AUD-related sick leave was significantly associated with higher mortality (hazard ratio (HR) 2.90 (95% Confidence interval (CI) 2.24-3.75) for men, HR 5.83 (CI 2.90-11.75) for women). The magnitude of the association was similar for receipt of AUD-related psychiatric inpatient treatment (HR 3.2 (CI 2.76-3.78) for men, HR 6.5 (CI 4.41-9.47) for women). Compared to those without the conditions, higher mortality was observed consistently for outpatients and inpatients across the three groups of alcohol-related conditions. Those with alcohol-related medical conditions who had AUD-related psychiatric inpatient treatment appeared to have the highest mortality. Alcohol use disorder-related sick leave as documented in health insurance records is associated with higher mortality. Such sick leave does

Nonstructural leaf carbohydrates dynamics of Pinus edulis during drought-induced tree mortality reveal role for carbon metabolism in mortality mechanism

Science.gov (United States)

Adams, Henry D.; Germino, Matthew J.; Breshears, David D.; Barron-Gafford, Greg A.; Guardiola-Claramonte, Maite; Zou, Chris B.; Huxman, Travis E.

2013-01-01

* Vegetation change is expected with global climate change, potentially altering ecosystem function and climate feedbacks. However, causes of plant mortality, which are central to vegetation change, are understudied, and physiological mechanisms remain unclear, particularly the roles of carbon metabolism and xylem function.

Oral delivery of double-stranded RNAs induces mortality in nymphs and adults of the Asian citrus psyllid, Diaphorina citri.

Directory of Open Access Journals (Sweden)

Diogo Manzano Galdeano

Full Text Available The Asian citrus psyllid (ACP, Diaphorina citri Kuwayama, is one of the most important citrus pests. ACP is the vector of the phloem-limited bacteria Candidatus Liberibacter americanus and Candidatus Liberibacter asiaticus, the causal agents of the devastating citrus disease huanglongbing (HLB. The management of HLB is based on the use of healthy young plants, eradication of infected plants and chemical control of the vector. RNA interference (RNAi has proven to be a promising tool to control pests and explore gene functions. Recently, studies have reported that target mRNA knockdown in many insects can be induced through feeding with double-stranded RNA (dsRNA. In the current study, we targeted the cathepsin D, chitin synthase and inhibitor of apoptosis genes of adult and nymph ACP by feeding artificial diets mixed with dsRNAs and Murraya paniculata leaves placed in dsRNAs solutions, respectively. Adult ACP mortality was positively correlated with the amount of dsRNA used. Both nymphs and adult ACP fed dsRNAs exhibited significantly increased mortality over time compared with that of the controls. Moreover, qRT-PCR analysis confirmed the dsRNA-mediated RNAi effects on target mRNAs. These results showed that RNAi can be a powerful tool for gene function studies in ACP and perhaps for HLB control.

Alleviation of mortality induced by salicylate and stress.

Science.gov (United States)

Jastreboff, P J; Brennan, J F

1994-05-15

Protection from the deleterious effects of the interaction of environmental stress and salicylate by calcium supplement was investigated in 96 pigmented rats. Within a 2 x 2 x 4 factorial design, rats were assigned to groups defined by: A) ad lib access to 1) plain tap water, or 2) 50 mM calcium chloride solution; B) exposure to stressors consisting of daily 10 h periods of 1) 98 dB SPL noise, or 2) confinement precluding movements; C) daily injections of 233, 350, or 410 mg/kg of sodium salicylate or the saline vehicle. For subjects maintained on tap water, weight loss and mortality increased with salicylate levels, with all subjects dying in the group drinking water and injected with 410 mg/kg. Calcium protected all of the subjects in the noise stress group but not in the confined group.

Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity

OpenAIRE

Koobkokkruad, Thongchai; Kadotani, Tatsuya; Hutamekalin, Pilaiwanwadee; Mizutani, Nobuaki; Yoshino, Shin

2011-01-01

Abstract Background The collagen antibody-induced arthritis (CAIA) model, which employs a cocktail of monoclonal antibodies (mAbs) to type II collagen (CII), has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes...

Linking carbon and water limitations to drought-induced mortality of Pinus flexilis seedlings

Science.gov (United States)

Reinhardt, Keith; Germino, Matthew J.; Kueppers, Lara M.; Domec, Jean-Christophe; Mitton, Jeffry

2015-01-01

Survival of tree seedlings at high elevations has been shown to be limited by thermal constraints on carbon balance, but it is unknown if carbon relations also limit seedling survival at lower elevations, where water relations may be more important. We measured and modeled carbon fluxes and water relations in first-year Pinus flexilis seedlings in garden plots just beyond the warm edge of their natural range, and compared these with dry-mass gain and survival across two summers. We hypothesized that mortality in these seedlings would be associated with declines in water relations, more so than with carbon-balance limitations. Rather than gradual declines in survivorship across growing seasons, we observed sharp, large-scale mortality episodes that occurred once volumetric soil-moisture content dropped below 10%. By this point, seedling water potentials had decreased below −5 MPa, seedling hydraulic conductivity had decreased by 90% and seedling hydraulic resistance had increased by >900%. Additionally, non-structural carbohydrates accumulated in aboveground tissues at the end of both summers, suggesting impairments in phloem-transport from needles to roots. This resulted in low carbohydrate concentrations in roots, which likely impaired root growth and water uptake at the time of critically low soil moisture. While photosynthesis and respiration on a leaf area basis remained high until critical hydraulic thresholds were exceeded, modeled seedling gross primary productivity declined steadily throughout the summers. At the time of mortality, modeled productivity was insufficient to support seedling biomass-gain rates, metabolism and secondary costs. Thus the large-scale mortality events that we observed near the end of each summer were most directly linked with acute, episodic declines in plant hydraulic function that were linked with important changes in whole-seedling carbon relations.

Linking carbon and water relations to drought-induced mortality in Pinus flexilis seedlings.

Science.gov (United States)

Reinhardt, Keith; Germino, Matthew J; Kueppers, Lara M; Domec, Jean-Christophe; Mitton, Jeffry

2015-07-01

Survival of tree seedlings at high elevations has been shown to be limited by thermal constraints on carbon balance, but it is unknown if carbon relations also limit seedling survival at lower elevations, where water relations may be more important. We measured and modeled carbon fluxes and water relations in first-year Pinus flexilis seedlings in garden plots just beyond the warm edge of their natural range, and compared these with dry-mass gain and survival across two summers. We hypothesized that mortality in these seedlings would be associated with declines in water relations, more so than with carbon-balance limitations. Rather than gradual declines in survivorship across growing seasons, we observed sharp, large-scale mortality episodes that occurred once volumetric soil-moisture content dropped below 10%. By this point, seedling water potentials had decreased below -5 MPa, seedling hydraulic conductivity had decreased by 90% and seedling hydraulic resistance had increased by >900%. Additionally, non-structural carbohydrates accumulated in aboveground tissues at the end of both summers, suggesting impairments in phloem-transport from needles to roots. This resulted in low carbohydrate concentrations in roots, which likely impaired root growth and water uptake at the time of critically low soil moisture. While photosynthesis and respiration on a leaf area basis remained high until critical hydraulic thresholds were exceeded, modeled seedling gross primary productivity declined steadily throughout the summers. At the time of mortality, modeled productivity was insufficient to support seedling biomass-gain rates, metabolism and secondary costs. Thus the large-scale mortality events that we observed near the end of each summer were most directly linked with acute, episodic declines in plant hydraulic function that were linked with important changes in whole-seedling carbon relations. © The Author 2015. Published by Oxford University Press. All rights reserved

Occupational mortality

DEFF Research Database (Denmark)

Lynge, Elsebeth

2011-01-01

-1975 revealed a considerable social class gradient in male mortality where university teachers and farmers had a 40% lower mortality and waiters and seamen had an about 100% higher mortality than the average for economically active men. The social class gradient was less steep for women. A similar pattern...

A synthesis of radial growth patterns preceding tree mortality

Science.gov (United States)

Cailleret, Maxime; Jansen, Steven; Robert, Elisabeth M.R.; Desoto, Lucia; Aakala, Tuomas; Antos, Joseph A.; Beikircher, Barbara; Bigler, Christof; Bugmann, Harald; Caccianiga, Marco; Cada, Vojtech; Camarero, Jesus J.; Cherubini, Paolo; Cochard, Herve; Coyea, Marie R.; Cufar, Katarina; Das, Adrian J.; Davi, Hendrik; Delzon, Sylvain; Dorman, Michael; Gea-Izquierdo, Guillermo; Gillner, Sten; Haavik, Laurel J.; Hartmann, Henrik; Heres, Ana-Maria; Hultine, Kevin R.; Janda, Pavel; Kane, Jeffrey M.; Kharuk, Vyacheslav I.; Kitzberger, Thomas; Klein, Tamir; Kramer, Koen; Lens, Frederic; Levanic, Tom; Calderon, Juan C. Linares; Lloret, Francisco; Lobo-Do-Vale, Raquel; Lombardi, Fabio; Lopez Rodriguez, Rosana; Makinen, Harri; Mayr, Stefan; Meszaros, IIona; Metsaranta, Juha M.; Minunno, Francesco; Oberhuber, Walter; Papadopoulos, Andreas; Peltoniemi, Mikko; Petritan, Any M.; Rohner, Brigitte; Sanguesa-Barreda, Gabriel; Sarris, Dimitrios; Smith, Jeremy M.; Stan, Amanda B.; Sterck, Frank; Stojanovic, Dejan B.; Suarez, Maria L.; Svoboda, Miroslav; Tognetti, Roberto; Torres-Ruiz, Jose M.; Trotsiuk, Volodymyr; Villalba, Ricardo; Vodde, Floor; Westwood, Alana R.; Wyckoff, Peter H.; Zafirov, Nikolay; Martinez-Vilalta, Jordi

2017-01-01

Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-continental tree-ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the mortality events. The extent and duration of these reductions were highly variable (1–100 years in 96% of events) due to the complex interactions among study species and the source(s) of mortality. Strong and long-lasting declines were found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term growth reductions. Our analysis did not highlight any universal trade-off between early growth and tree longevity within a species, although this result may also reflect high variability in sampling design among sites. The intersite and interspecific variability in growth patterns before mortality provides valuable information on the nature of the mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality. Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or

Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV closely resembles lung cancer in sheep infected with JSRV

Directory of Open Access Journals (Sweden)

York Denis

2006-12-01

Full Text Available Abstract Background Jaagsiekte sheep retrovirus (JSRV causes a lethal lung cancer in sheep and goats. Expression of the JSRV envelope (Env protein in mouse lung, by using a replication-defective adeno-associated virus type 6 (AAV6 vector, induces tumors resembling those seen in sheep. However, the mouse and sheep tumors have not been carefully compared to determine if Env expression alone in mice can account for the disease features observed in sheep, or whether additional aspects of virus replication in sheep are important, such as oncogene activation following retrovirus integration into the host cell genome. Results We have generated mouse monoclonal antibodies (Mab against JSRV Env and have used these to study mouse and sheep lung tumor histology. These Mab detect Env expression in tumors in sheep infected with JSRV from around the world with high sensitivity and specificity. Mouse and sheep tumors consisted mainly of well-differentiated adenomatous foci with little histological evidence of anaplasia, but at long times after vector exposure some mouse tumors did have a more malignant appearance typical of adenocarcinoma. In addition to epithelial cell tumors, lungs of three of 29 sheep examined contained fibroblastic cell masses that expressed Env and appeared to be separate neoplasms. The Mab also stained nasal adenocarcinoma tissue from one United States sheep, which we show was due to expression of Env from ovine enzootic nasal tumor virus (ENTV, a virus closely related to JSRV. Systemic administration of the AAV6 vector encoding JSRV Env to mice produced numerous hepatocellular tumors, and some hemangiomas and hemangiosarcomas, showing that the Env protein can induce tumors in multiple cell types. Conclusion Lung cancers induced by JSRV infection in sheep and by JSRV Env expression in mice have similar histologic features and are primarily characterized by adenomatous proliferation of peripheral lung epithelial cells. Thus it is

Analysis and out-year forecast of beetle, borer, and drought-induced tree mortality in California

Science.gov (United States)

Haiganoush K. Preisler; Nancy E. Grulke; Zachary Heath; Sheri L. Smith

2017-01-01

The level of tree mortality and drought observed over the past decade in North America has been described as ‘unparalleled’ in our modern history, in particular in the Sierra Nevada, California. Forest managers could use early warning of where and how much tree mortality to expect in the very near future to plan and prioritize hazard tree removal, pest suppression...

Stress-Induced Hyperglycemia, but Not Diabetic Hyperglycemia, Is Associated with Higher Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: Analysis of a Propensity Score-Matched Population.

Science.gov (United States)

Rau, Cheng-Shyuan; Wu, Shao-Chun; Chen, Yi-Chun; Chien, Peng-Chen; Hsieh, Hsiao-Yun; Kuo, Pao-Jen; Hsieh, Ching-Hua

2017-11-03

Background : Admission hyperglycemia is associated with higher morbidity and mortality in patients with traumatic brain injury (TBI). Stress-induced hyperglycemia (SIH), a form of hyperglycemia induced by the stress response, is associated with increased patient mortality following TBI. However, admission hyperglycemia occurs not only in SIH but also in patients with diabetic hyperglycemia (DH). Current information regarding whether trauma patients with SIH represent a distinct group with differential outcomes compared to those with DH remains limited. Methods : Serum glucose concentration ≥200 mg/dL upon arrival at the emergency department was defined as hyperglycemia. Presence of diabetes mellitus (DM) was determined by patient history and/or admission glycated hemoglobin (HbA1c) level ≥6.5%. In the present study, the patient cohort included those with moderate and severe TBI, as defined by an Abbreviated Injury Scale (AIS) score ≥3 points in the head, and excluded those who had additional AIS scores ≥3 points in any other region of the body. A total of 1798 adult patients with isolated moderate to severe TBI were allocated into four groups: SIH ( n = 140), DH ( n = 187), diabetic normoglycemia (DN, n = 186), and non-diabetic normoglycemia (NDN, n = 1285). Detailed patient information was retrieved from the Trauma Registry System at a level I trauma center between 1 January 2009, and 31 December 2015. Unpaired Student's t - and Mann-Whitney U -tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to propensity scores calculated by NCSS software. Logistic regression was used to evaluate the effect of SIH and DH on the adjusted mortality outcome. Results : In patients with isolated moderate to severe TBI, the presence of SIH and DH led to 9.1-fold and 2

Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

KAUST Repository

Madhoun, Nour Y.

2017-04-01

Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

Anti-idiotypic antibodies as cancer vaccines: achievements and future improvements

International Nuclear Information System (INIS)

Ladjemi, Maha Z.

2012-01-01

Since the discovery of tumor-associated antigens (TAAs), researchers have tried to develop immune-based anti-cancer therapies. Thanks to their specificity, monoclonal antibodies (mAbs) offer the major advantage to induce fewer side effects than those caused by non-specific conventional treatments (e.g., chemotherapy, radiotherapy). Passive immunotherapy by means of mAbs or cytokines has proved efficacy in oncology and validated the use of immune-based agents as part of anti-cancer treatment options. The next step was to try to induce an active immune protection aiming to boost own’s host immune defense against TAAs. Cancer vaccines are thus developed to specifically induce active immune protection targeting only tumor cells while preserving normal tissues from a non-specific toxicity. But, as most of TAAs are self antigens, an immune tolerance against them exists representing a barrier to effective vaccination against these oncoproteins. One promising approach to break this immune tolerance consists in the use of anti-idiotypic (anti-Id) mAbs, so called Ab2, as antigen surrogates. This vaccination strategy allows also immunization against non-proteic antigens (such as carbohydrates). In some clinical studies, anti-Id cancer vaccines indeed induced efficient humoral and/or cellular immune responses associated with clinical benefit. This review article will focus on recent achievements of anti-Id mAbs use as cancer vaccines in solid tumors.

Hyperprolactinemia and the Association with All-Cause Mortality and Cardiovascular Mortality

DEFF Research Database (Denmark)

Krogh, Jesper; Selmer, Christian; Torp-Pedersen, Christian

2017-01-01

Hyperprolactinemia has been suspected to increase mortality risk, but the available data are conflicting. The objective of this study was to estimate the association between hyperprolactinemia and all-cause and cardiovascular mortality among patients referred for assessment of prolactin......-cause mortality (95% CI 1.22-2.82) and 2.55 (95% CI 1.43-4.55) for cardiovascular mortality. The IRR for all-cause mortality was reduced to 1.37 (0.90-2.08) when adjusted for the use of antipsychotic medication. The association between hyperprolactinemia and cardiovascular mortality remained after adjusting...... for confounders, for example, chronic renal failure, diabetes, and antipsychotic medication. In females, hyperprolactinemia was not associated with all-cause mortality (IRR 1.45; CI 0.86-2.47) or cardiovascular mortality (IRR 0.58; CI 0.14-2.39). In conclusion, hyperprolactinemia was associated with increased...

CO2 and temperature effects on morphological and physiological traits affecting risk of drought-induced mortality.

Science.gov (United States)

Duan, Honglang; Chaszar, Brian; Lewis, James D; Smith, Renee A; Huxman, Travis E; Tissue, David T

2018-04-26

Despite a wealth of eco-physiological assessments of plant response to extreme drought, few studies have addressed the interactive effects of global change factors on traits driving mortality. To understand the interaction between hydraulic and carbon metabolic traits influencing tree mortality, which may be independently influenced by atmospheric [CO2] and temperature, we grew Eucalyptus sideroxylon A. Cunn. ex Woolls from seed in a full-factorial [CO2] (280, 400 and 640 μmol mol-1, Cp, Ca and Ce, respectively) and temperature (ambient and ambient +4 °C, Ta and Te, respectively) experiment. Prior to drought, growth across treatment combinations resulted in significant variation in physiological and morphological traits, including photosynthesis (Asat), respiration (Rd), stomatal conductance, carbohydrate storage, biomass and leaf area (LA). Ce increased Asat, LA and leaf carbohydrate concentration compared with Ca, while Cp generated the opposite response; Te reduced Rd. However, upon imposition of drought, Te hastened mortality (9 days sooner compared with Ta), while Ce significantly exacerbated drought stress when combined with Te. Across treatments, earlier time-to-mortality was mainly associated with lower (more negative) leaf water potential (Ψl) during the initial drought phase, along with higher water loss across the first 3 weeks of water limitation. Among many variables, Ψl was more important than carbon status in predicting time-to-mortality across treatments, yet leaf starch was associated with residual variation within treatments. These results highlight the need to carefully consider the integration, interaction and hierarchy of traits contributing to mortality, along with their responses to environmental drivers. Both morphological traits, which influence soil resource extraction, and physiological traits, which affect water-for-carbon exchange to the atmosphere, must be considered to adequately predict plant response to drought. Researchers have

Maternal obesity and neonatal mortality according to subtypes of preterm birth

DEFF Research Database (Denmark)

Nøhr, Ellen Aagaard; Vaeth, Michael; Bech, Bodil H

2007-01-01

: Compared with infants of mothers who were at a normal weight before pregnancy (BMI of 18.5 or more but less than 25), neonatal mortality was increased in infants of mothers who were overweight (BMI of 25 or more but less than 30) or obese (BMI of 30 or more) (adjusted hazard ratios 1.7, CI 1.2-2.5, and 1.......6, CI 1.0-2.4, respectively). For preterm infants (n=3,934, 136 deaths), neonatal mortality in infants born after preterm premature rupture of membranes (PROM) was significantly increased if they were born to an overweight or obese mother (adjusted hazard ratios 3.5, CI 1.4-8.7, and 5.7, CI 2.......2-14.8). There were no associations between high BMI and neonatal mortality in infants born after spontaneous preterm birth without preterm PROM or in infants born after induced preterm delivery. CONCLUSION: High maternal weight seems to increase the risk of neonatal mortality, especially in infants born after...

Perceived mortality and perceived morality: Perceptions of value-orientation are more likely when a decision is preceded by a mortality reminder

Directory of Open Access Journals (Sweden)

Mads eNordmo

2016-03-01

Full Text Available The questions addressed in this paper are whether and how reported mortality reminders can function as an indication of sincerity when communicating ambiguously motivated decisions. In two experiments, participants were exposed to a fictitious CEO who announced a decision to implement new organizational measures that were both environmentally and financially beneficial. In the experimental condition, the CEO attributed her new ideas to a recent mortality reminder. In the active control condition, the CEO attributed her decision to a non-lethal dentistry health scare, and in the passive control condition the CEO did not give any account of events preceding her decision. When a CEO implemented new corporate initiatives after a mortality reminder, her motivation for doing so was perceived as somewhat more motivated by intrinsic values, and significantly less motivated by financial gains. This change in attribution patterns was demonstrated to be indirectly related to a positive evaluation of the CEO, as well as an increased willingness to pay for the organization’s services. The second experiment further demonstrated that the reduced attribution to financial motivation associated with mortality awareness persisted even when the CEO in question was known for placing a high personal priority on financial goal attainment. The findings underscore the importance of perceived value-oriented motivation when communicating climate change mitigating policies, and the role of mortality awareness as one of many ways to induce such attributions.

Transient cultural influences on infant mortality: Fire-Horse daughters in Japan.

Science.gov (United States)

Bruckner, Tim A; Subbaraman, Meenakshi; Catalano, Ralph A

2011-01-01

Parental investment theory suggests that the quality and quantity of parental care depends, in part, on assessments of whether offspring will survive and yield grandchildren. Consistent with this theory, we hypothesize that parental perception that a birth cohort will have low reproductive success coincides with higher than expected infant mortality in the cohort. We test this hypothesis in industrialized Japan in 1966 when cultural aversion to females born in the astrological year of the Fire-Horse may have jeopardized the life of female infants. We applied time-series methods to cohort infant mortality data for Japan, from 1947 to 1976, to test whether female infant mortality in 1966 rose above levels expected from history, male infant mortality, and fertility. Methods control for the secular decline in infant mortality as well as other temporal patterns that could induce spurious associations. Findings support the hypothesis in that female infant mortality rises by 1.1 deaths per 1,000 live births above expected levels (coefficient = 0.0011; standard error = 0.0005; P = 0.03). The result indicates an excess of 721 female infant deaths statistically attributable to the Fire-Horse year. Findings remain robust to control for male infant mortality and the secular decline in mortality over the test period. The discovery of a predictable, acute increase in female infant mortality during the Fire-Horse year supports the relevance of parental investment theory to developed countries. Results should encourage further research on the health sequelae of abrupt, population-level shifts in culture. Copyright © 2011 Wiley-Liss, Inc.

Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation.

Science.gov (United States)

Tsukamoto, Hiroki; Takeuchi, Shino; Kubota, Kanae; Kobayashi, Yohei; Kozakai, Sao; Ukai, Ippo; Shichiku, Ayumi; Okubo, Misaki; Numasaki, Muneo; Kanemitsu, Yoshitomi; Matsumoto, Yotaro; Nochi, Tomonori; Watanabe, Kouichi; Aso, Hisashi; Tomioka, Yoshihisa

2018-05-14

Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS-induced TLR4 internalization and clarified the roles of the extracellular LPS-binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol-anchored protein (CD14). LPS stimulation of CD14-expressing cells induced TLR4 internalization in the presence of serum, and an inhibitory anti-LBP mAb blocked its internalization. Addition of LBP to serum-free cultures restored LPS-induced TLR4 internalization to comparable levels of serum. The secretory form of the CD14 (sCD14) induced internalization but required a much higher concentration than LBP. An inhibitory anti-sCD14 mAb was ineffective for serum-mediated internalization. LBP lacking the domain for LPS transfer to CD14 and a CD14 mutant with reduced LPS binding both attenuated TLR4 internalization. Accordingly, LBP is an essential serum molecule for TLR4 internalization, and its LPS transfer to membrane-anchored CD14 (mCD14) is a prerequisite. LBP induced the LPS-stimulated phosphorylation of TBK1, IKKϵ, and IRF3, leading to IFN-β expression. However, LPS-stimulated late activation of NFκB or necroptosis were not affected. Collectively, our results indicate that LBP controls LPS-induced TLR4 internalization, which induces TLR adaptor molecule 1 (TRIF)-dependent activation of the TBK1-IKKϵ-IRF3-IFN-β pathway. In summary, we showed that LBP-mediated LPS transfer to mCD14 is required for serum-dependent TLR4 internalization and activation of the TRIF pathway. Copyright © 2018, The American Society for Biochemistry and Molecular Biology.

Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment

International Nuclear Information System (INIS)

Stangl, Stefan; Themelis, George; Friedrich, Lars; Ntziachristos, Vasilis; Sarantopoulos, Athanasios; Molls, Michael; Skerra, Arne; Multhoff, Gabriele

2011-01-01

Background and purpose: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. Materials and methods: Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo. Results: The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4 deg. C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37 deg. C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55 h after i.v. injection. Conclusions: In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo.

Fundamental discrepancies in abortion estimates and abortion-related mortality: A reevaluation of recent studies in Mexico with special reference to the International Classification of Diseases

Science.gov (United States)

Koch, Elard; Aracena, Paula; Gatica, Sebastián; Bravo, Miguel; Huerta-Zepeda, Alejandra; Calhoun, Byron C

2012-01-01

In countries where induced abortion is legally restricted, as in most of Latin America, evaluation of statistics related to induced abortions and abortion-related mortality is challenging. The present article reexamines recent reports estimating the number of induced abortions and abortion-related mortality in Mexico, with special reference to the International Classification of Diseases (ICD). We found significant overestimations of abortion figures in the Federal District of Mexico (up to 10-fold), where elective abortion has been legal since 2007. Significant overestimation of maternal and abortion-related mortality during the last 20 years in the entire Mexican country (up to 35%) was also found. Such overestimations are most likely due to the use of incomplete in-hospital records as well as subjective opinion surveys regarding induced abortion figures, and due to the consideration of causes of death that are unrelated to induced abortion, including flawed denominators of live births. Contrary to previous publications, we found important progress in maternal health, reflected by the decrease in overall maternal mortality (30.6%) from 1990 to 2010. The use of specific ICD codes revealed that the mortality ratio associated with induced abortion decreased 22.9% between 2002 and 2008 (from 1.48 to 1.14 deaths per 100,000 live births). Currently, approximately 98% of maternal deaths in Mexico are related to causes other than induced abortion, such as hemorrhage, hypertension and eclampsia, indirect causes, and other pathological conditions. Therefore, only marginal or null effects would be expected from changes in the legal status of abortion on overall maternal mortality rates. Rather, maternal health in Mexico would greatly benefit from increasing access to emergency and specialized obstetric care. Finally, more reliable methodologies to assess abortion-related deaths are clearly required. PMID:23271925

The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18) in the regulation of the immune complex-elicited respiratory burst of polymorphonuclear leukocytes in whole blood

DEFF Research Database (Denmark)

Nielsen, C H; Antonsen, S; Matthiesen, S H

1997-01-01

cells using the monoclonal antibody (mAb) 3D9 resulted in a 1.9-fold increase in the IC-elicited PMN RB after 5 min of incubation, rising to 3.1-fold after 40 min. This enhancement was not due to increased IC deposition on PMN. Blockade of CR3 abrogated the mAb 3D9-induced rise in RB activity...... and inhibited the IC binding to PMN in a whole blood cell preparation, with or without mAb 3D9, by approximately 40% from 15-40 min while reducing their RB over 40 min to approximately one third. Blockade of CR1 on either erythrocytes (E) or leukocytes, before mixing the populations, revealed...... that the potentiation of the RB by mAb 3D9 was associated with abrogation of E-CR1 function, whereas blockade of leukocyte-CR1 had a diminishing effect. Exposure to IC at high concentrations induced release of both specific and azurophilic granule contents from PMN. The latter was CR3 dependent in that blockade...

Tree mortality from drought, insects, and their interactions in a changing climate

Science.gov (United States)

Anderegg, William R.L.; Hicke, Jeffrey A.; Fisher, Rosie A.; Allen, Craig D.; Aukema, Juliann E.; Bentz, Barbara; Hood, Sharon; Lichstein, Jeremy W.; Macalady, Alison K.; McDowell, Nate G.; Pan, Yude; Raffa, Kenneth; Sala, Anna; Shaw, John D.; Stephenson, Nathan L.; Tague, Christina L.; Zeppel, Melanie

2015-01-01

Climate change is expected to drive increased tree mortality through drought, heat stress, and insect attacks, with manifold impacts on forest ecosystems. Yet, climate-induced tree mortality and biotic disturbance agents are largely absent from process-based ecosystem models. Using data sets from the western USA and associated studies, we present a framework for determining the relative contribution of drought stress, insect attack, and their interactions, which is critical for modeling mortality in future climates. We outline a simple approach that identifies the mechanisms associated with two guilds of insects – bark beetles and defoliators – which are responsible for substantial tree mortality. We then discuss cross-biome patterns of insect-driven tree mortality and draw upon available evidence contrasting the prevalence of insect outbreaks in temperate and tropical regions. We conclude with an overview of tools and promising avenues to address major challenges. Ultimately, a multitrophic approach that captures tree physiology, insect populations, and tree–insect interactions will better inform projections of forest ecosystem responses to climate change.

Epipodial Tentacle Gene Expression and Predetermined Resilience to Summer Mortality in the Commercially Important Greenlip Abalone, Haliotis laevigata.

Science.gov (United States)

Shiel, Brett P; Hall, Nathan E; Cooke, Ira R; Robinson, Nicholas A; Strugnell, Jan M

2017-04-01

"Summer mortality" is a phenomenon that occurs during warm water temperature spikes that results in the mass mortality of many ecologically and economically important mollusks such as abalone. This study aimed to determine whether the baseline gene expression of abalone before a laboratory-induced summer mortality event was associated with resilience to summer mortality. Tentacle transcriptomes of 35 greenlip abalone (Haliotis laevigata) were sequenced prior to the animals being exposed to an increase in water temperature-simulating conditions which have previously resulted in summer mortality. Abalone derived from three source locations with different environmental conditions were categorized as susceptible or resistant to summer mortality depending on whether they died or survived after the water temperature was increased. We detected two genes showing significantly higher expression in resilient abalone relative to susceptible abalone prior to the laboratory-induced summer mortality event. One of these genes was annotated through the NCBI non-redundant protein database using BLASTX to an anemone (Exaiptasia pallida) Transposon Ty3-G Gag Pol polyprotein. Distinct gene expression signatures were also found between resilient and susceptible abalone depending on the population origin, which may suggest divergence in local adaptation mechanisms for resilience. Many of these genes have been suggested to be involved in antioxidant and immune-related functions. The identification of these genes and their functional roles have enhanced our understanding of processes that may contribute to summer mortality in abalone. Our study supports the hypothesis that prestress gene expression signatures are indicative of the likelihood of summer mortality.

Evaluating theories of drought-induced vegetation mortality using a multimodel-experiment framework

Science.gov (United States)

Nate G. McDowell; Rosie A. Fisher; Chonggang Xu; J. C. Domec; Teemu Holtta; D. Scott Mackay; John S. Sperry; Amanda Boutz; Lee Dickman; Nathan Gehres; Jean Marc Limousin; Alison Macalady; Jordi Martinez-Vilalta; Maurizio Mencuccini; Jennifer A. Plaut; Jerome Ogee; Robert E. Pangle; Daniel P. Rasse; Michael G. Ryan; Sanna Sevanto; Richard H. Waring; A. Park Williams; Enrico A. Yepez; William T. Pockman

2013-01-01

Model-data comparisons of plant physiological processes provide an understanding of mechanisms underlying vegetation responses to climate. We simulated the physiology of a pinon pine-juniper woodland (Pinus edulis-Juniperus monosperma) that experienced mortality during a 5 yr precipitation-reduction experiment, allowing a framework with which to examine our knowledge...

Warming and Acidification Induced Mass Mortality of a Coastal Keystone predator

Science.gov (United States)

Melzner, F.; Findeisen, U.

2016-02-01

The Baltic Sea is characterized by low salinity and pronounced fluctuations in pCO2. On-line monitoring of pCO2 in 2014 in Kiel Fjord demonstrated occurrence of peak values of >2,000 µatm in summer and autumn and average values >750 µatm. We assessed the impacts of elevated temperature (ambient temperature, ambient +3°C) and pCO2 (500, 1,500, 2,400 µatm) on the keystone species Asterias rubens in a fully crossed long - term experiment (N=5 replicate tanks each, 1 year duration). During spring and early summer (February - June), high temperature animals ingested significantly more food and spawned significantly earlier (April 30th) than ambient acclimated animals (May 23rd). Elevated pCO2 led to comparatively minor reductions in food intake and scope for growth during that period. During summer (June - August), elevated temperature >25°C caused negative energy budgets and >95% mortality in the warm acclimated groups, while mortality was low in the ambient temperature groups. Our results indicate that A. rubens may benefit from increased temperature during colder months, yet dramatically suffer during summer heat waves in warm years. Meaningful experimental approaches to assess species vulnerability to climate change need to encompass all seasons and realistic abiotic stressor levels.

Gram-negative periodontal bacteria induce the activation of Toll-like receptors 2 and 4, and cytokine production in human periodontal ligament cells.

Science.gov (United States)

Sun, Ying; Shu, Rong; Li, Chao-Lun; Zhang, Ming-Zhu

2010-10-01

Periodontitis is a bacterially induced chronic inflammatory disease. Toll-like receptors (TLRs), which could recognize microbial pathogens, are important components in the innate and adaptive immune systems. Both qualitatively and quantitatively distinct immune responses might result from different bacteria stimulation and the triggering of different TLRs. This study explores the interaction of Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) with TLR2 and TLR4. We studied the gene expression changes of TLR2 and TLR4 and cytokine production (interleukin-1β, -6, -8, -10, and tumor necrosis factor-alpha) in human periodontal ligament cells (HPDLCs) stimulated with heat-killed bacteria or P. gingivalis lipopolysaccharide (LPS) in the presence or absence of monoclonal antibodies to TLR2 or TLR4 (anti-TLR2/4 mAb). Both test bacteria and 10 microg/ml P. gingivalis LPS treatment increased the gene expression of TLR2 and TLR4 and cytokine production in HPDLCs. In addition, these upregulations could be blocked by anti-TLR2/4 mAb. However, the expression of TLR4 mRNA in HPDLCs stimulated with 1 microg/ml P. gingivalis LPS was not increased. No differences were found in the cytokine production caused by 1 microg/ml P. gingivalis LPS treatment in the presence or absence of anti-TLR4 mAb. These patterns of gene expression and cytokine production indicate that Gram-negative periodontal bacteria or their LPS might play a role in triggering TLR2 and/or TLR4, and be of importance for the immune responses in periodontitis.

Production, Characterization and Antioxidant Potential of Protease from Streptomyces sp. MAB18 Using Poultry Wastes

Directory of Open Access Journals (Sweden)

Panchanathan Manivasagan

2013-01-01

Full Text Available Poultry waste is an abundant renewable source for the recovery of several value-added metabolites with potential industrial applications. This study describes the production of protease on poultry waste, with the subsequent use of the same poultry waste for the extraction of antioxidants. An extracellular protease-producing strain was isolated from Cuddalore coast, India, and identified as Streptomyces sp. MAB18. Its protease was purified 17.13-fold with 21.62% yield with a specific activity of 2398.36 U/mg and the molecular weight was estimated as 43 kDa. The enzyme was optimally active at pH 8–10 and temperature 50–60°C and it was most stable up to pH 12 and 6–12% of NaCl concentration. The enzyme activity was reduced when treated with Hg2+, Pb2+, and SDS and stimulated by Fe2+, Mg2+, Triton X-100, DMSO (dimethyl sulfoxide, sodium sulphite, and β-mercaptoethanol. Furthermore, the antioxidant activities of protease were evaluated using in vitro antioxidant assays, such as DPPH radical-scavenging activity, O2 scavenging activity, NO scavenging activity, Fe2+ chelating activity, and reducing power. The enzyme showed important antioxidant potential with an IC50 value of 78±0.28 mg/mL. Results of the present study indicate that the poultry waste-derived protease may be useful as supplementary protein and antioxidant in the animal feed formulations.

Relation between trends in late middle age mortality and trends in old age mortality--is there evidence for mortality selection?

NARCIS (Netherlands)

Janssen, F.; Peeters, A.; Mackenbach, J. P.; Kunst, A. E.

2005-01-01

STUDY OBJECTIVE: To test whether mortality selection was a dominant factor in determining trends in old age mortality, by empirically studying the existence of a negative correlation between trends in late middle age mortality and trends in old age mortality among the same cohorts. DESIGN AND

Transient turbid water mass reduces temperature-induced coral bleaching and mortality in Barbados

Science.gov (United States)

Vallès, Henri

2016-01-01

Global warming is seen as one of the greatest threats to the world’s coral reefs and, with the continued rise in sea surface temperature predicted into the future, there is a great need for further understanding of how to prevent and address the damaging impacts. This is particularly so for countries whose economies depend heavily on healthy reefs, such as those of the eastern Caribbean. Here, we compare the severity of bleaching and mortality for five dominant coral species at six representative reef sites in Barbados during the two most significant warm-water events ever recorded in the eastern Caribbean, i.e., 2005 and 2010, and describe prevailing island-scale sea water conditions during both events. In so doing, we demonstrate that coral bleaching and subsequent mortality were considerably lower in 2010 than in 2005 for all species, irrespective of site, even though the anomalously warm water temperature profiles were very similar between years. We also show that during the 2010 event, Barbados was engulfed by a transient dark green turbid water mass of riverine origin coming from South America. We suggest that reduced exposure to high solar radiation associated with this transient water mass was the primary contributing factor to the lower bleaching and mortality observed in all corals. We conclude that monitoring these episodic mesoscale oceanographic features might improve risk assessments of southeastern Caribbean reefs to warm-water events in the future. PMID:27326377

Platelet-activating factor podoplanin: from discovery to drug development.

Science.gov (United States)

Takemoto, Ai; Miyata, Kenichi; Fujita, Naoya

2017-06-01

Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet-aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin-CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future.

Projecting future air pollution-related mortality under a changing climate: progress, uncertainties and research needs.

Science.gov (United States)

Madaniyazi, Lina; Guo, Yuming; Yu, Weiwei; Tong, Shilu

2015-02-01

Climate change may affect mortality associated with air pollutants, especially for fine particulate matter (PM2.5) and ozone (O3). Projection studies of such kind involve complicated modelling approaches with uncertainties. We conducted a systematic review of researches and methods for projecting future PM2.5-/O3-related mortality to identify the uncertainties and optimal approaches for handling uncertainty. A literature search was conducted in October 2013, using the electronic databases: PubMed, Scopus, ScienceDirect, ProQuest, and Web of Science. The search was limited to peer-reviewed journal articles published in English from January 1980 to September 2013. Fifteen studies fulfilled the inclusion criteria. Most studies reported that an increase of climate change-induced PM2.5 and O3 may result in an increase in mortality. However, little research has been conducted in developing countries with high emissions and dense populations. Additionally, health effects induced by PM2.5 may dominate compared to those caused by O3, but projection studies of PM2.5-related mortality are fewer than those of O3-related mortality. There is a considerable variation in approaches of scenario-based projection researches, which makes it difficult to compare results. Multiple scenarios, models and downscaling methods have been used to reduce uncertainties. However, few studies have discussed what the main source of uncertainties is and which uncertainty could be most effectively reduced. Projecting air pollution-related mortality requires a systematic consideration of assumptions and uncertainties, which will significantly aid policymakers in efforts to manage potential impacts of PM2.5 and O3 on mortality in the context of climate change. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Anti-NKG2D mAb

DEFF Research Database (Denmark)

Vadstrup, Kasper; Bendtsen, Flemming

2017-01-01

with a wide range of cell types and proteins involved. Natural Killer Group 2D (NKG2D) is an activating receptor constitutively expressed on human Natural Killer (NK), γδ T, mucosal-associated invariant T (MAIT), CD56⁺ T, and CD8⁺ T cells. Activation of NKG2D triggers cellular proliferation, cytokine...... production, and target cell killing. Research into the NKG2D mechanism of action has primarily been focused on cancer and viral infections where cytotoxicity evasion is a concern. In human inflammatory bowel disease (IBD) this system is less characterized, but the ligands have been shown to be highly...... expressed during intestinal inflammation and the following receptor activation may contribute to tissue degeneration. A recent phase II clinical trial showed that an antibody against NKG2D induced clinical remission of CD in some patients, suggesting NKG2D and its ligands to be of importance...

A receptor tyrosine kinase ROR1 inhibitor (KAN0439834 induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib.

Directory of Open Access Journals (Sweden)

Amir Hossein Daneshmanesh

Full Text Available There is a great unmet medical need in pancreatic carcinoma (PC for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834 (530 Da targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8 evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834 showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.

Monoclonal Antibodies Follow Distinct Aggregation Pathways During Production-Relevant Acidic Incubation and Neutralization

DEFF Research Database (Denmark)

Pedersen, Thomas Skamris; Tian, Xinsheng; Thorolfsson, Matthias

2016-01-01

and orthogonal analytical methods, including small-angle X-ray scattering and dynamic light scattering and supplemented the experimental data with crystal structure-based spatial aggregation propensity (SAP) calculations. RESULTS: We revealed distinct solution behaviors between the three mAb models: At acidic p......PURPOSE: Aggregation aspects of therapeutic monoclonal antibodies (mAbs) are of common concern to the pharmaceutical industry. Low pH treatment is applied during affinity purification and to inactivate endogenous retroviruses, directing interest to the mechanisms of acid-induced antibody...... distinguish between reversible and irreversible mAb aggregation pathways at early stages of acidic treatment....

Stand-structural effects on Heterobasidion abietinum-related mortality following drought events in Abies pinsapo.

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Linares, Juan Carlos; Camarero, Jesús Julio; Bowker, Matthew A; Ochoa, Victoria; Carreira, José Antonio

2010-12-01

Climate change may affect tree-pathogen interactions. This possibility has important implications for drought-prone forests, where stand dynamics and disease pathogenicity are especially sensitive to climatic stress. In addition, stand structural attributes including density-dependent tree-to-tree competition may modulate the stands' resistance to drought events and pathogen outbreaks. To assess the effects of stand structure on root-rot-related mortality after severe droughts, we focused on Heterobasidion abietinum mortality in relict Spanish stands of Abies pinsapo, a drought-sensitive fir. We compared stand attributes and tree spatial patterns in three plots with H. abietinum root-rot disease and three plots without root-rot. Point-pattern analyses were used to investigate the scale and extent of mortality patterns and to test hypotheses related to the spread of the disease. Dendrochronology was used to date the year of death and to assess the association between droughts and growth decline. We applied a structural equation modelling approach to test if tree mortality occurs more rapidly than predicted by a simple distance model when trees are subjected to high tree-to-tree competition and following drought events. Contrary to expectations of drought mortality, the effect of precipitation on the year of death was strong and negative, indicating that a period of high precipitation induced an earlier tree death. Competition intensity, related to the size and density of neighbour trees, also induced an earlier tree death. The effect of distance to the disease focus was negligible except in combination with intensive competition. Our results indicate that infected trees have decreased ability to withstand drought stress, and demonstrate that tree-to-tree competition and fungal infection act as predisposing factors of forest decline and mortality.

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016

DEFF Research Database (Denmark)

Moesgaard Iburg, Kim

2017-01-01

Background Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify...... with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other...... locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15–60 years) using adjusted...

Computational identification of epitopes in the glycoproteins of novel bunyavirus (SFTS virus) recognized by a human monoclonal antibody (MAb 4-5)

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Zhang, Wenshuai; Zeng, Xiaoyan; Zhang, Li; Peng, Haiyan; Jiao, Yongjun; Zeng, Jun; Treutlein, Herbert R.

2013-06-01

In this work, we have developed a new approach to predict the epitopes of antigens that are recognized by a specific antibody. Our method is based on the "multiple copy simultaneous search" (MCSS) approach which identifies optimal locations of small chemical functional groups on the surfaces of the antibody, and identifying sequence patterns of peptides that can bind to the surface of the antibody. The identified sequence patterns are then used to search the amino-acid sequence of the antigen protein. The approach was validated by reproducing the binding epitope of HIV gp120 envelop glycoprotein for the human neutralizing antibody as revealed in the available crystal structure. Our method was then applied to predict the epitopes of two glycoproteins of a newly discovered bunyavirus recognized by an antibody named MAb 4-5. These predicted epitopes can be verified by experimental methods. We also discuss the involvement of different amino acids in the antigen-antibody recognition based on the distributions of MCSS minima of different functional groups.

Evolving GIS technologies in nature conservation and the spatial planning strategy of Tara NP (Serbia as a potential UNECSO MAB reserve

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Radović Dejan

2008-01-01

Full Text Available Mt. Tara NP was nominated in 2004 within the UNESCO - ROSTE programme, for Man and the Biosphere (MAB Reserve status in Serbia as transboundary 'Peace Park' status between Serbia and Bosnia & Herzegovina. Mt. Tara is one of the most important centres of Balkans and European ecosystems and species diversity. They represent a unique example of well preserved forests in south eastern Europe with numerous endemic and relict species of flora and fauna. In this floristic diversity of Mt Tara of the greatest interest is the Serbian (Pančić's spruce Picea omorika. Mt. Tara NP is characterized by specific geomorphologic, hydrologic, geologic, soil and climatic features. The geographical information system (GIS that we have created has proved an excellent tool for the spatial planning strategy in assessment and conservation of all natural characteristics of Mt. Tara NP, and is helpful to Park management for sustainable use of landscape resources. GIS of Mt. Tara NP includes data on natural, artificial and management themes.

Association of BMI with risk of CVD mortality and all-cause mortality.

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Kee, Chee Cheong; Sumarni, Mohd Ghazali; Lim, Kuang Hock; Selvarajah, Sharmini; Haniff, Jamaiyah; Tee, Guat Hiong Helen; Gurpreet, Kaur; Faudzi, Yusoff Ahmad; Amal, Nasir Mustafa

2017-05-01

To determine the relationship between BMI and risk of CVD mortality and all-cause mortality among Malaysian adults. Population-based, retrospective cohort study. Participants were followed up for 5 years from 2006 to 2010. Mortality data were obtained via record linkages with the Malaysian National Registration Department. Multiple Cox regression was applied to compare risk of CVD and all-cause mortality between BMI categories adjusting for age, gender and ethnicity. Models were generated for all participants, all participants the first 2 years of follow-up, healthy participants, healthy never smokers, never smokers, current smokers and former smokers. All fourteen states in Malaysia. Malaysian adults (n 32 839) aged 18 years or above from the third National Health and Morbidity Survey. Total follow-up time was 153 814 person-years with 1035 deaths from all causes and 225 deaths from CVD. Underweight (BMIBMI ≥30·0 kg/m2) was associated with a heightened risk of CVD mortality. Overweight (BMI=25·0-29·9 kg/m2) was inversely associated with risk of all-cause mortality. Underweight was significantly associated with all-cause mortality in all models except for current smokers. Overweight was inversely associated with all-cause mortality in all participants. Although a positive trend was observed between BMI and CVD mortality in all participants, a significant association was observed only for severe obesity (BMI≥35·0 kg/m2). Underweight was associated with increased risk of all-cause mortality and obesity with increased risk of CVD mortality. Therefore, maintaining a normal BMI through leading an active lifestyle and healthy dietary habits should continue to be promoted.

Temperature extremes and infant mortality in Bangladesh: Hotter months, lower mortality.

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Babalola, Olufemi; Razzaque, Abdur; Bishai, David

2018-01-01

Our study aims to obtain estimates of the size effects of temperature extremes on infant mortality in Bangladesh using monthly time series data. Data on temperature, child and infant mortality were obtained for Matlab district of rural Bangladesh for January 1982 to December 2008 encompassing 49,426 infant deaths. To investigate the relationship between mortality and temperature, we adopted a regression with Autoregressive Integrated Moving Average (ARIMA) errors model of seasonally adjusted temperature and mortality data. The relationship between monthly mean and maximum temperature on infant mortality was tested at 0 and 1 month lags respectively. Furthermore, our analysis was stratified to determine if the results differed by gender (boys versus girls) and by age (neonates (≤ 30 days) versus post neonates (>30days and Bangladesh. Each degree Celsius increase in mean monthly temperature reduced monthly mortality by 3.672 (SE 1.544, pBangladesh. This may reflect a more heightened sensitivity of infants to hypothermia than hyperthermia in this environment.

CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor

DEFF Research Database (Denmark)

Jinquan, T; Quan, S; Jacobi, H H

2000-01-01

-induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 m......Ab blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig...... stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment...

Assessing insect-induced tree mortality across large areas with high-resolution aerial photography in a multistage sample

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Randy Hamilton; Kevin Megown; James Ellenwood; Henry Lachowski; Paul. Maus

2010-01-01

In recent years, unprecedented tree mortality has occurred throughout the national forests owing to insect infestations and disease outbreaks. The magnitude and extent of mortality, coupled with the lack of routine monitoring in some areas, has made it difficult to assess the damage, associated ecological impact, and fire hazard in a timely and cost-effective manner....

Woodland recovery following drought-induced tree mortality across an environmental stress gradient.

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Redmond, Miranda D; Cobb, Neil S; Clifford, Michael J; Barger, Nichole N

2015-10-01

Recent droughts and increasing temperatures have resulted in extensive tree mortality across the globe. Understanding the environmental controls on tree regeneration following these drought events will allow for better predictions of how these ecosystems may shift under a warmer, drier climate. Within the widely distributed piñon-juniper woodlands of the southwestern USA, a multiyear drought in 2002-2004 resulted in extensive adult piñon mortality and shifted adult woodland composition to a juniper-dominated, more savannah-type ecosystem. Here, we used pre- (1998-2001) and 10-year post- (2014) drought stand structure data of individually mapped trees at 42 sites to assess the effects of this drought on tree regeneration across a gradient of environmental stress. We found declines in piñon juvenile densities since the multiyear drought due to limited new recruitment and high (>50%) juvenile mortality. This is in contrast to juniper juvenile densities, which increased over this time period. Across the landscape, piñon recruitment was positively associated with live adult piñon densities and soil available water capacity, likely due to their respective effects on seed and water availability. Juvenile piñon survival was strongly facilitated by certain types of nurse trees and shrubs. These nurse plants also moderated the effects of environmental stress on piñon survival: Survival of interspace piñon juveniles was positively associated with soil available water capacity, whereas survival of nursed piñon juveniles was negatively associated with perennial grass cover. Thus, nurse plants had a greater facilitative effect on survival at sites with higher soil available water capacity and perennial grass cover. Notably, mean annual climatic water deficit and elevation were not associated with piñon recruitment or survival across the landscape. Our findings reveal a clear shift in successional trajectories toward a more juniper-dominated woodland and highlight the

Fir Decline and Mortality in the Southern Siberian Mountains

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Kharuk, Viacheslav I.; Im, Sergei T.; Petrov, Ilya A.; Dvinskaya, Mariya, L.; Fedotova, Elena V.; Ranson, Kenneth J.

2016-01-01

Increased dieback and mortality of dark needle conifer (DNC) stands (composed of fir (Abies sibirica),Siberian pine (Pinus sibirica) and spruce (Picea obovata))were documented in Russia during recent decades. Here we analyzed spatial and temporal patterns of fir decline and mortality in the southern Siberian Mountains based on satellite, in situ and dendrochronological data. The studied stands are located within the boundary between DNC taiga to the north and forest-steppe to the south. Fir decline and mortality were observed to originate where topographic features contributed to maximal water-stress risk, i.e., steep (1825),convex, south-facing slopes with a shallow well-drained root zone. Fir regeneration survived droughts and increased stem radial growth, while upper canopy trees died. Tree ring width(TRW) growth negatively correlated with vapor pressure deficit (VPD), drought index and occurrence of late frosts, and positively with soil water content. Previous year growth conditions (i.e., drought index, VPD, soil water anomalies)have a high impact on current TRW (r 0.600.74). Fir mortality was induced by increased water stress and severe droughts (as a primary factor) in synergy with bark-beetles and fungi attacks (as secondary factors). Dendrochronology data indicated that fir mortality is a periodic process. In a future climate with increased aridity and drought frequency, fir (and Siberian pine) may disappear from portions of its current range (primarily within the boundary with the forest steppe)and is likely to be replaced by drought-tolerant species such as Pinus sylvestris and Larix sibirica.

Smoking-related general and cause-specific mortality in Estonia.

Science.gov (United States)

Kõks, Gea; Fischer, Krista; Kõks, Sulev

2017-07-19

Tobacco smoking is known to be the single largest cause of premature death worldwide. The aim of present study was to analyse the effect of smoking on general and cause-specific mortality in the Estonian population. The data from 51,756 adults in the Estonian Genome Center of the University of Tartu was used. Information on dates and causes of death was retrieved from the National Causes of Death Registry. Smoking status, general survival, general mortality and cause-specific mortality were analysed using Kaplan-Meier estimator and Cox proportional hazards models. The study found that smoking reduces median survival in men by 11.4 years and in women by 5.8 years. Tobacco smoking produces a very specific pattern in the cause of deaths, significantly increasing the risks for different cancers and cardiovascular diseases as causes of death for men and women. This study also identified that external causes, such as alcohol intoxication and intentional self-harm, are more prevalent causes of death among smokers than non-smokers. Additionally, smoking cessation was found to reverse the increased risks for premature mortality. Tobacco smoking remains the major cause for losses of life inducing cancers and cardiovascular diseases. In addition to the common diseases, external causes also reduce substantially the years of life. External causes of death indicate that smoking has a long-term influence on the behaviour of smokers, provoking self-destructive behaviour. Our study supports the idea, that tobacco smoking generates complex harm to our health increasing mortality from both somatic and mental disorders.

Homotypic aggregation of human cell lines by HLA class II-, class Ia- and HLA-G-specific monoclonal antibodies

DEFF Research Database (Denmark)

Odum, Niels; Ledbetter, J A; Martin, P

1991-01-01

Major histocompatibility complex (MHC) class II molecules have been implicated in cell adhesion in two ways. In addition to the well-established role of class II antigens in low-affinity adhesion provided by interactions between class II and CD4, recent data indicated that class II may also induce...... adhesion between T and B cells by activating the CD18/CD11a (LFA-1) adhesion pathway. Here we report that monoclonal antibodies (mAb) against HLA-DR (L243, p4.1, HB10a, VI15) and certain broad class II reacting mAb (TU35, TU39), but not anti-DQ (TU22, Leu-10) mAb, induced homotypic aggregation of human...... class II-positive monocytic (I937) and T leukemic (HUT78) tumor cell lines and Epstein-Barr virus (EBV) transformed B-lymphoid cell lines (EBV-LCL). Class II-negative cell lines (U-937 and the EBV-LCL mutant line 616) were not induced to aggregate. An HLA-G-transfected EBV-LCL, 221-AGN...

Requirement for noncognate interaction with T cells for the activation of B cell immunoglobulin secretion by IL-2

DEFF Research Database (Denmark)

Owens, T

1991-01-01

23.1+ TH1 clone E9.D4 in F23.1 (anti-T cell receptor V-beta 8)-coated microwells. This induced polyclonal B cell activation to enter cell cycle (thymidine incorporation) at 2 days and to secrete immunoglobulin at 5 days. An anti-IL-2 mAb (S4B6) inhibited antibody production completely. Anti-IL-2 did......The mechanism whereby noncognate contact with activated IL-2-producing Type 1 helper T cells (TH1) induces B cell activation was examined. Small resting B cells from C57B1/6 mice were cultured, in the absence of any ligand for surface Ig, with irradiated cells of the hapten-specific, CBA-derived, F...... not inhibit either LPS-induced B cell responses, or T cell activation (measured as IL-3 secretion). Anti-IL-2 receptor (anti-Tac) mAbs also inhibited T-dependent B cell responses, without affecting LPS responses. An anti-IFN-gamma mAb partially inhibited Ig secretion, without affecting entry into cycle. LPS...

Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms

International Nuclear Information System (INIS)

Shedlock, Devon J.; Bailey, Michael A.; Popernack, Paul M.; Cunningham, James M.; Burton, Dennis R.; Sullivan, Nancy J.

2010-01-01

Human Ebola virus causes severe hemorrhagic fever disease with high mortality and there is no vaccine or treatment. Antibodies in survivors occur early, are sustained, and can delay infection when transferred into nonhuman primates. Monoclonal antibodies (mAbs) from survivors exhibit potent neutralizing activity in vitro and are protective in rodents. To better understand targets and mechanisms of neutralization, we investigated a panel of mAbs shown previously to react with the envelope glycoprotein (GP). While one non-neutralizing mAb recognized a GP epitope in the nonessential mucin-like domain, the rest were specific for GP1, were neutralizing, and could be further distinguished by reactivity with secreted GP. We show that survivor antibodies, human KZ52 and monkey JP3K11, were specific for conformation-dependent epitopes comprising residues in GP1 and GP2 and that neutralization occurred by two distinct mechanisms; KZ52 inhibited cathepsin cleavage of GP whereas JP3K11 recognized the cleaved, fusion-active form of GP.

National surgical mortality audit may be associated with reduced mortality after emergency admission.

Science.gov (United States)

Kiermeier, Andreas; Babidge, Wendy J; McCulloch, Glenn A J; Maddern, Guy J; Watters, David A; Aitken, R James

2017-10-01

The Western Australian Audit of Surgical Mortality was established in 2002. A 10-year analysis suggested it was the primary driver in the subsequent fall in surgeon-related mortality. Between 2004 and 2010 the Royal Australasian College of Surgeons established mortality audits in other states. The aim of this study was to examine national data from the Australian Institute of Health and Welfare (AIHW) to determine if a similar fall in mortality was observed across Australia. The AIHW collects procedure and outcome data for all surgical admissions. AIHW data from 2005/2006 to 2012/2013 was used to assess changes in surgical mortality. Over the 8 years surgical admissions increased by 23%, while mortality fell by 18% and the mortality per admission fell by 33% (P audit was associated with a sharp decline in perioperative mortality. In the absence of any influences from other changes in clinical governance or new quality programmes it is probable it had a causal effect. The reduced mortality was most evident in high-risk patients. This study adds to the evidence that national audits are associated with improved outcomes. © 2017 Royal Australasian College of Surgeons.

Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6–specific IgA mAb

Science.gov (United States)

Feng, Ningguo; Lawton, Jeffrey A.; Gilbert, Joana; Kuklin, Nelly; Vo, Phuoc; Prasad, B.V. Venkataram; Greenberg, Harry B.

2002-01-01

Rotaviruses are the leading cause of severe diarrheal disease in young children. Intestinal mucosal IgA responses play a critical role in protective immunity against rotavirus reinfection. Rotaviruses consist of three concentric capsid layers surrounding a genome of 11 segments of double-stranded RNA. The outer layer proteins, VP4 and VP7, which are responsible for viral attachment and entry, are targets for protective neutralizing antibodies. However, IgA mAb’s directed against the intermediate capsid protein VP6, which do not neutralize the virus, have also been shown to protect mice from rotavirus infection and clear chronic infection in SCID mice. We investigated whether the anti-VP6 IgA (7D9) mAb could inhibit rotavirus replication inside epithelial cells and found that 7D9 acted at an early stage of infection to neutralize rotavirus following antibody lipofection. Using electron cryomicroscopy, we determined the three-dimensional structure of the virus-antibody complex. The attachment of 7D9 IgA to VP6 introduces a conformational change in the VP6 trimer, rendering the particle transcriptionally incompetent and preventing the elongation of initiated transcripts. Based on these observations, we suggest that anti-VP6 IgA antibodies confers protection in vivo by inhibiting viral transcription at the start of the intracellular phase of the viral replication cycle. PMID:11994409

Chapter 5 - Tree Mortality

Science.gov (United States)

Mark J. Ambrose

2014-01-01

Tree mortality is a natural process in all forest ecosystems. Extremely high mortality, however, can also be an indicator of forest health issues. On a regional scale, high mortality levels may indicate widespread insect or disease problems. High mortality may also occur if a large proportion of the forest in a particular region is made up of older, senescent stands....

Fundamental discrepancies in abortion estimates and abortion-related mortality: A reevaluation of recent studies in Mexico with special reference to the International Classification of Diseases

Directory of Open Access Journals (Sweden)

Koch E

2012-12-01

Full Text Available Elard Koch,1,2 Paula Aracena,1 Sebastián Gatica,1 Miguel Bravo,1 Alejandra Huerta-Zepeda,3 Byron C Calhoun41Institute of Molecular Epidemiology (MELISA, Center of Embryonic Medicine and Maternal Health, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción, Chile; 2Faculty of Medicine, University of Chile, Santiago, Chile; 3Universidad Popular Autónoma del Estado de Puebla UPAEP, Puebla, México; 4Department of Obstetrics and Gynecology, West Virginia University, Charleston, WV, USAAbstract: In countries where induced abortion is legally restricted, as in most of Latin America, evaluation of statistics related to induced abortions and abortion-related mortality is challenging. The present article reexamines recent reports estimating the number of induced abortions and abortion-related mortality in Mexico, with special reference to the International Classification of Diseases (ICD. We found significant overestimations of abortion figures in the Federal District of Mexico (up to 10-fold, where elective abortion has been legal since 2007. Significant overestimation of maternal and abortion-related mortality during the last 20 years in the entire Mexican country (up to 35% was also found. Such overestimations are most likely due to the use of incomplete in-hospital records as well as subjective opinion surveys regarding induced abortion figures, and due to the consideration of causes of death that are unrelated to induced abortion, including flawed denominators of live births. Contrary to previous publications, we found important progress in maternal health, reflected by the decrease in overall maternal mortality (30.6% from 1990 to 2010. The use of specific ICD codes revealed that the mortality ratio associated with induced abortion decreased 22.9% between 2002 and 2008 (from 1.48 to 1.14 deaths per 100,000 live births. Currently, approximately 98% of maternal deaths in Mexico are related to causes other than

Model-directed engineering of "difficult-to-express" monoclonal antibody production by Chinese hamster ovary cells.

Science.gov (United States)

Pybus, Leon P; Dean, Greg; West, Nathan R; Smith, Andrew; Daramola, Olalekan; Field, Ray; Wilkinson, Stephen J; James, David C

2014-02-01

Despite improvements in volumetric titer for monoclonal antibody (MAb) production processes using Chinese hamster ovary (CHO) cells, some "difficult-to-express" (DTE) MAbs inexplicably reach much lower process titers. These DTE MAbs require intensive cell line and process development activity, rendering them more costly or even unsuitable to manufacture. To rapidly and rationally identify an optimal strategy to improve production of DTE MAbs, we have developed an engineering design platform combining high-yielding transient production, empirical modeling of MAb synthesis incorporating an unfolded protein response (UPR) regulatory loop with directed expression and cell engineering approaches. Utilizing a panel of eight IgG1 λ MAbs varying >4-fold in volumetric titer, we showed that MAb-specific limitations on folding and assembly rate functioned to induce a proportionate UPR in host CHO cells with a corresponding reduction in cell growth rate. Derived from comparative empirical modeling of cellular constraints on the production of each MAb we employed two strategies to increase production of DTE MAbs designed to avoid UPR induction through an improvement in the rate/cellular capacity for MAb folding and assembly reactions. Firstly, we altered the transfected LC:HC gene ratio and secondly, we co-expressed a variety of molecular chaperones, foldases or UPR transactivators (BiP, CypB, PDI, and active forms of ATF6 and XBP1) with recombinant MAbs. DTE MAb production was significantly improved by both strategies, although the mode of action was dependent upon the approach employed. Increased LC:HC ratio or CypB co-expression improved cell growth with no effect on qP. In contrast, BiP, ATF6c and XBP1s co-expression increased qP and reduced cell growth. This study demonstrates that expression-engineering strategies to improve production of DTE proteins in mammalian cells should be product specific, and based on rapid predictive tools to assess the relative impact of

Mortality among plutonium and other workers at a nuclear facility

International Nuclear Information System (INIS)

Wilkinson, G.S.; Voelz, G.L.; Acquavella, J.F.; Tietjen, G.L.; Reyes, M.; Brackbill, R.; Wiggs, L.

1983-01-01

Mortality among plutonium and other nuclear workers has been investigated to assess the effects of exposures to low levels of internal and external radiation. Standarized mortality ratios (SMRs) for white male workers employed at least two years from 1951 through 1977 were significantly lower than expected for all causes, all cancers, cancers of the respiratory system, and lung cancer. Benign neoplasms, all of which were intracranial tumors, were significantly elevated. No bone cancers were discovered and other radiogenic cancers did not differ significantly from expectation. Duration of employment and latency did not affect these results. SMRs for a subcohort of plutonium exposed workers were significantly low for all causes of deaths and all cancers. Estimates of relative risk for workers exposed to 2 or more nCi compared to unexposed workers were not significantly higher or lower than unity. These findings do not support the hypothesis of increased mortality among plutonium and other nuclear workers. The excess for benign and unspecified intracranial tumors is not consistent with previous studies on radiation induced brain tumors in terms of latency and exposure levels

Reducing infant mortality.

Science.gov (United States)

Johnson, T R

1994-01-01

Public health and social policies at the population level (e.g., oral rehydration therapy and immunization) are responsible for the major reduction in infant mortality worldwide. The gap in infant mortality rates between developing and developed regions is much less than that in maternal mortality rates. This indicates that maternal and child health (MCH) programs and women's health care should be combined. Since 1950, 66% of infant deaths occur in the 1st 28 days, indicating adverse prenatal and intrapartum events (e.g., congenital malformation and birth injuries). Infection, especially pneumonia and diarrhea, and low birth weight are the major causes of infant mortality worldwide. An estimated US$25 billion are needed to secure the resources to control major childhood diseases, reduce malnutrition 50%, reduce child deaths by 4 million/year, provide potable water and sanitation to all communities, provide basic education, and make family planning available to all. This cost for saving children's lives is lower than current expenditures for cigarettes (US$50 billion in Europe/year). Vitamin A supplementation, breast feeding, and prenatal diagnosis of congenital malformations are low-cost strategies that can significantly affect infant well-being and reduce child mortality in many developing countries. The US has a higher infant mortality rate than have other developed countries. The American College of Obstetricians and Gynecologists and the US National Institutes of Health are focusing on prematurity, low birth weight, multiple pregnancy, violence, alcohol abuse, and poverty to reduce infant mortality. Obstetricians should be important members of MCH teams, which also include traditional birth attendants, community health workers, nurses, midwives, and medical officers. We have the financial resources to allocate resources to improve MCH care and to reduce infant mortality.

Studies of the mortality of A-bomb survivors: report 7. Mortality, 1950-1978: part II. Mortality from causes other than cancer and mortality in early entrants

International Nuclear Information System (INIS)

Kato, H.; Brown, C.C.; Hoel, D.G.; Shull, W.J.

1982-01-01

Deaths in the Radiation Effects Research Foundation (REFR) Life Span Study (LSS) sample have been determined for the 4 years 1975-1978, and mortality examined for the 28 years since 1950. An analysis of cancer mortality is presented separately. In this report, we examine whether mortality from causes other than cancer is also increased or whether a nonspecific acceleration of aging occurs. 1. Cumulative mortality from causes other than cancer, estimated by the life table method, does not increase with radiation dose in either city, in either sex, or in any of the five different age-at-the-time-of-bomb groups. 2. No specific cause of death, other than cancer, exhibits a significant relationship with A-bomb exposure. Thus there is still no evidence of a nonspecific acceleration of aging due to radiation in this cohort. 3. Mortality before the LSS sample was established has been reanalyzed using three supplementary mortality surveys to determine the magnitude of the possible bias from the exclusion of deaths prior to 1950. It is unlikely that such a bias seriously affects the interpretation of the radiation effects observed in the cohort after 1950. 4. No excess of deaths from leukemia or other malignant tumors is observed among early entrants into these cities in this cohort

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

Science.gov (United States)

McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; MacDonald, Kelli P. A.; Hill, Geoffrey R.; Luznik, Leo; Serody, Jonathan S.; Murphy, William J.; Maillard, Ivan; Munn, David H.; Turka, Laurence A.; Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome

2016-01-01

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. PMID:27385791

Excess mortality in hyperthyroidism

DEFF Research Database (Denmark)

Hjelm Brandt Kristensen, Frans; Pedersen, Dorthe Almind; Christensen, Kaare

2012-01-01

Hyperthyroidism is associated with severe comorbidity, such as stroke, and seems to confer increased mortality. However, it is unknown whether this increased mortality is explained by hyperthyroidism per se, comorbidity, and/or genetic confounding.......Hyperthyroidism is associated with severe comorbidity, such as stroke, and seems to confer increased mortality. However, it is unknown whether this increased mortality is explained by hyperthyroidism per se, comorbidity, and/or genetic confounding....

The effects of the 1996–2012 summer heat events on human mortality in Slovakia

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Výberči Dalibor

2015-09-01

Full Text Available The impacts of summer heat events on the mortality of the Slovak population, both in total and for selected population sub-groups, are the foci of this study. This research is the first of its kind, focusing on a given population, and therefore one priority was to create a knowledge base for the issue and to basically evaluate existing conditions for the heat-mortality relationship in Slovakia. This article also aims to fill a void in current research on these issues in Europe. In addition to overall effects, we focused individually on the major historical heat events which occurred in the summers of 2007, 2010 and 2012. During the heat events, a non-negligible negative response in mortality was recorded and fatal effects were more pronounced during particularly strong heat events and periods which lasted for two or more days. In general, females and the elderly were the most sensitive groups in the population and mortality was characterized by several specific effects in individual population groups. The most extreme heat periods were commonly followed by a deficit in mortality, corresponding to a short-term mortality displacement, the pattern of which varied in specific cases. In general, displaced mortality appeared to compensate for a large part of heat-induced excess deaths.

The impact of mild induced hypothermia on the rate of transfusion and the mortality in severely injured patients: a retrospective multi-centre study.

Science.gov (United States)

Jensen, Kai Oliver; Held, Leonhard; Kraus, Andrea; Hildebrand, Frank; Mommsen, Philipp; Mica, Ladislav; Wanner, Guido A; Steiger, Peter; Moos, Rudolf M; Simmen, Hans-Peter; Sprengel, Kai

2016-10-06

Although under discussion, induced hypothermia (IH) is an established therapy for patients with cardiac arrest or traumatic brain injuries. The influences on coagulopathy and bleeding tendency in severely injured patients (SIP) with concomitant traumatic brain injury are most widely unclear. Therefore, the aim of this study was to quantify the effect of mild IH in SIP with concomitant severe traumatic brain injuries on transfusion rate and mortality. In this retrospective multi-centre study, SIP from three European level-1 trauma centres with an ISS ≥16 between 2009 and 2011 were included. At hospital A, patients qualified for IH with age ≤70 years and a severe head injury with an abbreviated injury scale (AIS Head ) of ≥3. IH was defined as target core body temperature of 35 °C. Hypothermic patients were matched with two patients, one from hospital B and one from hospital C using age and AIS Head . The effect of IH on the transfusion rate, complications and mortality was quantified with 95 % confidence intervals (CI). Patients not treated with IH in hospital A and those from hospital B and C, who were not matched, were used to adjust the CI for the effect of inter-hospital therapy protocol differences. Mean age of patients in the IH-group (n = 43) was 35.7 years, mean ISS 30 points and sex distribution showed 83.7 % male. Mean age of matched patients in the normotherm-group (n = 86) was 36.7 years, mean ISS 33 points and there were 75.6 % males. For the hypothermic patients, we pointed out an estimate of mean difference for the number of transfused units of packed red blood cells as well as for mortality which does not indicate a decrease in the benefit gained by hypothermia. It is suggested that hypothermic patients tend to a higher rate of lung failure and thromboembolisms. Though tending to an increased rate of complications, there is no evidence for a difference in both; rate of transfusion and mortality in SIP. Mild IH as an option for

Rituximab (MabThera) til behandling af aktiv reumatoid artritis

DEFF Research Database (Denmark)

El Fassi, Daniel; Nielsen, Claus Henrik; Bendtzen, Klaus

2006-01-01

Rituximab (RTX) is a murine/human monoclonal antibody to CD20, a protein expressed almost exclusively on human B-lymphocytes. RTX induces rapid and marked B-cell depletion with beneficial clinical effects in 1/3 to 1/2 of rheumatoid arthritis patients. Treatment is given as two iv. infusions with...

Basin-Wide Amazon Forest Tree Mortality From a Large 2005 Storm

Science.gov (United States)

Negron Juarez, R. I.; Chambers, J. Q.; Guimaraes, G.; Zeng, H.; Raupp, C.; Marra, D. M.; Ribeiro, G.; Saatchi, S. S.; Higuchi, N.

2010-12-01

Blowdowns are a recurrent characteristic of Amazon forests and are produced, among others, by squall lines. Squall lines are aligned clusters (typical length of 1000 km, width of 200 km) of deep convective cells that produce heavy rainfall during the dry season and significant rainfall during the wet season. These squall lines (accompanied by intense downbursts from convective cells) have been associated with large blowdowns characterized by uprooted, snapped trees, and trees being dragged down by other falling trees. Most squall lines in Amazonia form along the northeastern coast of South America as sea breeze-induced instability lines and propagate inside the continent. They occur frequently (~4 times per month), and can reach the central and even extreme western parts of Amazonia. Squall lines can also be generated inside the Amazon and propagate toward the equator. In January 2005 a squall line propagated from south to north across the entire Amazon basin producing widespread forest tree mortality and contributed to the elevated mortality observed that year. Over the Manaus region (3.4 x104 km2), disturbed forest patches generated by the squall produced a mortality of 0.3-0.5 million trees, equivalent to 30% of the observed annual deforestation reported in 2005 over the same area. The elevated mortality observed in the Central Amazon in 2005 is unlikely to be related to the 2005 Amazon drought since drought did not affect Central or Eastern Amazonia. Assuming a similar rate of forest mortality across the basin, the squall line could have potentially produced tree mortality estimated at 542 ± 121 million trees, equivalent to 23% of the mean annual biomass accumulation estimated for these forests. Our results highlight the vulnerability of Amazon trees to wind-driven mortality associated with convective storms. This vulnerability is likely to increase in a warming climate with models projecting an increase in storm intensity.

Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins.

Science.gov (United States)

Luo, Shen; Zhang, Baolin

2015-01-01

Many therapeutic monoclonal antibodies (mAbs) are clinically administered through intravenous infusion after mixing with a diluent, e.g., saline, 5% dextrose. Such a clinical setting increases the likelihood of interactions among mAb molecules, diluent, and plasma components, which may adversely affect product safety and efficacy. Avastin® (bevacizumab) and Herceptin® (trastuzumab), but not Remicade® (infliximab), were shown to undergo rapid aggregation upon dilution into 5% dextrose when mixed with human plasma in vitro; however, the biochemical pathways leading to the aggregation were not clearly defined. Here, we show that dextrose-mediated aggregation of Avastin or Herceptin in plasma involves isoelectric precipitation of complement proteins. Using mass spectrometry, we found that dextrose-induced insoluble aggregates were composed of mAb itself and multiple abundant plasma proteins, namely complement proteins C3, C4, factor H, fibronectin, and apolipoprotein. These plasma proteins, which are characterized by an isoelectronic point of 5.5-6.7, lost solubility at the resulting pH in the mixture with formulated Avastin (pH 6.2) and Herceptin (pH 6.0). Notably, switching formulation buffers for Avastin (pH 6.2) and Remicade (pH 7.2) reversed their aggregation profiles. Avastin formed little, if any, insoluble aggregates in dextrose-plasma upon raising the buffer pH to 7.2 or above. Furthermore, dextrose induced pH-dependent precipitation of plasma proteins, with massive insoluble aggregates being detected at pH 6.5-6.8. These data show that isoelectric precipitation of complement proteins is a prerequisite of dextrose-induced aggregation of mAb in human plasma. This finding highlights the importance of assessing the compatibility of a therapeutic mAb with diluent and human plasma during product development.

Detection of koi herpesvirus (KHV) using a monoclonal antibody against Cyprinus carpio IgM.

Science.gov (United States)

Li, Yingying; Zheng, Shucheng; Wang, Qing; Bergmann, Sven M; Zeng, Weiwei; Wang, Yingying; Liu, Chun; Shi, Cunbin

2017-08-01

Koi herpesvirus disease (KHVD) is associated with high mortality in both common carp and koi carp (Cyprinus carpio L.) worldwide. The indirect detection of fish viruses based on the identification of antibodies has emerged as a practical and reliable means of diagnosis. Thus, it is important to create monoclonal antibodies (MAbs) against carp IgM. By using hybridoma-monoclonal antibody technology, one hybridoma cell line secreting MAbs against IgM from carp was established. In western blot analysis, the secreted MAb from cell line A5-E10 recognized the heavy chain of IgM from common carp or koi but did not react with immunoglobulins from three different fish species: grass carp (Ctenopharyngodon idella), tilapia (Oreochromis mossambicus) and Mandarin fish (Siniperca chuatsi). These results demonstrated that this MAb is highly specific for the IgM of carp and suggested that it can be used for monitoring the immunity level of carp, for example for indirect KHV diagnosis by antibody ELISA. We therefore established an indirect ELISA, which was tested using 200 serum samples from koi from three farms. The final results showed that 147 (73.5%) samples were confirmed to be KHV antibody negative and 53 (26.5%) were definitely positive, containing antibodies against KHV.

Beta3 subunits promote expression and nicotine-induced up-regulation of human nicotinic alpha6* nicotinic acetylcholine receptors expressed in transfected cell lines.

Science.gov (United States)

Tumkosit, Prem; Kuryatov, Alexander; Luo, Jie; Lindstrom, Jon

2006-10-01

Nicotinic acetylcholine receptors (AChRs) containing alpha6 subunits are typically found at aminergic nerve endings where they play important roles in nicotine addiction and Parkinson's disease. alpha6* AChRs usually contain beta3 subunits. beta3 subunits are presumed to assemble only in the accessory subunit position within AChRs where they do not participate in forming acetylcholine binding sites. Assembly of subunits in the accessory position may be a critical final step in assembly of mature AChRs. Human alpha6 AChRs subtypes were permanently transfected into human tsA201 human embryonic kidney (HEK) cell lines. alpha6beta2beta3 and alpha6beta4beta3 cell lines were found to express much larger amounts of AChRs and were more sensitive to nicotine-induced increase in the amount of AChRs than were alpha6beta2 or alpha6beta4 cell lines. The increased sensitivity to nicotine-induced up-regulation was due not to a beta3-induced increase in affinity for nicotine but probably to a direct effect on assembly of AChR subunits. HEK cells express only a small amount of mature alpha6beta2 AChRs, but many of these subunits are on the cell surface. This contrasts with Xenopus laevis oocytes, which express a large amount of incorrectly assembled alpha6beta2 subunits that bind cholinergic ligands but form large amorphous intracellular aggregates. Monoclonal antibodies (mAbs) were made to the alpha6 and beta3 subunits to aid in the characterization of these AChRs. The alpha6 mAbs bind to epitopes C-terminal of the extracellular domain. These data demonstrate that both cell type and the accessory subunit beta3 can play important roles in alpha6* AChR expression, stability, and up-regulation by nicotine.

Multi-scale predictions of massive conifer mortality due to chronic temperature rise

Science.gov (United States)

McDowell, N. G.; Williams, A. P.; Xu, C.; Pockman, W. T.; Dickman, L. T.; Sevanto, S.; Pangle, R.; Limousin, J.; Plaut, J.; Mackay, D. S.; Ogee, J.; Domec, J. C.; Allen, C. D.; Fisher, R. A.; Jiang, X.; Muss, J. D.; Breshears, D. D.; Rauscher, S. A.; Koven, C.

2016-03-01

Global temperature rise and extremes accompanying drought threaten forests and their associated climatic feedbacks. Our ability to accurately simulate drought-induced forest impacts remains highly uncertain in part owing to our failure to integrate physiological measurements, regional-scale models, and dynamic global vegetation models (DGVMs). Here we show consistent predictions of widespread mortality of needleleaf evergreen trees (NET) within Southwest USA by 2100 using state-of-the-art models evaluated against empirical data sets. Experimentally, dominant Southwest USA NET species died when they fell below predawn water potential (Ψpd) thresholds (April-August mean) beyond which photosynthesis, hydraulic and stomatal conductance, and carbohydrate availability approached zero. The evaluated regional models accurately predicted NET Ψpd, and 91% of predictions (10 out of 11) exceeded mortality thresholds within the twenty-first century due to temperature rise. The independent DGVMs predicted >=50% loss of Northern Hemisphere NET by 2100, consistent with the NET findings for Southwest USA. Notably, the global models underestimated future mortality within Southwest USA, highlighting that predictions of future mortality within global models may be underestimates. Taken together, the validated regional predictions and the global simulations predict widespread conifer loss in coming decades under projected global warming.

The effect of preoperative internal and external biliary drainage on mortality of jaundiced rats

NARCIS (Netherlands)

Gouma, D. J.; Coelho, J. C.; Schlegel, J. F.; Li, Y. F.; Moody, F. G.

1987-01-01

Mortality following abdominal infection induced by cecal ligation and puncture was studied in rats with obstructive jaundice and after relief of the obstruction by preoperative internal or external biliary drainage. Four groups of adult Sprague-Dawley rats were used: common bile duct ligation (BDL),

The Effect of Mortality Shocks on the Age-Pattern of Adult Mortality

DEFF Research Database (Denmark)

Zarulli, Virginia

2013-01-01

increase by age is missing. In the case of a shock, three scenarios may occur: mortality may be raised proportionally at all ages, more at older ages, or more at younger ages. Two cases of natural mortality experiments were analysed: Australian civilian prisoners in a Japanese camp during the Second World...... War and the Ukrainian Famine of 1933. The death rates of the prisoners of war were higher during imprisonment but the slope of the curve appeared to resemble that of the normal mortality regime. During the Ukrainian Famine, by contrast, the mortality curves in the different famine years were raised...

In vivo antibody-mediated modulation of aminopeptidase A in mouse proximal tubular epithelial cells.

Science.gov (United States)

Mentzel, S; Dijkman, H B; van Son, J P; Wetzels, J F; Assmann, K J

1999-07-01

Aminopeptidase A (APA) is one of the many renal hydrolases. In mouse kidney, APA is predominantly expressed on the brush borders and sparsely on the basolateral membranes of proximal tubular epithelial cells. However, when large amounts of monoclonal antibodies (MAbs) against APA were injected into mice, we observed strong binding of the MAbs to the basolateral membranes, whereas the MAbs bound only transiently to the brush borders of the proximal tubular epithelial cells. In parallel, APA itself disappeared from the brush borders by both endocytosis and shedding, whereas it was increasingly expressed on the basolateral sides. Using ultrastructural immunohistology, we found no evidence for transcellular transport of endocytosed APA to the basolateral side of the proximal tubular epithelial cells. The absence of transcellular transport was confirmed by experiments in which we used a low dose of the MAbs. Such a low dose did not result in binding of the MAbs to the brush borders and had no effect on the presence of APA in the brush borders of the proximal tubular epithelial cells. In these experiments we still could observe binding of the MAbs to the basolateral membranes in parallel with the local appearance of APA. In addition, treatment of mice with chlorpromazine, a calmodulin antagonist that interferes with cytoskeletal function, largely inhibited the MAb-induced modulation of APA. Our studies suggest that injection of MAbs to APA specifically interrupts the normal intracellular traffic of this enzyme in proximal tubular epithelial cells. This intracellular transport is dependent on the action of cytoskeletal proteins.

Three-year progression of emerald ash borer-induced decline and mortality in southeastern Michigan

Science.gov (United States)

Kamal J.K. Gandhi; Annemarie Smith; Robert P. Long; Robin A.J. Taylor; Daniel A. Herms

2008-01-01

We monitored the progression of ash (Fraxinus spp.) decline and mortality due to emerald ash borer (EAB), Agrilus planipennis, in 38 forest stands in the upper Huron River watershed region of southeastern Michigan from 2004-2007. Black ash (F. nigra), green ash (F. pennsylvanica), and white ash...

Changes in cause-specific mortality during heat waves in central Spain, 1975-2008

Science.gov (United States)

Miron, Isidro Juan; Linares, Cristina; Montero, Juan Carlos; Criado-Alvarez, Juan Jose; Díaz, Julio

2015-09-01

The relationship between heat waves and mortality has been widely described, but there are few studies using long daily data on specific-cause mortality. This study is undertaken in central Spain and analysing natural causes, circulatory and respiratory causes of mortality from 1975 to 2008. Time-series analysis was performed using ARIMA models, including data on specific-cause mortality and maximum and mean daily temperature and mean daily air pressure. The length of heat waves and their chronological number were analysed. Data were stratified in three decadal stages: 1975-1985, 1986-1996 and 1997-2008. Heat-related mortality was triggered by a threshold temperature of 37 °C. For each degree that the daily maximum temperature exceeded 37 °C, the percentage increase in mortality due to circulatory causes was 19.3 % (17.3-21.3) in 1975-1985, 30.3 % (28.3-32.3) in 1986-1996 and 7.3 % (6.2-8.4) in 1997-2008. The increase in respiratory cause ranged from 12.4 % (7.8-17.0) in the first period, to 16.3 % (14.1-18.4) in the second and 13.7 % (11.5-15.9) in the last. Each day of heat-wave duration explained 5.3 % (2.6-8.0) increase in respiratory mortality in the first period and 2.3 % (1.6-3.0) in the last. Decadal scale differences exist for specific-causes mortality induced by extreme heat. The impact on heat-related mortality by natural and circulatory causes increases between the first and the second period and falls significantly in the last. For respiratory causes, the increase is no reduced in the last period. These results are of particular importance for the estimation of future impacts of climate change on health.

Prevention and reversal of experimental autoimmune thyroiditis (EAT) in mice by administration of anti-L3T4 monoclonal antibody at different stages of disease development.

Science.gov (United States)

Stull, S J; Kyriakos, M; Sharp, G C; Braley-Mullen, H

1988-11-01

Experimental autoimmune thyroiditis (EAT) can be induced in CBA/J mice following the transfer of spleen cells from mouse thyroglobulin (MTg)-sensitized donors that have been activated in vitro with MTg. Since L3T4+ T cells are required to transfer EAT in this model, the present study was undertaken to assess the effectiveness of the anti-L3T4 monoclonal antibody (mAb) GK1.5 in preventing or arresting the development of EAT. Spleen cells from mice given mAb GK1.5 prior to sensitization with MTg and adjuvant could not transfer EAT to normal recipients and cells from these mice did not proliferate in vitro to MTg. Donor mice given GK1.5 before immunization did not develop anti-MTg autoantibody and recipients of cells from such mice also produced little anti-MTg. GK1.5 could also prevent the proliferation and activation of sensitized effector cell precursors when added to in vitro cultures. When a single injection of mAb GK1.5 was given to recipients of in vitro-activated spleen cells, EAT was reduced whether the mAb was given prior to cell transfer or as late as 19 days after cell transfer. Whereas the incidence and severity of EAT was consistently reduced by injecting recipient mice with GK1.5, the same mice generally had no reduction in anti-MTg autoantibody. Since EAT is consistently induced in control recipients by 14-19 days after cell transfer, the ability of mAb GK1.5 to inhibit EAT when injected 14 or 19 days after cell transfer indicates that a single injection of the mAb GK1.5 can cause reversal of the histopathologic lesions of EAT in mice. These studies further establish the important role of L3T4+ T cells in the pathogenesis of EAT in mice and also suggest that therapy with an appropriate mAb may be an effective treatment for certain autoimmune diseases even when the therapy is initiated late in the course of the disease.

Characterisation of the epitope for a herpes simplex virus glycoprotein B-specific monoclonal antibody with high protective capacity.

Science.gov (United States)

Däumer, Martin P; Schneider, Beate; Giesen, Doris M; Aziz, Sheriff; Kaiser, Rolf; Kupfer, Bernd; Schneweis, Karl E; Schneider-Mergener, Jens; Reineke, Ulrich; Matz, Bertfried; Eis-Hübinger, Anna M

2011-05-01

Monoclonal antibody (MAb) 2c, specific for glycoprotein B of herpes simplex virus (HSV), had been shown to mediate clearance of infection from the mucous membranes of mice, thereby completely inhibiting mucocutaneous inflammation and lethality, even in mice depleted of both CD4(+) and CD8(+) cells. Additionally, ganglionic infection was highly restricted. In vitro, MAb 2c exhibits a potent complement-independent neutralising activity against HSV type 1 and 2, completely inhibits the viral cell-to-cell spread as well as the syncytium formation induced by syncytial HSV strains (Eis-Hübinger et al. in Intervirology 32:351-360, 1991; Eis-Hübinger et al. in J Gen Virol 74:379-385, 1993). Here, we describe the mapping of the epitope for MAb 2c. The antibody was found to recognise a discontinuous epitope comprised of the HSV type 1 glycoprotein B residues 299 to 305 and one or more additional discontinuous regions that can be mimicked by the sequence FEDF. Identification of the epitope was confirmed by loss of antibody binding to mutated glycoprotein B with replacement of the epitopic key residues, expressed in COS-1 cells. Similarly, MAb 2c was not able to neutralise HSV mutants with altered key residues, and MAb 2c was ineffective in mice inoculated with such mutants. Interestingly, identification and fine-mapping of the discontinuous epitope was not achieved by binding studies with truncated glycoprotein B variants expressed in COS cells but by peptide scanning with synthetic overlapping peptides and peptide key motif analysis. Reactivity of MAb 2c was immensely increased towards a peptide composed of the glycoprotein B residues 299 to 305, a glycine linker, and a C-terminal FEDF motif. If it could be demonstrated that antibodies of the specificity and bioactivity of MAb 2c can be induced by the epitope or a peptide mimicking the epitope, strategies for active immunisation might be conceivable.

Testing the additive versus the compensatory hypothesis of mortality from ring recovery data using a random effects model

Directory of Open Access Journals (Sweden)

Schaub, M.

2004-06-01

Full Text Available The interaction of an additional source of mortality with the underlying “natural” one strongly affects population dynamics. We propose an alternative way to test between two forms of interaction, total additivity and compensation. In contrast to existing approaches, only ring-recovery data where the cause of death of each recovered individual is known are needed. Cause-specific mortality proportions are estimated based on a multistate capture-recapture model. The hypotheses are tested by inspecting the correlation between the cause-specific mortality proportions. A variance decomposition is performed to obtain a proper estimate of the true process correlation. The estimation of the cause-specific mortality proportions is the most critical part of the approach. It works well if at least one of the two mortality rates varies across time and the two recovery rates are constant across time. We illustrate this methodology by a case study of White Storks Ciconia ciconia where we tested whether mortality induced by power line collision is additive to other forms of mortality.

Projecting future mortality in the Netherlands taking into account mortality delay and smoking

NARCIS (Netherlands)

Janssen, F.; de Beer, J.A.A.

2016-01-01

Estimates of future mortality often prove inaccurate as conventional extrapolative mortality projection methods do not capture the impact of smoking nor the mortality delay: the shift in the age-at-death distribution towards older ages. The added value of incorporating information on smoking into

Maternal Mortality in Texas.

Science.gov (United States)

Baeva, Sonia; Archer, Natalie P; Ruggiero, Karen; Hall, Manda; Stagg, Julie; Interis, Evelyn Coronado; Vega, Rachelle; Delgado, Evelyn; Hellerstedt, John; Hankins, Gary; Hollier, Lisa M

2017-05-01

A commentary on maternal mortality in Texas is provided in response to a 2016 article in Obstetrics & Gynecology by MacDorman et al. While the Texas Department of State Health Services and the Texas Maternal Mortality and Morbidity Task Force agree that maternal mortality increased sharply from 2010 to 2011, the percentage change or the magnitude of the increase in the maternal mortality rate in Texas differs depending on the statistical methods used to compute and display it. Methodologic challenges in identifying maternal death are also discussed, as well as risk factors and causes of maternal death in Texas. Finally, several state efforts currently underway to address maternal mortality in Texas are described. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Gallstone disease and mortality

DEFF Research Database (Denmark)

Shabanzadeh, Daniel Mønsted; Sørensen, Lars Tue; Jørgensen, Torben

2017-01-01

OBJECTIVES: The objective of this cohort study was to determine whether subjects with gallstone disease identified by screening of a general population had increased overall mortality when compared to gallstone-free participants and to explore causes of death. METHODS: The study population (N...... built. RESULTS: Gallstone disease was present in 10%. Mortality was 46% during median 24.7 years of follow-up with 1% lost. Overall mortality and death from cardiovascular diseases were significantly associated to gallstone disease. Death from unknown causes was significantly associated to gallstone...... disease and death from cancer and gastrointestinal disease was not associated. No differences in mortality for ultrasound-proven gallstones or cholecystectomy were identified. CONCLUSIONS: Gallstone disease is associated with increased overall mortality and to death from cardiovascular disease. Gallstones...

The Change of Perinatal Mortality Over Three Decades in a Reference Centre in the Aegean Region: Neonatal Mortality has decreased but Foetal Mortality Remains Unchanged

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Nilgün Kültürsay

2017-12-01

Full Text Available Background: Perinatal, foetal and neonatal mortality statistics are important to show the development of a health care system in a country. However, in our country there are very few national and regional data about the changing pattern of perinatal neonatal mortality along with the development of new technologies in this area. Aims: Evaluation of the changes in mortality rates and the causes of perinatal and neonatal deaths within years in a perinatal reference centre which serves a high-risk population. Study Design: Cross-sectional retrospective study. Methods: The perinatal, neonatal and foetal mortality rates in the years 1979-1980 (1st time point and 1988-1989 (2nd time point were compared with the year 2008 (3rd time point. The causes of mortality were assessed by Wigglesworth classification and death reports. The neonatal mortality in the neonatal intensive care unit was also calculated. Results: Foetal mortality rates were 44/1000, 31.4/1000 and 41.75/1000 births, perinatal mortality rates were 35.6/1000, 18.8/1000 and 9/1000 births, and neonatal mortality rates were 35.6/1000, 18.8/1000 and 9/1000 live births for the three study time points, respectively. The mortality rate in neonatal intensive care unit decreased consistently from 33%, to 22.6% and 10%, respectively, together with decreasing neonatal mortality rates. The causes of perinatal deaths were foetal death 85%, immaturity 4%, and lethal congenital malformations 8% according to Wigglesworth classification in 2008, showing the high impact of foetal deaths on this high perinatal mortality rate. Infectious causes of neonatal deaths decreased but congenital anomalies increased in the last decades. Conclusion: Although neonatal mortality rate decreased significantly; foetal mortality rate has stayed unchanged since the late eighties. In order to decrease foetal and perinatal mortality rates more efficiently, reducing consanguineous marriages and providing better antenatal care for

Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.

Science.gov (United States)

Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

2016-01-01

We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro . Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8 + and CD4 + ). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs.

Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape

Energy Technology Data Exchange (ETDEWEB)

Wang, Lingshu; Shi, Wei; Chappell, James D.; Joyce, M. Gordon; Zhang, Yi; Kanekiyo, Masaru; Becker, Michelle M.; van Doremalen, Neeltje; Fischer, Robert; Wang, Nianshuang; Corbett, Kizzmekia S.; Choe, Misook; Mason, Rosemarie D.; Van Galen, Joseph G.; Zhou, Tongqing; Saunders, Kevin O.; Tatti, Kathleen M.; Haynes, Lia M.; Kwong, Peter D.; Modjarrad, Kayvon; Kong, Wing-Pui; McLellan, Jason S.; Denison, Mark R.; Munster, Vincent J.; Mascola, John R.; Graham, Barney S.; Gallagher, Tom

2018-03-07

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the “out” position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.

IMPORTANCEMERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using

Indirect effects of emerald ash borer-induced ash mortality and canopy gap formation on epigaeic beetles.

Science.gov (United States)

Gandhi, Kamal J K; Smith, Annemarie; Hartzler, Diane M; Herms, Daniel A

2014-06-01

Exotic herbivorous insects have drastically and irreversibly altered forest structure and composition of North American forests. For example, emerald ash borer (Agrilus planipennis Fairmaire) from Asia has caused wide-scale mortality of ash trees (Fraxinus spp.) in eastern United States and Canada. We studied the effects of forest changes resulting from emerald ash borer invasion on epigaeic or ground beetles (Coleoptera: Carabidae) along a gradient of ash dieback and gap sizes in southeastern Michigan. Ground beetles were sampled in hydric, mesic, and xeric habitats in which black (Fraxinus nigra Marshall), green (Fraxinus pennsylvanica Marshall), and white (Fraxinus americana L.) ash were the most common species, respectively. During 2006-2007, we trapped 2,545 adult ground beetles comprising 52 species. There was a negative correlation between percent ash tree mortality in 2006 and catches of all beetles. Catches of Agonum melanarium Dejean (in 2006) and Pterostichus mutus (Say) (in 2006-2007) were negatively correlated with tree mortality and gap size, respectively. However, catches of Pterostichus corvinus Dejean were positively correlated with gap size in 2006. As ash mortality and average gap size increased from 2006 to 2007, catches of all beetles as well as P. mutus and Pterostichus stygicus (Say) increased (1.3-3.9 times), while species diversity decreased, especially in mesic and xeric stands. Cluster analysis revealed that beetle assemblages in hydric and mesic stand diverged (25 and 40%, respectively) in their composition from 2006 to 2007, and that hydric stands had the most unique beetle assemblages. Overall, epigaeic beetle assemblages were altered in ash stands impacted by emerald ash borer; however, these impacts may dissipate as canopy gaps close.

VEGF induces proliferation of human hair follicle dermal papilla cells through VEGFR-2-mediated activation of ERK

International Nuclear Information System (INIS)

Li, Wei; Man, Xiao-Yong; Li, Chun-Ming; Chen, Jia-Qi; Zhou, Jiong; Cai, Sui-Qing; Lu, Zhong-Fa; Zheng, Min

2012-01-01

Vascular endothelial growth factor (VEGF) is one of the strongest regulators of physiological and pathological angiogenesis. VEGF receptor 2 (VEGFR-2), the primary receptor for VEGF, is thought to mediate major functional effects of VEGF. Previously, we have localized both VEGF and VEGFR-2 in human hair follicles. In this study, we further defined the expression and roles of VEGFR-2 on human hair follicle dermal papilla (DP) cells. The expression of VEGFR-2 on DP cells was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis separately, and localization of VEGFR-2 was defined by immunofluorescence. The effect of VEGF on DP cells was analyzed by MTT assays and specific inhibitors. Finally, the role of VEGF involved in the signaling pathways was investigated by Western blot. RT-PCR and Western blot analysis demonstrated the expression of VEGFR-2 on DP cells. Immunostaining for VEGFR-2 showed strong signal on cultured human DP cells in vitro. Exogenous VEGF 165 stimulated proliferation of DP cells in a dose-dependent manner. Furthermore, this stimulation was blocked by a VEGFR-2 neutralizing antibody (MAB3571) and an ERK inhibitor (PD98059). VEGF 165 -induced phosphorylation of ERK1/2 was abolished by MAB3571 and PD98059, while the phosphorylation of p38, JNK and AKT were not changed by VEGF 165 . Taken together, VEGFR-2 is expressed on primary human hair follicle DP cells and VEGF induces proliferation of DP cells through VEGFR-2/ERK pathway, but not p38, JNK or AKT signaling. -- Highlights: ► We examine the expression of VEGFR-2 on cultured human dermal papilla (DP) cells. ► VEGF 165 stimulated proliferation of human DP cells in a dose-dependent manner. ► This stimulation was through VEGFR-2-mediated activation of ERK.

Mortality associated with phaeochromocytoma.

Science.gov (United States)

Prejbisz, A; Lenders, J W M; Eisenhofer, G; Januszewicz, A

2013-02-01

Two major categories of mortality are distinguished in patients with phaeochromocytoma. First, the effects of excessive circulating catecholamines may result in lethal complications if the disease is not diagnosed and/or treated timely. The second category of mortality is related to development of metastatic disease or other neoplasms. Improvements in disease recognition and diagnosis over the past few decades have reduced mortality from undiagnosed tumours. Nevertheless, many tumours remain unrecognised until they cause severe complications. Death resulting from unrecognised or untreated tumour is caused by cardiovascular complications. There are also numerous drugs and diagnostic or therapeutic manipulations that can cause fatal complications in patients with phaeochromocytoma. Previously it has been reported that operative mortality was as high as 50% in unprepared patients with phaeochromocytoma who were operated and in whom the diagnosis was unsuspected. Today mortality during surgery in medically prepared patients with the tumour is minimal. Phaeochromocytomas may be malignant at presentation or metastases may develop later, but both scenarios are associated with a potentially lethal outcome. Patients with phaeochromocytoma run an increased risk to develop other tumours, resulting in an increased mortality risk compared to the general population. Phaeochromocytoma during pregnancy represents a condition with potentially high maternal and foetal mortality. However, today phaeochromocytoma in pregnancy is recognised earlier and in conjunction with improved medical management, maternal mortality has decreased to less than 5%. © Georg Thieme Verlag KG Stuttgart · New York.

Impact of reproductive laws on maternal mortality: the chilean natural experiment.

Science.gov (United States)

Koch, Elard

2013-05-01

Improving maternal health and decreasing morbidity and mortality due to induced abortion are key endeavors in developing countries. One of the most controversial subjects surrounding interventions to improve maternal health is the effect of abortion laws. Chile offers a natural laboratory to perform an investigation on the determinants influencing maternal health in a large parallel time-series of maternal deaths, analyzing health and socioeconomic indicators, and legislative policies including abortion banning in 1989. Interestingly, abortion restriction in Chile was not associated with an increase in overall maternal mortality or with abortion deaths and total number of abortions. Contrary to the notion proposing a negative impact of restrictive abortion laws on maternal health, the abortion mortality ratio did not increase after the abortion ban in Chile. Rather, it decreased over 96 percent, from 10.8 to 0.39 per 100,000 live births. Thus, the Chilean natural experiment provides for the first time, strong evidence supporting the hypothesis that legalization of abortion is unnecessary to improve maternal health in Latin America.

Parasitic Wasps Can Reduce Mortality of Teosinte Plants Infested With Fall Armyworm: Support for a Defensive Function of Herbivore-Induced Plant Volatiles

Directory of Open Access Journals (Sweden)

Elvira S. de Lange

2018-05-01

Full Text Available Many parasitic wasps use volatiles emitted by plants under herbivore attack to find their hosts. It has therefore been proposed that these inducible plant volatiles serve an indirect defense function by recruiting parasitoids and other natural enemies. This suggested function remains controversial because there is little evidence that, in terms of fitness, plants benefit from the actions of natural enemies, particularly parasitoids, which do not immediately kill their hosts. We aimed to address this controversy in a semi-natural field experiment in Mexico, where we used large screen tents to evaluate how parasitoids can affect plant performance. The tritrophic study system comprised teosinte (Zea spp., the ancestor of maize, Spodoptera frugiperda Smith (Lepidoptera: Noctuidae and Campoletis sonorensis Cameron (Hymenoptera: Ichneumonidae, which have a long evolutionary history together. In tents without parasitoids, S. frugiperda larvae inflicted severe damage to the plants, whereas in the presence of parasitoid wasps, leaf damage was reduced by as much as 80%. Parasitoids also mitigated herbivore-mediated mortality among young teosinte plants. Although these findings will not resolve the long-standing debate on the adaptive function of herbivore-induced plant volatiles (HIPVs, they do present strong support for the hypothesis that plants can benefit from the presence of parasitoid natural enemies of their herbivores.

Chronological production of thioacetamide-induced cirrhosis in the rat with no mortality.

Science.gov (United States)

Norasingha, Arthit; Pradidarcheep, Wisuit; Chayaburakul, Kanokporn

2012-01-01

Cirrhotic animal models are useful in studying complications of chronic liver disease. The authors chronologically investigated the effect of thioacetamide (TAA), administered intraperitoneally and adapted individually to weight changes, focusing on the optimal moment to obtain typical features of cirrhosis. Male Wistar Rats,150-200 g, were intoxicated three times per week with TAA of 200 mg/kg for 4, 8, 12 or 16 weeks (n = 8 per group), respectively and compared with age-matched controls (n = 4 per group). The individual body weight and liver function test were also measured in each group. Liver samples from each group were histologically stained with Sirius red in order to identify the degree of liver fibrosis. Rats intoxicated for 4, 8, 12 or 16 weeks had no mortality and histologically showed hepatitis and advanced fibrosis. At 12 and 16 weeks, all animals showed macronodular cirrhosis with signs of high-grade hepatocellular dysplasia. The weight of the treated groups at different time points was significantly lower than the controls. Routine liver function tests between cirrhotic and control rats showed significantly higher only in alanine transaminase (ALT) and aspartate aminotransferase (AST) at 8 and 12 weeks. However in the cirrhotic rats at 16 weeks, the ALT and AST were much lower than that at 8 and 12 weeks but did not show any difference from the controls. Thioacetamide, adapted to individual weight changes, leads to a model of cirrhosis in the rat at 12 and 16 weeks with zero mortality.

Decreased carbon limitation of litter respiration in a mortality-affected piñon–juniper woodland

Directory of Open Access Journals (Sweden)

E. Berryman

2013-03-01

Full Text Available Microbial respiration depends on microclimatic variables and carbon (C substrate availability, all of which are altered when ecosystems experience major disturbance. Widespread tree mortality, currently affecting piñon–juniper ecosystems in southwestern North America, may affect C substrate availability in several ways, for example, via litterfall pulses and loss of root exudation. To determine piñon mortality effects on C and water limitation of microbial respiration, we applied field amendments (sucrose and water to two piñon–juniper sites in central New Mexico, USA: one with a recent (2 flux on the girdled site and a non-significant increase on the control. We speculate that the reduction may have been driven by water-induced carbonate dissolution, which serves as a sink for CO2 and would reduce the net flux. Widespread piñon mortality may decrease labile C limitation of litter respiration, at least during the first growing season following mortality.

Inequalities in mortality: study rates, not standardised mortality ratios [Letter

NARCIS (Netherlands)

Bonneux, L.G.A.

2010-01-01

In their study from 1921 to 2007 Thomas and colleagues conclude on the basis of standardised mortality ratios that inequalities in mortality continue to rise and are now almost as high as in the 1930s. Relative ratios are, however, misleading when absolute rates change strongly. I calculated the

Increased Mortality After Prosthetic Joint Infection in Primary THA.

Science.gov (United States)

Gundtoft, Per Hviid; Pedersen, Alma Becic; Varnum, Claus; Overgaard, Søren

2017-11-01

patients who underwent revision for PJI died. The adjusted relative mortality risk for patients with revision for PJI was 2.18 (95% CI, 1.54-3.08) compared with the patients who did not undergo revision for any cause (p infected THA had a 3.10 (95% CI, 1.66-5.81) higher mortality risk than patients infected with other bacteria (p < 0.001). Revision for PJI within 1 year after primary THA induces an increased mortality risk during the first year after the revision surgery. This study should incentivize further studies on prevention of PJI and on risk to patients with the perspective to reduce mortality in patients who have had THA in general and for patients with PJI specifically. Level III, therapeutic study.

Respiratory tract mortality in cement workers: a proportionate mortality study

Science.gov (United States)

2012-01-01

Background The evidence regarding the association between lung cancer and occupational exposure to cement is controversial. This study investigated causes of deaths from cancer of respiratory tract among cement workers. Methods The deaths of the Greek Cement Workers Compensation Scheme were analyzed covering the period 1969-1998. All respiratory, lung, laryngeal and urinary bladder cancer proportionate mortality were calculated for cement production, maintenance, and office workers in the cement industry. Mortality from urinary bladder cancer was used as an indirect indicator of the confounding effect of smoking. Results Mortality from all respiratory cancer was significantly increased in cement production workers (PMR = 1.91; 95% CI 1.54 to 2.33). The proportionate mortality from lung cancer was significantly elevated (PMR = 2.05; 95% CI 1.65 to 2.52). A statistically significant increase in proportionate mortality due to respiratory (PMR = 1.7; 95% CI 1.2 to 2.34). and lung cancer (PMR = 1.67;95% CI = 1.15-2.34) among maintenance workers has been observed. The PMR among the three groups of workers (production, maintenance, office) did differ significantly for lung cancer (p = 0.001), while the PMR for urinary bladder cancer found to be similar among the three groups of cement workers. Conclusion Cement production, and maintenance workers presented increased lung and respiratory cancer proportionate mortality, and this finding probably cannot be explained by the confounding effect of smoking alone. Further research including use of prospective cohort studies is needed in order to establish a causal association between occupational exposure to cement and risk of lung cancer. PMID:22738120

Effect of healthcare on mortality: trends in avoidable mortality in Umbria, Italy, 1994-2009

Directory of Open Access Journals (Sweden)

Fabrizio Stracci

2013-06-01

Full Text Available OBJECTIVE: Avoidable mortality trends over the period 1994-2009 were calculated to evaluate health intervention by the health system of Umbria, a region of central Italy. MATERIALS AND METHODS: Mortality data were supplied by the regional causes of death registry. Rates were standardized to the 2001 census Italian population. Joinpoint regression was used to analyze the trends. RESULTS: Overall avoidable mortality rates decreased significantly both in males (-3.9% per year and in females (-3.6% per year. Mortality rates from ischemic heart and cerebrovascular disease about halved in the study period in both sexes. Avoidable mortality increased slightly only for a few causes (e.g. lung cancer in females. CONCLUSION: The overall trend of avoidable mortality indicates that the regional health/ preventive system is performing well.

An analysis of hereditary increase in frequency of cell mortality induced by external factors (Experiments on nuclear transplantation in amoebae)

International Nuclear Information System (INIS)

Bychkovskaya, I.B.; Ochinskaya, G.K.; Yudin, A.L.; AN SSSR, Leningrad. Inst. Tsitologii)

1980-01-01

By using nuclear transplantations in Amoeba proteus a study was made of a peculiar heritable effect, a stable increase in the frequency of cell mortality incuced by comparatively low doses of x radiation (50 Gy) or slight heating (29 0 C during 6 to 7 h). This effect differs qualitatively from the known radiation effects (reproductive death, lethal sectoring) by its being non-specific for radiation. In addition, the effect is saltatory appearing in 100% of the treated cells and the extent of its expression is not dependent on the dose of an inducing factor (at supra-threshold doses) and the period of time after treatment. It was found that (1) the hereditary changes in amoebae, unlike those resulting in reproductive death, are transmitted during intercellular transplantations both by the nucleus and cytoplasm of an altered cell; (2) the transfer of the character under test is accomplished by means of a certiin factor capable of shuttling between the nucleus and cytoplasm, (3) the effect is not necessarily a consequence of primary injury of nuclear structures and it may be induced by treatment of the cytoplasm of an enucleated cell renucleated then by the nucleus of a normal amoeba. In this respect, the effect under test differs also from the known types of hereditary post-radiation lethal effects which are commonly suggested to involve primary injury of the nucleus. Possible mechanisms of genetic control over the character tested are discussed. (author)

Induced Innovation and Social Inequality: Evidence from Infant Medical Care.

Science.gov (United States)

Cutler, David M; Meara, Ellen; Richards-Shubik, Seth

2012-01-01

We develop a model of induced innovation that applies to medical research. Our model yields three empirical predictions. First, initial death rates and subsequent research effort should be positively correlated. Second, research effort should be associated with more rapid mortality declines. Third, as a byproduct of targeting the most common conditions in the population as a whole, induced innovation leads to growth in mortality disparities between minority and majority groups. Using information on infant deaths in the U.S. between 1983 and 1998, we find support for all three empirical predictions.

Variation in woody plant mortality and dieback from severe drought among soils, plant groups, and species within a northern Arizona ecotone.

Science.gov (United States)

Koepke, Dan F; Kolb, Thomas E; Adams, Henry D

2010-08-01

Vegetation change from drought-induced mortality can alter ecosystem community structure, biodiversity, and services. Although drought-induced mortality of woody plants has increased globally with recent warming, influences of soil type, tree and shrub groups, and species are poorly understood. Following the severe 2002 drought in northern Arizona, we surveyed woody plant mortality and canopy dieback of live trees and shrubs at the forest-woodland ecotone on soils derived from three soil parent materials (cinder, flow basalt, sedimentary) that differed in texture and rockiness. Our first of three major findings was that soil parent material had little effect on mortality of both trees and shrubs, yet canopy dieback of trees was influenced by parent material; dieback was highest on the cinder for pinyon pine (Pinus edulis) and one-seed juniper (Juniperus monosperma). Ponderosa pine (Pinus ponderosa) dieback was not sensitive to parent material. Second, shrubs had similar mortality, but greater canopy dieback, than trees. Third, pinyon and ponderosa pines had greater mortality than juniper, yet juniper had greater dieback, reflecting different hydraulic characteristics among these tree species. Our results show that impacts of severe drought on woody plants differed among tree species and tree and shrub groups, and such impacts were widespread over different soils in the southwestern U.S. Increasing frequency of severe drought with climate warming will likely cause similar mortality to trees and shrubs over major soil types at the forest-woodland ecotone in this region, but due to greater mortality of other tree species, tree cover will shift from a mixture of species to dominance by junipers and shrubs. Surviving junipers and shrubs will also likely have diminished leaf area due to canopy dieback.

Accumulation of 111In-neutrophils in rabbit skin in allergic and non-allergic inflammatory reactions in vivo. Inhibition by neutrophil pretreatment in vitro with a monoclonal antibody recognizing the CD18 antigen

International Nuclear Information System (INIS)

Nourshargh, S.; Rampart, M.; Hellewell, P.G.; Jose, P.J.; Harlan, J.M.; Edwards, A.J.; Williams, T.J.

1989-01-01

The mAb 60.3 recognizes the neutrophil CD18 Ag. We have investigated the effect of in vitro pretreatment of radiolabeled neutrophils with mAb 60.3 on their accumulation in vivo. Further, we have compared the in vivo effects of mAb 60.3 with its effects on neutrophil adherence in vitro. Neutrophil accumulation in vivo was measured in response to: (1) exogenous mediators FMLP, C5a des Arg, LTB4 and IL-1; (2) endogenous mediators generated in a non-allergic inflammatory reaction induced by zymosan; and (3) endogenous mediators generated in two allergic inflammatory reactions, a passive cutaneous anaphylactic reaction and a reversed passive Arthus reaction in rabbit skin. Pretreatment of neutrophils with mAb 60.3 inhibited their accumulation in all the responses. The results demonstrate that there is a common mechanism mediating neutrophil accumulation in these inflammatory reactions. Neutrophils pretreated with mAb 60.3 were also unresponsive to chemoattractants in in vitro adherence assays. However, the antibody-treated neutrophils responded normally to FMLP and C5a with respect to granular enzyme release. These results suggest that the basal expression of CD18 Ag is important for the adherence of neutrophils to microvascular endothelial cells stimulated by the local generation, or administration, of chemical mediators in vivo. Despite the fact that mediators such as FMLP can increase CD18 expression in vitro, it appears more likely that such mediators act in vivo by inducing a conformational change in the basally expressed neutrophil adhesive molecules

Tree mortality estimates and species distribution probabilities in southeastern United States forests

Science.gov (United States)

Martin A. Spetich; Zhaofei Fan; Zhen Sui; Michael Crosby; Hong S. He; Stephen R. Shifley; Theodor D. Leininger; W. Keith Moser

2017-01-01

Stresses to trees under a changing climate can lead to changes in forest tree survival, mortality and distribution.  For instance, a study examining the effects of human-induced climate change on forest biodiversity by Hansen and others (2001) predicted a 32% reduction in loblolly–shortleaf pine habitat across the eastern United States.  However, they also...

Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

International Nuclear Information System (INIS)

Kakita, Hiroki; Aoyama, Mineyoshi; Nagaya, Yoshiaki; Asai, Hayato; Hussein, Mohamed Hamed; Suzuki, Mieko; Kato, Shin; Saitoh, Shinji; Asai, Kiyofumi

2013-01-01

Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N G -monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for IAE

Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

Energy Technology Data Exchange (ETDEWEB)

Kakita, Hiroki [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Aoyama, Mineyoshi, E-mail: ao.mine@med.nagoya-cu.ac.jp [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Nagaya, Yoshiaki; Asai, Hayato [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Hussein, Mohamed Hamed [Neonatal Intensive Care Unit, Pediatric Hospital, Cairo University, Cairo 11559 (Egypt); Maternal and Child Health Department, VACSERA, 51 Wizaret El-Zeraa-Agouza, Giza 22311 (Egypt); Suzuki, Mieko [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Kato, Shin [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Saitoh, Shinji [Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan)

2013-04-15

Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N{sup G}-monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for

Bark beetle-induced tree mortality alters stand energy budgets due to water budget changes

Science.gov (United States)

Reed, David E.; Ewers, Brent E.; Pendall, Elise; Frank, John; Kelly, Robert

2018-01-01

Insect outbreaks are major disturbances that affect a land area similar to that of forest fires across North America. The recent mountain pine bark beetle ( D endroctonus ponderosae) outbreak and its associated blue stain fungi ( Grosmannia clavigera) are impacting water partitioning processes of forests in the Rocky Mountain region as the spatially heterogeneous disturbance spreads across the landscape. Water cycling may dramatically change due to increasing spatial heterogeneity from uneven mortality. Water and energy storage within trees and soils may also decrease, due to hydraulic failure and mortality caused by blue stain fungi followed by shifts in the water budget. This forest disturbance was unique in comparison to fire or timber harvesting because water fluxes were altered before significant structural change occurred to the canopy. We investigated the impacts of bark beetles on lodgepole pine ( Pinus contorta) stand and ecosystem level hydrologic processes and the resulting vertical and horizontal spatial variability in energy storage. Bark beetle-impacted stands had on average 57 % higher soil moisture, 1.5 °C higher soil temperature, and 0.8 °C higher tree bole temperature over four growing seasons compared to unimpacted stands. Seasonal latent heat flux was highly correlated with soil moisture. Thus, high mortality levels led to an increase in ecosystem level Bowen ratio as sensible heat fluxes increased yearly and latent heat fluxes varied with soil moisture levels. Decline in canopy biomass (leaf, stem, and branch) was not seen, but ground-to-atmosphere longwave radiation flux increased, as the ground surface was a larger component of the longwave radiation. Variability in soil, latent, and sensible heat flux and radiation measurements increased during the disturbance. Accounting for stand level variability in water and energy fluxes will provide a method to quantify potential drivers of ecosystem processes and services as well as lead to greater

Mortality in epilepsy.

Science.gov (United States)

Hitiris, Nikolas; Mohanraj, Rajiv; Norrie, John; Brodie, Martin J

2007-05-01

All studies report an increased mortality risk for people with epilepsy compared with the general population. Population-based studies have demonstrated that the increased mortality is often related to the cause of the epilepsy. Common etiologies include neoplasia, cerebrovascular disease, and pneumonia. Deaths in selected cohorts, such as sudden unexpected death in epilepsy (SUDEP), status epilepticus (SE), suicides, and accidents are more frequently epilepsy-related. SUDEP is a particular cause for concern in younger people, and whether and when SUDEP should be discussed with patients with epilepsy remain problematic issues. Risk factors for SUDEP include generalized tonic-clonic seizures, increased seizure frequency, concomitant learning disability, and antiepileptic drug polypharmacy. The overall incidence of SE may be increasing, although case fatality rates remain constant. Mortality is frequently secondary to acute symptomatic disorders. Poor compliance with treatment in patients with epilepsy accounts for a small proportion of deaths from SE. The incidence of suicide is increased, particularly for individuals with epilepsy and comorbid psychiatric conditions. Late mortality figures in patients undergoing epilepsy surgery vary and are likely to reflect differences in case selection. Future studies of mortality should be prospective and follow agreed guidelines to better quantify risk and causation in individual populations.

Mortality Implications of Mortality Plateaus

DEFF Research Database (Denmark)

Missov, T. I.; Vaupel, J. W.

2015-01-01

This article aims to describe in a unified framework all plateau-generating random effects models in terms of (i) plausible distributions for the hazard (baseline mortality) and the random effect (unobserved heterogeneity, frailty) as well as (ii) the impact of frailty on the baseline hazard...

Mortality, fog and atmospheric pollution

Energy Technology Data Exchange (ETDEWEB)

Martin, A E; Bradley, W H

1960-01-01

A study was made associating climate and atmospheric pollution with excess mortality in greater London during the winter of 1958 and 1959. It was a particularly foggy winter with 6 major episodes, 4 of which resembled previous dangerous smogs. There were two additional periods of high pollution without fog. Excess mortality during these 8 periods ranged from 70 to 230. During one period, a flu epidemic accompanied the fog. In 4 to 6 foggy periods, morbidity (hospital bed demand) also increased. This small number of observations indicates mortality association: on 2/3 of days with high SO/sub 2/ (2.5 pphM) or high particulate soot (10 mg/m/sup 3/), and on all days with thick fog, there was an increase in mortality (20 deaths more than previous day) on that or the following day. Fifteen-day moving mortality index and bronchitis mortality index were significantly correlated with black suspended matter and SO/sub 2/; association with pneumonia was not significant. Also little or no relation between mortality and humidity, mean temperature, or barometric pressure was found. Rapid response of mortality to air pollution may indicate that pollution affects mostly those already ill.

A Relational Database of WHO Mortality Data Prepared to Facilitate Global Mortality Research

Directory of Open Access Journals (Sweden)

Albert de Roos

2015-09-01

Full Text Available Detailed world mortality data such as collected by the World Health Organization gives a wealth of information about causes of death worldwide over a time span of 60 year. However, the raw mortality data in text format as provided by the WHO is not directly suitable for systematic research and data mining. In this Data Paper, a relational database is presented that is created from the raw WHO mortality data set and includes mortality rates, an ICD-code table and country reference data. This enriched database, as a corpus of global mortality data, can be readily imported in relational databases but can also function as the data source for other types of databases. The use of this database can therefore greatly facilitate global epidemiological research that may provide new clues to genetic or environmental factors in the origins of diseases.

Smoking-Attributable Mortality, Morbidity, and Economic Costs (SAMMEC) - Smoking-Attributable Mortality (SAM)

Data.gov (United States)

U.S. Department of Health & Human Services — 2005-2009. SAMMEC - Smoking-Attributable Mortality, Morbidity, and Economic Costs. Smoking-attributable mortality (SAM) is the number of deaths caused by cigarette...

Clinical Cancer Therapy by NK Cells via Antibody-Dependent Cell-Mediated Cytotoxicity

Directory of Open Access Journals (Sweden)

Kory L. Alderson

2011-01-01

Full Text Available Natural killer (NK cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs. Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings.

Intestine-Specific Mttp Deletion Decreases Mortality and Prevents Sepsis-Induced Intestinal Injury in a Murine Model of Pseudomonas aeruginosa Pneumonia

Science.gov (United States)

Dominguez, Jessica A.; Xie, Yan; Dunne, W. Michael; Yoseph, Benyam P.; Burd, Eileen M.; Coopersmith, Craig M.; Davidson, Nicholas O.

2012-01-01

Background The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the “motor” of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. Methodology/Principal Findings Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. Conclusions/Significance These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by

Intestine-specific Mttp deletion decreases mortality and prevents sepsis-induced intestinal injury in a murine model of Pseudomonas aeruginosa pneumonia.

Directory of Open Access Journals (Sweden)

Jessica A Dominguez

Full Text Available The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the "motor" of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO, which exhibit a block in chylomicron assembly together with lipid malabsorption.Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0% dying compared to 5/17 (29% control mice (p<0.05. This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice.These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and

Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Directory of Open Access Journals (Sweden)

Laetitia Fend

Full Text Available Tumor progression is promoted by Tumor-Associated Macrophages (TAMs and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+ CD163(+ M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+CD163(+ M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

Asthma mortality in Uruguay, 1984-1998.

Science.gov (United States)

Baluga, J C; Sueta, A; Ceni, M

2001-08-01

Asthma mortality rates have increased worldwide during the past several years despite the increased availability of new and effective medications. Few studies show reliable data from Latin American countries. To determine asthma mortality rates from 1984 to 1998 and to relate mortality to sales of asthma medications. We conducted a retrospective epidemiologic study in the total population of Uruguay. Data were obtained from the Department of Statistics of the Ministry of Public Health. Trends in mortality rates were analyzed using linear regression procedures. Spearman rank correlations were used to relate mortality rates to sales of asthma medications. The mean overall mortality rate was 5.10 per 100,000 during the period 1984 to 1998, (range 6.08 to 3.39) and showed a decreasing trend (P = 0.001). During the period 1995 to 1998, a more pronounced decrease was observed (mean mortality rate, 4.10 per 100,000). In the 5- to 34-year-old age group the mean mortality rate was 0.43 (range 0.65 to 0.13). Similarly, the mortality rate in this age group decreased particularly in the 1994 to 1998 period (mean 0.19; P = 0.005). Finally, the mortality rate was inversely correlated with sales of inhaled corticosteroids; for the overall mortality rate, p = -0.71, P = 0.003; for 5- to 34-year-old age group, p = -0.63, P = 0.01. Although mortality attributable to asthma seems to be decreasing, the overall mortality rate is still high compared with more economically developed countries. A more pronounced decrease in asthma mortality has been seen in the 5- to 34-year-old group. At present, Uruguay is a Latin American country with a low rate of asthma mortality. This is probably related to the use of new therapies to treat asthma.

Long-term association between the intensity of cosmic rays and mortality rates in the city of Sao Paulo

Science.gov (United States)

Vieira, C. L. Z.; Janot-Pacheco, E.; Lage, C.; Pacini, A.; Koutrakis, P.; Cury, P. R.; Shaodan, H.; Pereira, L. A.; Saldiva, P. H. N.

2018-02-01

Human beings are constantly exposed to many kinds of environmental agents which affect their health and lifespan. Galactic cosmic rays (GCRs) are the main source of ionizing radiation in the lower troposphere, in which secondary products can penetrate the ground and underground layers. GCRs affect the physical-chemical properties of the terrestrial atmosphere, as well as the biosphere. GCRs are modulated by solar activity and latitudinal geomagnetic field distribution. In our ecological/populational retrospective study, we analyzed the correlation between the annual flux of local secondary GCR-induced ionization (CRII) and mortality rates in the city of Sao Paulo, Brazil, between 1951-2012. The multivariate linear regression analyses adjusted by demographic and weather parameters showed that CRII are significantly correlated with total mortality, infectious disease mortality, maternal mortality, and perinatal mortality rates (p < 0.001). The underlying mechanisms are still unclear. Further cross-sectional and experimental cohort studies are necessary to understand the biophysical mechanisms of the association found here.

High mortality in the Thule cohort

DEFF Research Database (Denmark)

Juel, K

1994-01-01

The objective was to study mortality in the Thule cohort in order to clarify whether it is a selected population and to ascertain the possibility of misinterpretation when national mortality rates are used as reference in the analysis of occupational mortality.......The objective was to study mortality in the Thule cohort in order to clarify whether it is a selected population and to ascertain the possibility of misinterpretation when national mortality rates are used as reference in the analysis of occupational mortality....

Time course and reasons for 90-day mortality in fast-track hip and knee arthroplasty

DEFF Research Database (Denmark)

Jørgensen, C C; Kehlet, H

2017-01-01

: Prospective observational study in 13,775 consecutive THA/TKAs with similar fast-track protocols and a median length of stay of 2 days. Complete 90-days follow-up through national registries, followed by review of medical records and death certificates. Relation between mortality and surgically induced organ...

The role of HSP70 in mediating age-dependent mortality in sepsis

Science.gov (United States)

McConnell, Kevin W.; Fox, Amy C.; Clark, Andrew T.; Chang, Nai-Yuan Nicholas; Dominguez, Jessica A.; Farris, Alton B.; Buchman, Timothy G.; Hunt, Clayton R.; Coopersmith, Craig M.

2011-01-01

Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6–12week old) and aged (16–17 month old) HSP70−/− and wild type (WT) mice to determine if HSP70 modulated outcome in an age-dependent fashion. Young HSP70−/− and WT mice subjected to cecal ligation and puncture (CLP), Pseudomonas aeruginosa pneumonia or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70−/− mice than aged WT mice subjected to CLP (p=0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared to WT mice, aged septic HSP70−/− mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70−/−mice had increased systemic levels of TNF-α, IL-6, IL-10 and IL-1β compared to WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation. PMID:21296977

Stochastic portfolio specific mortality and the quantification of mortality basis risk

NARCIS (Netherlands)

Plat, R.

2009-01-01

In the last decade a vast literature on stochastic mortality models has been developed. However, these models are often not directly applicable to insurance portfolios because: (a) For insurers and pension funds it is more relevant to model mortality rates measured in insured amounts instead of

Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever.

Science.gov (United States)

Marzi, Andrea; Yoshida, Reiko; Miyamoto, Hiroko; Ishijima, Mari; Suzuki, Yasuhiko; Higuchi, Megumi; Matsuyama, Yukie; Igarashi, Manabu; Nakayama, Eri; Kuroda, Makoto; Saijo, Masayuki; Feldmann, Friederike; Brining, Douglas; Feldmann, Heinz; Takada, Ayato

2012-01-01

Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.

Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever.

Directory of Open Access Journals (Sweden)

Andrea Marzi

Full Text Available Ebola virus (EBOV is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF. Single monoclonal antibodies (MAbs specific for Zaire ebolavirus (ZEBOV have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226 with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.

Excess Early Mortality in Schizophrenia

DEFF Research Database (Denmark)

Laursen, Thomas Munk; Nordentoft, Merete; Mortensen, Preben Bo

2014-01-01

Schizophrenia is often referred to as one of the most severe mental disorders, primarily because of the very high mortality rates of those with the disorder. This article reviews the literature on excess early mortality in persons with schizophrenia and suggests reasons for the high mortality...... as well as possible ways to reduce it. Persons with schizophrenia have an exceptionally short life expectancy. High mortality is found in all age groups, resulting in a life expectancy of approximately 20 years below that of the general population. Evidence suggests that persons with schizophrenia may...... not have seen the same improvement in life expectancy as the general population during the past decades. Thus, the mortality gap not only persists but may actually have increased. The most urgent research agenda concerns primary candidates for modifiable risk factors contributing to this excess mortality...

Aeroallergen analyses and their clinical relevance. I. Immunochemical quantification of allergens by RAST-inhibition, Mab-ELISA, basophil histamine release, and counter current immuno electrophoresis

DEFF Research Database (Denmark)

Johnsen, C R; Abrahamsen, L; Stahl Skov, P

1991-01-01

of indoor aeroallergens, cat, dog, and Derm. pter. allergen extracts were selected for the experiments. To evaluate unspecific interference, these allergens were compared mutually and with Cladosporium herbarum. Allergen extracts in varying dilutions were mixed with crushed glass fibre filter materials......, eluted, recovered by centrifugation, and allergen concentration quantified by the assays. Equal sensitivity was found for both IgE- and IgG4-RI assaying cat allergen (in the range 5-50 SQ-U/ml) and dog allergen (in the range 10(2)-10(3) SQ-U/ml). The IgG4-RI assaying Derm. pter. was more sensitive (50 SQ......-U/ml) than IgE-RI (2*10(3) SQ-U/ml). The ranges of allergen detection limits for the Mab-ELISA were equal for cat and Derm. pter. (10-10(2) SQ-U/ml). The range of allergen detection limits for CCIE, assaying dog were 10(4)-10(5) SQ-U/ml. The ranges of allergen detection limits for HR were equal for cat...

An integrated national mortality surveillance system for death registration and mortality surveillance, China.

Science.gov (United States)

Liu, Shiwei; Wu, Xiaoling; Lopez, Alan D; Wang, Lijun; Cai, Yue; Page, Andrew; Yin, Peng; Liu, Yunning; Li, Yichong; Liu, Jiangmei; You, Jinling; Zhou, Maigeng

2016-01-01

In China, sample-based mortality surveillance systems, such as the Chinese Center for Disease Control and Prevention's disease surveillance points system and the Ministry of Health's vital registration system, have been used for decades to provide nationally representative data on health status for health-care decision-making and performance evaluation. However, neither system provided representative mortality and cause-of-death data at the provincial level to inform regional health service needs and policy priorities. Moreover, the systems overlapped to a considerable extent, thereby entailing a duplication of effort. In 2013, the Chinese Government combined these two systems into an integrated national mortality surveillance system to provide a provincially representative picture of total and cause-specific mortality and to accelerate the development of a comprehensive vital registration and mortality surveillance system for the whole country. This new system increased the surveillance population from 6 to 24% of the Chinese population. The number of surveillance points, each of which covered a district or county, increased from 161 to 605. To ensure representativeness at the provincial level, the 605 surveillance points were selected to cover China's 31 provinces using an iterative method involving multistage stratification that took into account the sociodemographic characteristics of the population. This paper describes the development and operation of the new national mortality surveillance system, which is expected to yield representative provincial estimates of mortality in China for the first time.

Numerical experiments to explain multiscale hydrological responses to mountain pine beetle tree mortality in a headwater watershed

Science.gov (United States)

Penn, Colin A.; Bearup, Lindsay A.; Maxwell, Reed M.; Clow, David W.

2016-01-01

The effects of mountain pine beetle (MPB)-induced tree mortality on a headwater hydrologic system were investigated using an integrated physical modeling framework with a high-resolution computational grid. Simulations of MPB-affected and unaffected conditions, each with identical atmospheric forcing for a normal water year, were compared at multiple scales to evaluate the effects of scale on MPB-affected hydrologic systems. Individual locations within the larger model were shown to maintain hillslope-scale processes affecting snowpack dynamics, total evapotranspiration, and soil moisture that are comparable to several field-based studies and previous modeling work. Hillslope-scale analyses also highlight the influence of compensating changes in evapotranspiration and snow processes. Reduced transpiration in the Grey Phase of MPB-induced tree mortality was offset by increased late-summer evaporation, while overall snowpack dynamics were more dependent on elevation effects than MPB-induced tree mortality. At the watershed scale, unaffected areas obscured the magnitude of MPB effects. Annual water yield from the watershed increased during Grey Phase simulations by 11 percent; a difference that would be difficult to diagnose with long-term gage observations that are complicated by inter-annual climate variability. The effects on hydrology observed and simulated at the hillslope scale can be further damped at the watershed scale, which spans more life zones and a broader range of landscape properties. These scaling effects may change under extreme conditions, e.g., increased total MPB-affected area or a water year with above average snowpack.

Data base on animal mortality

International Nuclear Information System (INIS)

Jones, T.D.

1987-01-01

A data base on animal mortality has been compiled. The literature on LD 50 and the dose-response function for radiation-induced lethality, reflect several inconsistencies - primarily due to dose assignments and to analytical methods and/or mathematical models used. Thus, in order to make the individual experiments which were included in the data base as consistent as possible, an estimate of the uniform dose received by the bone marrow in each treatment group was made so that the interspecies differences are minimized. The LD 50 was recalculated using a single estimation procedure for all studies for which sufficient experimental data are available. For small animals such as mice, the dose to the hematopoietic system is approximately equal to the treatment dose, but for large animals the marrow dose may be about half of the treatment dose

Perflurooctanoic Acid Induces Developmental Cardiotoxicity in Chicken Embryos and Hatchlings

Science.gov (United States)

Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxi...

Qualification and application of a surface plasmon resonance-based assay for monitoring potential HAHA responses induced after passive administration of a humanized anti Lewis-Y antibody.

Science.gov (United States)

Szolar, O H J; Stranner, S; Zinoecker, I; Mudde, G C; Himmler, G; Waxenecker, G; Nechansky, A

2006-06-16

A sensitive, surface plasmon resonance (SPR)-based assay monitoring potential human-anti-human antibody (HAHA) reactions against the monoclonal antibody (mAb) IGN311 is presented. The latter is a fully humanized Lewis-Y carbohydrate specific mAb that is currently tested in a passive immune therapy approach in a clinical phase I trial. For the SPR experiments a BIACORE 3000 analyzer was used. The ligand IGN311 was covalently coupled to the carboxy-methylated dextran matrix of a CM5 research grade chip (BIACORE). In the course of a fully nested experimental design, a four parameter logistic equation was identified as appropriate calibration model ranging from 0.3 microg/mL (lower limit of quantitation, LLOQ) to 200 microg/mL (upper limit of quantitation, ULOQ) using an anti-idiotypic mAb ('HAHA mimic') as calibrator. The bias ranged from -2.4% to 5.5% and the intermediate precision expressed as 95% CI revealed values from 5.6% to 8.3%. Specificity was evaluated using six human serum matrices from healthy donors spiked with calibrator at the limit of quantitation (LOQ) with >80% of values being recovered with less than 25% relative error. The qualified assay was applied to monitor potentially induced HAHA reactivity in 11 patients from a clinical phase I trial with passively administered IGN311. Of the 11 patients, one high HAHA responder and several low responders were identified. Protein-G depletion experiments with human serum samples revealed that the observed response is predominantly caused by IgG binding to the ligand. The characteristics of these HAHA responses were all of the so-called 'Type I' which is defined by a peak response around day 15 that decreases from this point steadily suggesting that some kind of tolerance is established. Therefore, this type of HAHA response is regarded as non critical for the patient's safety.

Abrupt increases in Amazonian tree mortality due to drought–fire interactions

OpenAIRE

Brando, Paulo Monteiro; Balch, Jennifer K.; Nepstad, Daniel C.; Morton, Douglas C.; Putz, Francis E.; Coe, Michael T.; Silvério, Divino; Macedo, Marcia N.; Davidson, Eric A.; Nóbrega, Caroline C.; Alencar, Ane; Soares-Filho, Britaldo S.

2014-01-01

Climate change alone is unlikely to drive severe tropical forest degradation in the next few decades, but an alternative process associated with severe weather and forest fires is already operating in southeastern Amazonia. Recent droughts caused greatly elevated fire-induced tree mortality in a fire experiment and widespread regional forest fires that burned 5–12% of southeastern Amazon forests. These results suggest that feedbacks between fires and extreme climatic conditions could increase...

Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.

Science.gov (United States)

Mishra, Shikha; Guan, Jian; Plovie, Eva; Seldin, David C; Connors, Lawreen H; Merlini, Giampaolo; Falk, Rodney H; MacRae, Calum A; Liao, Ronglih

2013-07-01

Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.

Under-Five Mortality

African Journals Online (AJOL)

under-five mortality rate (U5MR) by two thirds between. 1990 and 2015. For Zambia, this means ... 1Institute of Economic and Social Research, University of Zambia ... live births;. 2. Neonatal mortality: Deaths during the first 28 days of life. 3. Post-neonatal ... children born/woman) and rapid (3%) population growth on living ...

Mortality in acromegaly: a metaanalysis

NARCIS (Netherlands)

Dekkers, O. M.; Biermasz, N. R.; Pereira, A. M.; Romijn, J. A.; Vandenbroucke, J. P.

2008-01-01

Several studies have assessed mortality risk in patients treated for acromegaly. All studies found a mortality that was higher than expected for the general population, but most of these increases were not statistically significant. For this reason, it is not formally established whether mortality

Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.

Science.gov (United States)

Fox, Amy C; Breed, Elise R; Liang, Zhe; Clark, Andrew T; Zee-Cheng, Brendan R; Chang, Katherine C; Dominguez, Jessica A; Jung, Enjae; Dunne, W Michael; Burd, Eileen M; Farris, Alton B; Linehan, David C; Coopersmith, Craig M

2011-08-15

Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44% 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim(-/-) mice. Septic Bim(-/-) mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.

Loneliness, health and mortality

DEFF Research Database (Denmark)

Henriksen, J; Larsen, E R; Mattisson, C

2017-01-01

Aims.: Literature suggests an association between loneliness and mortality for both males and females. Yet, the linkage of loneliness to mortality is not thoroughly examined, and need to be replicated with a long follow-up time. This study assessed the association between loneliness and mortality...... not been previously reported. If replicated, our results indicate that loneliness may have differential physical implications in some subgroups. Future studies are needed to further investigate the influence of gender on the relationship....

A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells.

Science.gov (United States)

Kobayashi, Eiji; Kishi, Hiroyuki; Ozawa, Tatsuhiko; Hamana, Hiroshi; Nakagawa, Hidetoshi; Jin, Aishun; Lin, Zhezhu; Muraguchi, Atsushi

2014-10-31

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its associated receptors (TRAIL-R/TR) are attractive targets for cancer therapy because TRAIL induces apoptosis in tumor cells through TR while having little cytotoxicity on normal cells. Therefore, many agonistic monoclonal antibodies (mAbs) specific for TR have been produced, and these induce apoptosis in multiple tumor cell types. However, some TR-expressing tumor cells are resistant to TR-specific mAb-induced apoptosis. In this study, we constructed a chimeric antigen receptor (CAR) of a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR) and expressed it on a Jurkat T cell line, the KHYG-1 NK cell line, and human peripheral blood lymphocytes (PBLs). We found that the TR1-scFv-CAR-expressing Jurkat cells killed target cells via TR1-mediated apoptosis, whereas TR1-scFv-CAR-expressing KHYG-1 cells and PBLs killed target cells not only via TR1-mediated apoptosis but also via CAR signal-induced cytolysis, resulting in cytotoxicity on a broader range if target cells than with TR1-scFv-CAR-expressing Jurkat cells. The results suggest that TR1-scFv-CAR could be a new candidate for cancer gene therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein.

Directory of Open Access Journals (Sweden)

Dianyuan Zhao

2016-03-01

Full Text Available Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP is involved in this process through activating dendritic cells (DCs and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12 and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response.

Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy

DEFF Research Database (Denmark)

Lajer, Maria Stenkil; Jorsal, Anders; Tarnow, Lise

2010-01-01

Growth deferentiation factor-15 (GDF-15) is involved in inflammation and apoptosis. Expression is induced in the heart in response to ischemia and in atherosclerotic plaques. The aim of this study was to investigate GDF-15 levels in relation to all-cause mortality, cardiovascular mortality and mo...

Model calculated global, regional and megacity premature mortality due to air pollution

Directory of Open Access Journals (Sweden)

J. Lelieveld

2013-07-01

Full Text Available Air pollution by fine particulate matter (PM2.5 and ozone (O3 has increased strongly with industrialization and urbanization. We estimate the premature mortality rates and the years of human life lost (YLL caused by anthropogenic PM2.5 and O3 in 2005 for epidemiological regions defined by the World Health Organization (WHO. This is based upon high-resolution global model calculations that resolve urban and industrial regions in greater detail compared to previous work. Results indicate that 69% of the global population is exposed to an annual mean anthropogenic PM2.5 concentration of >10 μg m−3 (WHO guideline and 33% to > 25 μg m−3 (EU directive. We applied an epidemiological health impact function and find that especially in large countries with extensive suburban and rural populations, air pollution-induced mortality rates have been underestimated given that previous studies largely focused on the urban environment. We calculate a global respiratory mortality of about 773 thousand/year (YLL ≈ 5.2 million/year, 186 thousand/year by lung cancer (YLL ≈ 1.7 million/year and 2.0 million/year by cardiovascular disease (YLL ≈ 14.3 million/year. The global mean per capita mortality caused by air pollution is about 0.1% yr−1. The highest premature mortality rates are found in the Southeast Asia and Western Pacific regions (about 25% and 46% of the global rate, respectively where more than a dozen of the most highly polluted megacities are located.

Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

International Nuclear Information System (INIS)

Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard; Schmid, Ernst; Abend, Michael; Becker, Karl-Friedrich; Apostolidis, Christos; Nikula, Tuomo K.; Kremmer, Elisabeth

2005-01-01

Radioimmunotherapy with α-particle-emitting nuclides, such as 213 Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213 Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213 Bi-d9MAb targeting d9-E-cadherin and 213 Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213 Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213 Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213 Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of α-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213 Bi-d9MAb compared with unspecific 213 Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213 Bi-immunoconjugates per cell exceeded 2 x 10 4 , most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213 Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. 213 Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells

Cell death triggered by alpha-emitting {sup 213}Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

Energy Technology Data Exchange (ETDEWEB)

Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Schmid, Ernst [National Research Center for Environment and Health, Institute of Radiation Biology, GSF, Neuherberg (Germany); Abend, Michael [German Armed Forces, Institute of Radiobiology, Munich (Germany); Becker, Karl-Friedrich [Technische Universitaet Muenchen, Institute of Pathology, Munich (Germany); National Research Center for Environment and Health, Institute of Pathology, GSF, Neuherberg (Germany); National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany); Apostolidis, Christos; Nikula, Tuomo K. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Kremmer, Elisabeth [National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany)

2005-03-01

Radioimmunotherapy with {alpha}-particle-emitting nuclides, such as{sup 213}Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by {sup 213}Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of {sup 213}Bi-d9MAb targeting d9-E-cadherin and {sup 213}Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as {sup 213}Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and {sup 213}Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with {sup 213}Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of {alpha}-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific {sup 213}Bi-d9MAb compared with unspecific {sup 213}Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound {sup 213}Bi-immunoconjugates per cell exceeded 2 x 10{sup 4}, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by {sup 213}Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. {sup 213}Bi-immunoconjugates seem

Suppression of the increasing level of acetylcholine-stimulated intracellular Ca2+ in guinea pig airway smooth muscle cells by mabuterol.

Science.gov (United States)

Song, Xirui; Zhao, Chao; Dai, Cailing; Ren, Yanxin; An, Nan; Wen, Huimin; Pan, L I; Cheng, Maosheng; Zhang, Yuyang

2015-11-01

The present study aimed to establish an effective method for the in vitro culture of guinea pig airway smooth muscle (ASM) cells, and also investigate the suppressive effect of mabuterol hydrochloride (Mab) on the increased level of intracellular Ca 2+ in ASM cells induced with acetylcholine (Ach). Two different methods, i.e. with or without collagenase to pretreat tracheal tissues, were applied to the manufacture of ASM cells. Cell viability was determined with the 3-(4,5-dimethylthinazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunocytochemistry and immunofluorescence were used for the identification of ASM cells. Different concentration levels (10 -3 , 10 -4 , 10 -5 , 10 -6 and 10 -7 mmol/l) of Mab were administered 5 min before Ach (10 -4 M) treatment, respectively. The Ca 2+ fluorescent probe, Fura-2/AM or Fluo-3/AM were applied to the inspection of Ca 2+ fluorescent intensity with Varioskan Flash, immunocytometry systems and an inverted system microscope, respectively. The results showed that the fresh method, in which isolated tracheal tissues were previously treated with collagenase for 20 min, was more advantageous for the preparation of guinea pig ASM cells compared to when the enzyme was not used. The time for the ASM cells to initially migrate out of the 'tissue blocks' and the culture having to be generated due to the thick cell density was significantly less. On identification with immunocytochemistry or immunofluorescent staining, >95% of the cells were ASM cells. Mab (10 -3 -10 -7 mmol/l) significantly suppressed the elevation of intracellular Ca 2+ induced by Ach in a concentration-dependent manner. The inhibitory rates of intracellular Ca 2+ by different concentrations of Mab, from low to high, were 14.93, 24.73, 40.06, 48.54 and 57.13%, respectively, when Varioskan Flash was used for determination. In conclusion, this novel method has a shorter harvesting period for ASM cells. Mab can suppress the increasing level of intracellular Ca 2

Proteins of bovine viral diarrhea virus: characterization, biotype-specific differences, and immunological properties

International Nuclear Information System (INIS)

Donis, R.O.

1987-01-01

Virus-specific polypeptides in bovine viral diarrhea-mucosal disease (BVD) virus-infected bovine cells were studied by radiolabeling. A total of 12 polypeptides with apparent Mr of 165, 135, 118, 80, 75, 62, 56-58, 48, 37, 32, 25 and 19 kilodaltons (k) were identified in infected cells. Five glycoproteins were detected in infected cells. Two abundant species had apparent Mr of 48 k and 56-58 k while the minor species had masses of 118, 75 and 65 k. When cells were radiolabeled with L-[ 35 S]-methionine in the presence of tunicamycin the 56-58 k migrated with apparent masses of 54 k and 48-50 K in PAGE. Endoglycosidase F digestion of virus-induced polypeptides caused a 4-6 K reduction in the apparent molecular mass of the 56-58 k yielding a 52 k digested product. Tunicamycin caused a drastic reduction in the yield of infectious virus indicating that the carbohydrate moieties serve a vital role in the infection cycle of BVD virus. The noncytopathic biotype BVD (NCB-BVD) virus isolates can be consistently differentiated from cytopathic biotype BVD (CB-BVD) isolates on the basis of unique polypeptide profiles they induce in the infected cell: the most abundant polypeptide in CB-BVD infected cells is the 80 kD polypeptide while NCB-BVD lack this polypeptide and induce a predominant 118 k polypeptide. A panel of 25 murine monoclonal antibodies (Mabs) against the two major glycoproteins of BVD virus was produced. Based on their viral polypeptide specificity and on their ability to neutralize viral infectivity the Mabs in the panel were divided into 3 classes: Class 1 Mabs reacted with the 56-58 k glycoprotein and neutralized the virus, Class 2 Mabs recognized the 56-58 k glycoprotein but were not neutralizing and Class 3 Mabs reacted with the 48 k glycoprotein and did not neutralize the virus. These results identify the 56-58 k as one of the envelope glycoproteins of BVD virus

TWEAK induces liver progenitor cell proliferation

Science.gov (United States)

Jakubowski, Aniela; Ambrose, Christine; Parr, Michael; Lincecum, John M.; Wang, Monica Z.; Zheng, Timothy S.; Browning, Beth; Michaelson, Jennifer S.; Baestcher, Manfred; Wang, Bruce; Bissell, D. Montgomery; Burkly, Linda C.

2005-01-01

Progenitor (“oval”) cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors. PMID:16110324

[Time-series analysis on effect of air pollution on stroke mortality in Tianjin, China].

Science.gov (United States)

Wang, De-zheng; Gu, Qing; Jiang, Guo-hong; Yang, De-yi; Zhang, Hui; Song, Gui-de; Zhang, Ying

2012-12-01

To investigate the effect of air pollution on stroke mortality in Tianjin, China, and to provide basis for stroke control and prevention. Total data of mortality surveillance were collected by Tianjin Centers for Disease Control and Prevention. Meteorological data and atmospheric pollution data were from Tianjin Meteorological Bureau and Tianjin Environmental Monitoring Center, respectively. Generalized additive Poisson regression model was used in time-series analysis on the relationship between air pollution and stroke mortality in Tianjin. Single-pollutant analysis and multi-pollutant analysis were performed after adjustment for confounding factors such as meteorological factors, long-term trend of death, "days of the week" effect and population. The crude death rates of stroke in Tianjin were from 136.67 in 2001 to 160.01/100000 in 2009, with an escalating trend (P = 0.000), while the standardized mortality ratios of stroke in Tianjin were from 138.36 to 99.14/100000, with a declining trend (P = 0.000). An increase of 10 µg/m³ in daily average concentrations of atmospheric SO₂, NO₂ and PM₁₀ led to 1.0105 (95%CI: 1.0060 ∼ 1.0153), 1.0197 (95%CI: 1.0149 ∼ 1.0246) and 1.0064 (95%CI: 1.0052 ∼ 1.0077), respectively, in relative risks of stroke mortality. SO₂ effect peaked after 1-day exposure, while NO₂ and PM₁₀ effects did within 1 day. Air pollution in Tianjin may increase the risk of stroke mortality in the population and induce acute onset of stroke. It is necessary to carry out air pollution control and allocate health resources rationally to reduce the hazard of stroke mortality.

Cancer incidence and mortality rate in children of A-bomb survivors

International Nuclear Information System (INIS)

Yoshimoto, Yasuhiko

1992-01-01

The purpose of this paper is to summarize the previous findings of carcinogenesis and mortality rate in children born to A-bomb survivors. The Radiation Effects Research Foundation has collected 72,228 children born to A-bomb survivors from May 1946 through 1984. Of their parents, 31,159 parents had been exposed to significant doses (≥0.01 Sv), with a mean genital dose of 0.435 Sv. Among a hypothetic population of 100,000 children of A-bomb survivors exposed to an mean genital dose of 0.4 SV, radiation-induced diseases were considered to occur in only 250 children or less. An earlier large-scale survey during the period 1948-1956 has revealed an evidence of significant increase in stillborn, congenital malformation, and infantile death. In the 1946-1982 survey concerning carcinogenesis in 72,216 children of A-bomb survivors, cancer was found to be detected in 92 children, with no statistically significant increase in cancer risk with increasing radiation doses in their parents. The survey on mortality rate in 67,586 children of A-bomb survivors has revealed no evidence of significant increase in mortality rate from diseases, other than cancer, and in the incidence of lethal cancer. For A-bomb survivors, genetic doubling doses were considered to be 1 Sv or more. Further, when genetic doubling doses are calculated, the contribution rate of genital cell disturbance should be considered in the incidence of spontaneously induced disease. There is no supportive evidence of genetic effects of A-bomb radiation in children of A-bomb survivors; however, genetic effects of A-bomb radiation cannot be denied completely. Continuing survey is expected to be done for children of A-bomb survivors. (N.K.)

The different clinical effects of anti-BLyS, anti-APRIL and anti-CD20 antibodies point at a critical pathogenic role of γ-herpesvirus infected B cells in the marmoset EAE model.

Science.gov (United States)

Anwar Jagessar, S; Fagrouch, Zahra; Heijmans, Nicole; Bauer, Jan; Laman, Jon D; Oh, Luke; Migone, Thi; Verschoor, Ernst J; 't Hart, Bert A

2013-06-01

The robust and rapid clinical effect of depleting anti-CD20 monoclonal antibodies (mAb) in multiple sclerosis (MS) demonstrates a critical pathogenic contribution of B cells. The clinical effect of anti-CD20 mAb has been replicated in a relevant preclinical MS model, experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys (Callithrix jacchus). By contrast, treatment with mAbs against two essential cytokines in B cell activation growth and survival, i.e. BlyS/BAFF and APRIL, was only partially effective. All three mAbs induced depletion of CD20+ B cells from the circulation, albeit with different kinetics and based on distinct mechanisms of action. In the current study we analyzed whether the different clinical effect of anti-CD20 mAb or the anti-BLyS and anti-APRIL mAbs is due to different depletion of B cells infected with the EBV of marmosets, CalHV3. Employing a novel PCR-based assay, half of the colony of group-housed marmosets was tested positive for CalHV3 DNA in secondary lymphoid organs. The same prevalence was observed in placebo-treated monkeys. In marmosets treated with anti-CD20 mAb the load of CalHV3 DNA in lymphoid organs was substantially reduced, while this was not observed in the monkeys treated with anti-BLyS or anti-APRIL mAbs. To examine the pathogenic role of virus-transformed B cells, we infused EBV-transformed B lymphoblastic cell (BLC) lines presenting the immunodominant MOG34-56 peptide. We observed in the recipients of MOG34-56 pulsed BLC, but not in their fraternal siblings infused with non-pulsed BLC, activation of anti-MOG34-56 T cells and meningeal inflammation. Collectively, the data show that among CD20+ B cells, the herpesvirus-transformed subset has a particularly important pathogenic role in the marmoset EAE model.

Longitudinal study of parasite-induced mortality of a long-lived host: the importance of exposure to non-parasitic stressors.

Science.gov (United States)

Chin, Hilary M-H; Luong, Lien T; Shostak, Allen W

2017-12-01

Hosts face mortality from parasitic and environmental stressors, but interactions of parasitism with other stressors are not well understood, particularly for long-lived hosts. We monitored survival of flour beetles (Tribolium confusum) in a longitudinal design incorporating cestode (Hymenolepis diminuta) infection, starvation and exposure to the pesticide diatomaceous earth (DE). We found that cestode cysticercoids exhibit increasing morphological damage and decreasing ability to excyst over time, but were never eliminated from the host. In the presence of even mild environmental stressors, host lifespan was reduced sufficiently that extensive degradation of cysticercoids was never realized. Median host lifespan was 200 days in the absence of stressors, and 3-197 days with parasitism, starvation and/or DE. Early survival of parasitized hosts was higher relative to controls in the presence of intermediate concentrations of DE, but reduced under all other conditions tested. Parasitism increased host mortality in the presence of other stressors at times when parasitism alone did not cause mortality, consistent with an interpretation of synergy. Environmental stressors modified the parasite numbers needed to reveal intensity-dependent host mortality, but only rarely masked intensity dependence. The longitudinal approach produced observations that would have been overlooked or misinterpreted if survival had only been monitored at a single time point.

Nutritional Interventions for Cancer-induced Cachexia

OpenAIRE

Gullett, Norleena P.; Mazurak, Vera; Hebbar, Gautam; Ziegler, Thomas R.

2011-01-01

Cancer-induced cachexia remains a significant cause of morbidity and mortality in cancer treatment. Cancer research and development continues at an aggressive pace and yet a degree of cancer-induced cachexia is experienced by up to 80% of advanced stage cancer patients. Unfortunately, there are no established treatment regimens for this condition. Weight loss and fatigue consistently appear in patient oncologic histories and progress notes. However, few oncologists fully understand the pathol...

Heat-Related Mortality in India: Excess All-Cause Mortality Associated with the 2010 Ahmedabad Heat Wave

Science.gov (United States)

Azhar, Gulrez Shah; Mavalankar, Dileep; Nori-Sarma, Amruta; Rajiva, Ajit; Dutta, Priya; Jaiswal, Anjali; Sheffield, Perry; Knowlton, Kim; Hess, Jeremy J.; Azhar, Gulrez Shah; Deol, Bhaskar; Bhaskar, Priya Shekhar; Hess, Jeremy; Jaiswal, Anjali; Khosla, Radhika; Knowlton, Kim; Mavalankar, Mavalankar; Rajiva, Ajit; Sarma, Amruta; Sheffield, Perry

2014-01-01

Introduction In the recent past, spells of extreme heat associated with appreciable mortality have been documented in developed countries, including North America and Europe. However, far fewer research reports are available from developing countries or specific cities in South Asia. In May 2010, Ahmedabad, India, faced a heat wave where the temperatures reached a high of 46.8°C with an apparent increase in mortality. The purpose of this study is to characterize the heat wave impact and assess the associated excess mortality. Methods We conducted an analysis of all-cause mortality associated with a May 2010 heat wave in Ahmedabad, Gujarat, India, to determine whether extreme heat leads to excess mortality. Counts of all-cause deaths from May 1–31, 2010 were compared with the mean of counts from temporally matched periods in May 2009 and 2011 to calculate excess mortality. Other analyses included a 7-day moving average, mortality rate ratio analysis, and relationship between daily maximum temperature and daily all-cause death counts over the entire year of 2010, using month-wise correlations. Results The May 2010 heat wave was associated with significant excess all-cause mortality. 4,462 all-cause deaths occurred, comprising an excess of 1,344 all-cause deaths, an estimated 43.1% increase when compared to the reference period (3,118 deaths). In monthly pair-wise comparisons for 2010, we found high correlations between mortality and daily maximum temperature during the locally hottest “summer” months of April (r = 0.69, pheat (May 19–25, 2010), mortality rate ratios were 1.76 [95% CI 1.67–1.83, pheat wave in Ahmedabad, Gujarat, India had a substantial effect on all-cause excess mortality, even in this city where hot temperatures prevail through much of April-June. PMID:24633076

Drought-induced mortality patterns and rapid biomass recovery in a terra firme forest in the Colombian Amazon.

Science.gov (United States)

Zuleta, Daniel; Duque, Alvaro; Cardenas, Dairon; Muller-Landau, Helene C; Davies, Stuart J

2017-10-01

Extreme climatic events affecting the Amazon region are expected to become more frequent under ongoing climate change. In this study, we assessed the responses to the 2010 drought of over 14,000 trees ≥10 cm dbh in a 25 ha lowland forest plot in the Colombian Amazon and how these responses varied among topographically defined habitats, with tree size, and with species wood density. Tree mortality was significantly higher during the 2010-2013 period immediately after the drought than in 2007-2010. The post-drought increase in mortality was stronger for trees located in valleys (+243%) than for those located on slopes (+67%) and ridges (+57%). Tree-based generalized linear mixed models showed a significant negative effect of species wood density on mortality and no effect of tree size. Despite the elevated post-drought mortality, aboveground biomass increased from 2007 to 2013 by 1.62 Mg ha -1  yr -1 (95% CI 0.80-2.43 Mg ha -1  yr -1 ). Biomass change varied among habitats, with no significant increase on the slopes (1.05, 95% CI -0.76 to 2.85 Mg ha -1  yr -1 ), a significant increase in the valleys (1.33, 95% CI 0.37-2.34 Mg ha -1  yr -1 ), and a strong increase on the ridges (2.79, 95% CI 1.20-4.21 Mg ha -1  yr -1 ). These results indicate a high carbon resilience of this forest to the 2010 drought due to habitat-associated and interspecific heterogeneity in responses including directional changes in functional composition driven by enhanced performance of drought-tolerant species that inhabit the drier ridges. © 2017 by the Ecological Society of America.

Exploring mortality among drug treatment clients: The relationship between treatment type and mortality.

Science.gov (United States)

Lloyd, Belinda; Zahnow, Renee; Barratt, Monica J; Best, David; Lubman, Dan I; Ferris, Jason

2017-11-01

Studies consistently identify substance treatment populations as more likely to die prematurely compared with age-matched general population, with mortality risk higher out-of-treatment than in-treatment. While opioid-using pharmacotherapy cohorts have been studied extensively, less evidence exists regarding effects of other treatment types, and clients in treatment for other drugs. This paper examines mortality during and following treatment across treatment modalities. A retrospective seven-year cohort was utilised to examine mortality during and in the two years following treatment among clients from Victoria, Australia, recorded on the Alcohol and Drug Information Service database by linking with National Death Index. 18,686 clients over a 12-month period were included. Crude (CMRs) and standardised mortality rates (SMRs) were analysed in terms of treatment modality, and time in or out of treatment. Higher risk of premature death was associated with residential withdrawal as the last type of treatment engagement, while mortality following counselling was significantly lower than all other treatment types in the year post-treatment. Both CMRs and SMRs were significantly higher in-treatment than post-treatment. Better understanding of factors contributing to elevated mortality risk for clients engaged in, and following treatment, is needed to ensure that treatment systems provide optimal outcomes during and after treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Temperature response surfaces for mortality risk of tree species with future drought

Energy Technology Data Exchange (ETDEWEB)

Adams, Henry D.; Barron-Gafford, Greg A.; Minor, Rebecca L.; Gardea, Alfonso A.; Bentley, Lisa Patrick; Law, Darin J.; Breshears, David D.; McDowell, Nate G.; Huxman, Travis E.

2017-11-01

Widespread, high levels of tree mortality, termed forest die-off, associated with drought and rising temperatures, are disrupting forests worldwide. Drought will likely become more frequent with climate change, but even without more frequent drought, higher temperatures can exacerbate tree water stress. The temperature sensitivity of drought-induced mortality of tree species has been evaluated experimentally for only single-step changes in temperature (ambient compared to ambient + increase) rather than as a response surface (multiple levels of temperature increase), which constrains our ability to relate changes in the driver with the biological response. Here we show that time-to-mortality during drought for seedlings of two western United States tree species, Pinus edulis (Engelm.) and Pinus ponderosa (Douglas ex C. Lawson), declined in continuous proportion with increasing temperature spanning a 7.7 °C increase. Although P. edulis outlived P. ponderosa at all temperatures, both species had similar relative declines in time-to-mortality as temperature increased (5.2% per °C for P. edulis; 5.8% per °C for P. ponderosa). When combined with the non-linear frequency distribution of drought duration—many more short droughts than long droughts—these findings point to a progressive increase in mortality events with global change due to warming alone and independent of additional changes in future drought frequency distributions. As such, dire future forest recruitment patterns are projected assuming the calculated 7-9 seedling mortality events per species by 2100 under business-as-usual warming occurs, congruent with additional vulnerability predicted for adult trees from stressors like pathogens and pests. Our progressive projection for increased mortality events was driven primarily by the non-linear shape of the drought duration frequency distribution, a common climate feature of drought-affected regions. These

Temperature response surfaces for mortality risk of tree species with future drought

Science.gov (United States)

Adams, Henry D.; Barron-Gafford, Greg A.; Minor, Rebecca L.; Gardea, Alfonso A.; Bentley, Lisa Patrick; Law, Darin J.; Breshears, David D.; McDowell, Nate G.; Huxman, Travis E.

2017-11-01

Widespread, high levels of tree mortality, termed forest die-off, associated with drought and rising temperatures, are disrupting forests worldwide. Drought will likely become more frequent with climate change, but even without more frequent drought, higher temperatures can exacerbate tree water stress. The temperature sensitivity of drought-induced mortality of tree species has been evaluated experimentally for only single-step changes in temperature (ambient compared to ambient + increase) rather than as a response surface (multiple levels of temperature increase), which constrains our ability to relate changes in the driver with the biological response. Here we show that time-to-mortality during drought for seedlings of two western United States tree species, Pinus edulis (Engelm.) and Pinus ponderosa (Douglas ex C. Lawson), declined in continuous proportion with increasing temperature spanning a 7.7 °C increase. Although P. edulis outlived P. ponderosa at all temperatures, both species had similar relative declines in time-to-mortality as temperature increased (5.2% per °C for P. edulis; 5.8% per °C for P. ponderosa). When combined with the non-linear frequency distribution of drought duration—many more short droughts than long droughts—these findings point to a progressive increase in mortality events with global change due to warming alone and independent of additional changes in future drought frequency distributions. As such, dire future forest recruitment patterns are projected assuming the calculated 7-9 seedling mortality events per species by 2100 under business-as-usual warming occur, congruent with additional vulnerability predicted for adult trees from stressors like pathogens and pests. Our progressive projection for increased mortality events was driven primarily by the non-linear shape of the drought duration frequency distribution, a common climate feature of drought-affected regions. These results illustrate profound benefits for

Mortality risk factor analysis in colonic perforation: would retroperitoneal contamination increase mortality in colonic perforation?

Science.gov (United States)

Yoo, Ri Na; Kye, Bong-Hyeon; Kim, Gun; Kim, Hyung Jin; Cho, Hyeon-Min

2017-10-01

Colonic perforation is a lethal condition presenting high morbidity and mortality in spite of urgent surgical treatment. This study investigated the surgical outcome of patients with colonic perforation associated with retroperitoneal contamination. Retrospective analysis was performed for 30 patients diagnosed with colonic perforation caused by either inflammation or ischemia who underwent urgent surgical treatment in our facility from January 2005 to December 2014. Patient characteristics were analyzed to find risk factors correlated with increased postoperative mortality. Using the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) audit system, the mortality and morbidity rates were estimated to verify the surgical outcomes. Patients with retroperitoneal contamination, defined by the presence of retroperitoneal air in the preoperative abdominopelvic CT, were compared to those without retroperitoneal contamination. Eight out of 30 patients (26.7%) with colonic perforation had died after urgent surgical treatment. Factors associated with mortality included age, American Society of Anesthesiologists (ASA) physical status classification, and the ischemic cause of colonic perforation. Three out of 6 patients (50%) who presented retroperitoneal contamination were deceased. Although the patients with retroperitoneal contamination did not show significant increase in the mortality rate, they showed significantly higher ASA physical status classification than those without retroperitoneal contamination. The mortality rate predicted from Portsmouth POSSUM was higher in the patients with retroperitoneal contamination. Patients presenting colonic perforation along with retroperitoneal contamination demonstrated severe comorbidity. However, retroperitoneal contamination was not found to be correlated with the mortality rate.

Mortality of in-utero children exposed to the A-bomb and of offspring of A-bomb survivors

International Nuclear Information System (INIS)

Kato, H.

1978-01-01

A cohort-type follow-up study has been carried out by the Radiation Effects Research Foundation on the mortality of children exposed to A-bomb radiation while in utero. The mortality increased with tissue dose during the first year of life and did not increase during the following nine years, but an increase with dose was again suggested during 10-32 years of age. A detailed analysis of infant mortality revealed that the dose-associated excess in mortality among those under one year of age, especially within one month after birth, was attributable partly to the mechanical injury of the mother, but this does not provide the whole explanation. There was no increase of mortality from cancer including leukaemia with dose. As the number of cancer deaths is at present only five, further careful follow-up on this cohort is necessary to determine the state of radiation-induced cancer among this cohort. The continuing study on mortality rates among children born to A-bomb survivors has been updated to 1976. No clearly significant effect of parental exposure on survival of the offspring (average age 24 years) could be demonstrated either by a contingency chi 2 -type of analysis or regression analysis. (author)

Age structure and mortality of walleyes in Kansas reservoirs: Use of mortality caps to establish realistic management objectives

Science.gov (United States)

Quist, M.C.; Stephen, J.L.; Guy, C.S.; Schultz, R.D.

2004-01-01

Age structure, total annual mortality, and mortality caps (maximum mortality thresholds established by managers) were investigated for walleye Sander vitreus (formerly Stizostedion vitreum) populations sampled from eight Kansas reservoirs during 1991-1999. We assessed age structure by examining the relative frequency of different ages in the population; total annual mortality of age-2 and older walleyes was estimated by use of a weighted catch curve. To evaluate the utility of mortality caps, we modeled threshold values of mortality by varying growth rates and management objectives. Estimated mortality thresholds were then compared with observed growth and mortality rates. The maximum age of walleyes varied from 5 to 11 years across reservoirs. Age structure was dominated (???72%) by walleyes age 3 and younger in all reservoirs, corresponding to ages that were not yet vulnerable to harvest. Total annual mortality rates varied from 40.7% to 59.5% across reservoirs and averaged 51.1% overall (SE = 2.3). Analysis of mortality caps indicated that a management objective of 500 mm for the mean length of walleyes harvested by anglers was realistic for all reservoirs with a 457-mm minimum length limit but not for those with a 381-mm minimum length limit. For a 500-mm mean length objective to be realized for reservoirs with a 381-mm length limit, managers must either reduce mortality rates (e.g., through restrictive harvest regulations) or increase growth of walleyes. When the assumed objective was to maintain the mean length of harvested walleyes at current levels, the observed annual mortality rates were below the mortality cap for all reservoirs except one. Mortality caps also provided insight on management objectives expressed in terms of proportional stock density (PSD). Results indicated that a PSD objective of 20-40 was realistic for most reservoirs. This study provides important walleye mortality information that can be used for monitoring or for inclusion into

Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication.

Science.gov (United States)

Sevigny, Leila M; Booth, Brian J; Rowley, Kirk J; Leav, Brett A; Cheslock, Peter S; Garrity, Kerry A; Sloan, Susan E; Thomas, William; Babcock, Gregory J; Wang, Yang

2013-11-01

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.

IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia.

Science.gov (United States)

Aoyagi, T; Newstead, M W; Zeng, X; Kunkel, S L; Kaku, M; Standiford, T J

2017-07-01

Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.

MortalityPredictors.org: a manually-curated database of published biomarkers of human all-cause mortality.

Science.gov (United States)

Peto, Maximus V; De la Guardia, Carlos; Winslow, Ksenia; Ho, Andrew; Fortney, Kristen; Morgen, Eric

2017-08-31

Biomarkers of all-cause mortality are of tremendous clinical and research interest. Because of the long potential duration of prospective human lifespan studies, such biomarkers can play a key role in quantifying human aging and quickly evaluating any potential therapies. Decades of research into mortality biomarkers have resulted in numerous associations documented across hundreds of publications. Here, we present MortalityPredictors.org , a manually-curated, publicly accessible database, housing published, statistically-significant relationships between biomarkers and all-cause mortality in population-based or generally healthy samples. To gather the information for this database, we searched PubMed for appropriate research papers and then manually curated relevant data from each paper. We manually curated 1,576 biomarker associations, involving 471 distinct biomarkers. Biomarkers ranged in type from hematologic (red blood cell distribution width) to molecular (DNA methylation changes) to physical (grip strength). Via the web interface, the resulting data can be easily browsed, searched, and downloaded for further analysis. MortalityPredictors.org provides comprehensive results on published biomarkers of human all-cause mortality that can be used to compare biomarkers, facilitate meta-analysis, assist with the experimental design of aging studies, and serve as a central resource for analysis. We hope that it will facilitate future research into human mortality and aging.

Mortality after shoulder arthroplasty

DEFF Research Database (Denmark)

Amundsen, Alexander; Rasmussen, Jeppe Vejlgaard; Olsen, Bo Sanderhoff

2016-01-01

BACKGROUND: The primary aim was to quantify the 30-day, 90-day, and 1-year mortality rates after primary shoulder replacement. The secondary aims were to assess the association between mortality and diagnoses and to compare the mortality rate with that of the general population. METHODS: The study...... included 5853 primary operations reported to the Danish Shoulder Arthroplasty Registry between 2006 and 2012. Information about deaths was obtained from the Danish Cause of Death Register and the Danish Civil Registration System. Age- and sex-adjusted control groups were retrieved from Statistics Denmark...

The role of heat shock protein 70 in mediating age-dependent mortality in sepsis.

Science.gov (United States)

McConnell, Kevin W; Fox, Amy C; Clark, Andrew T; Chang, Nai-Yuan Nicholas; Dominguez, Jessica A; Farris, Alton B; Buchman, Timothy G; Hunt, Clayton R; Coopersmith, Craig M

2011-03-15

Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6- to 12-wk-old) and aged (16- to 17-mo-old) HSP70(-/-) and wild-type (WT) mice to determine whether HSP70 modulated outcome in an age-dependent fashion. Young HSP70(-/-) and WT mice subjected to cecal ligation and puncture, Pseudomonas aeruginosa pneumonia, or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70(-/-) mice than aged WT mice subjected to cecal ligation and puncture (p = 0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared with WT mice, aged septic HSP70(-/-) mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70(-/-) mice had increased systemic levels of TNF-α, IL-6, IL-10, and IL-1β compared with WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged, but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation.

Social Capital and Human Mortality: Explaining the Rural Paradox with County-Level Mortality Data

Science.gov (United States)

Jensen, Leif; Haran, Murali

2014-01-01

The “rural paradox” refers to standardized mortality rates in rural areas that are unexpectedly low in view of well-known economic and infrastructural disadvantages there. We explore this paradox by incorporating social capital, a promising explanatory factor that has seldom been incorporated into residential mortality research. We do so while being attentive to spatial dependence, a statistical problem often ignored in mortality research. Analyzing data for counties in the contiguous United States, we find that: (1) the rural paradox is confirmed with both metro/non-metro and rural-urban continuum codes, (2) social capital significantly reduces the impacts of residence on mortality after controlling for race/ethnicity and socioeconomic covariates, (3) this attenuation is greater when a spatial perspective is imposed on the analysis, (4) social capital is negatively associated with mortality at the county level, and (5) spatial dependence is strongly in evidence. A spatial approach is necessary in county-level analyses such as ours to yield unbiased estimates and optimal model fit. PMID:25392565

Human mortality improvement in evolutionary context

DEFF Research Database (Denmark)

Burger, Oskar; Baudisch, Annette; Vaupel, James W

2012-01-01

Life expectancy is increasing in most countries and has exceeded 80 in several, as low-mortality nations continue to make progress in averting deaths. The health and economic implications of mortality reduction have been given substantial attention, but the observed malleability of human mortality...... about 4 of the roughly 8,000 human generations that have ever lived. Moreover, mortality improvement in humans is on par with or greater than the reductions in mortality in other species achieved by laboratory selection experiments and endocrine pathway mutations. This observed plasticity in age...

Relationships between treated hypertension and subsequent mortality in an insured population.

Science.gov (United States)

Ivanovic, Brian; Cumming, Marianne E; Pinkham, C Allen

2004-01-01

To investigate if a mortality differential exists between insurance policyholders with treated hypertension and policyholders who are not under such treatment, where both groups are noted to have the same blood pressure at the time of policy issue. Hypertension is a known mortality risk factor in the insured and general population. Treatment for hypertension is very common in the insured population, especially as age increases. At the time of insurance application, a subset of individuals with treated hypertension will have blood pressures that are effectively controlled and are in the normal range. These individuals often meet established preferred underwriting criteria for blood pressure. In some life insurance companies, they may be offered insurance at the same rates as individuals who are not hypertensive with the same blood pressure. Such companies make the assumption that the pharmacologically induced normotensive state confers no excess risk relative to the natural normotensive state. Given the potential pricing implications of this decision, we undertook an investigation to test this hypothesis. We studied internal data on direct and reinsurance business between 1975 and 2001 followed through anniversaries in 2002 or prior termination with an average duration of 5.2 years per policy. Actual-to-expected analyses and Cox proportional hazards models were used to assess if a mortality differential existed between policyholders coded for hypertension and policyholders with the same blood pressure that were not coded as hypertensive. Eight thousand six hundred forty-seven deaths were observed during follow-up in the standard or preferred policy cohort. Within the same blood pressure category, mortality was higher in policyholders identified as treated hypertensives compared with those in the subset of individuals who were not coded for hypertension. This finding was present in males and females and persisted across age groups in almost all age

Adult mortality in preindustrial Quebec

Directory of Open Access Journals (Sweden)

Claudine Lacroix - - - Bertrand Desjardins

2012-01-01

Full Text Available This paper presents the main results of a detailed study on adult mortality in French Canadians born before 1750 and having married inthe colony of New France. Using data from parish registers, mortality is studied using abridged life tables, with staggered entries according to age at first marriage. Survival tables and log-Rank tests are used to support the results. Three features were selected for the study of differential mortality: gender, type of residence area (urban or rural, and cohort. The mortality of French Canadians is compared to that of their French contemporaries.

Telomere Length and Mortality

DEFF Research Database (Denmark)

Kimura, Masayuki; Hjelmborg, Jacob V B; Gardner, Jeffrey P

2008-01-01

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality...

Geographic distribution of dementia mortality: elevated mortality rates for black and white Americans by place of birth.

Science.gov (United States)

Glymour, M Maria; Kosheleva, Anna; Wadley, Virginia G; Weiss, Christopher; Manly, Jennifer J

2011-01-01

We hypothesized that patterns of elevated stroke mortality among those born in the United States Stroke Belt (SB) states also prevailed for mortality related to all-cause dementia or Alzheimer Disease. Cause-specific mortality (contributing cause of death, including underlying cause cases) rates in 2000 for United States-born African Americans and whites aged 65 to 89 years were calculated by linking national mortality records with population data based on race, sex, age, and birth state or state of residence in 2000. Birth in a SB state (NC, SC, GA, TN, AR, MS, or AL) was cross-classified against SB residence at the 2000 Census. Compared with those who were not born in the SB, odds of all-cause dementia mortality were significantly elevated by 29% for African Americans and 19% for whites born in the SB. These patterns prevailed among individuals who no longer lived in the SB at death. Patterns were similar for Alzheimer Disease-related mortality. Some non-SB states were also associated with significant elevations in dementia-related mortality. Dementia mortality rates follow geographic patterns similar to stroke mortality, with elevated rates among those born in the SB. This suggests important roles for geographically patterned childhood exposures in establishing cognitive reserve.

Intrinsic and extrinsic mortality reunited

DEFF Research Database (Denmark)

Koopman, Jacob J E; Wensink, Maarten J; Rozing, Maarten P

2015-01-01

Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However......, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well...... as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic...

The Rural Inpatient Mortality Study: Does Urban-Rural County Classification Predict Hospital Mortality in California?

Science.gov (United States)

Linnen, Daniel T; Kornak, John; Stephens, Caroline

2018-03-28

Evidence suggests an association between rurality and decreased life expectancy. To determine whether rural hospitals have higher hospital mortality, given that very sick patients may be transferred to regional hospitals. In this ecologic study, we combined Medicare hospital mortality ratings (N = 1267) with US census data, critical access hospital classification, and National Center for Health Statistics urban-rural county classifications. Ratings included mortality for coronary artery bypass grafting, stroke, chronic obstructive pulmonary disease, heart attack, heart failure, and pneumonia across 277 California hospitals between July 2011 and June 2014. We used generalized estimating equations to evaluate the association of urban-rural county classifications on mortality ratings. Unfavorable Medicare hospital mortality rating "worse than the national rate" compared with "better" or "same." Compared with large central "metro" (metropolitan) counties, hospitals in medium-sized metro counties had 6.4 times the odds of rating "worse than the national rate" for hospital mortality (95% confidence interval = 2.8-14.8, p centers may contribute to these results, a potential factor that future research should examine.

Quantitative assessment of antibody internalization with novel monoclonal antibodies against Alexa fluorophores.

Science.gov (United States)

Liao-Chan, Sindy; Daine-Matsuoka, Barbara; Heald, Nathan; Wong, Tiffany; Lin, Tracey; Cai, Allen G; Lai, Michelle; D'Alessio, Joseph A; Theunissen, Jan-Willem

2015-01-01

Antibodies against cell surface antigens may be internalized through their specific interactions with these proteins and in some cases may induce or perturb antigen internalization. The anti-cancer efficacy of antibody-drug conjugates is thought to rely on their uptake by cancer cells expressing the surface antigen. Numerous techniques, including microscopy and flow cytometry, have been used to identify antibodies with desired cellular uptake rates. To enable quantitative measurements of internalization of labeled antibodies, an assay based on internalized and quenched fluorescence was developed. For this approach, we generated novel anti-Alexa Fluor monoclonal antibodies (mAbs) that effectively and specifically quench cell surface-bound Alexa Fluor 488 or Alexa Fluor 594 fluorescence. Utilizing Alexa Fluor-labeled mAbs against the EphA2 receptor tyrosine kinase, we showed that the anti-Alexa Fluor reagents could be used to monitor internalization quantitatively over time. The anti-Alexa Fluor mAbs were also validated in a proof of concept dual-label internalization assay with simultaneous exposure of cells to two different mAbs. Importantly, the unique anti-Alexa Fluor mAbs described here may also enable other single- and dual-label experiments, including label detection and signal enhancement in macromolecules, trafficking of proteins and microorganisms, and cell migration and morphology.

Quantitative assessment of antibody internalization with novel monoclonal antibodies against Alexa fluorophores.

Directory of Open Access Journals (Sweden)

Sindy Liao-Chan

Full Text Available Antibodies against cell surface antigens may be internalized through their specific interactions with these proteins and in some cases may induce or perturb antigen internalization. The anti-cancer efficacy of antibody-drug conjugates is thought to rely on their uptake by cancer cells expressing the surface antigen. Numerous techniques, including microscopy and flow cytometry, have been used to identify antibodies with desired cellular uptake rates. To enable quantitative measurements of internalization of labeled antibodies, an assay based on internalized and quenched fluorescence was developed. For this approach, we generated novel anti-Alexa Fluor monoclonal antibodies (mAbs that effectively and specifically quench cell surface-bound Alexa Fluor 488 or Alexa Fluor 594 fluorescence. Utilizing Alexa Fluor-labeled mAbs against the EphA2 receptor tyrosine kinase, we showed that the anti-Alexa Fluor reagents could be used to monitor internalization quantitatively over time. The anti-Alexa Fluor mAbs were also validated in a proof of concept dual-label internalization assay with simultaneous exposure of cells to two different mAbs. Importantly, the unique anti-Alexa Fluor mAbs described here may also enable other single- and dual-label experiments, including label detection and signal enhancement in macromolecules, trafficking of proteins and microorganisms, and cell migration and morphology.