Clinical and Dosimetric Predictors of Late Rectal Syndrome After 3D-CRT for Localized Prostate Cancer: Preliminary Results of a Multicenter Prospective Study

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

Fiorino, Claudio; Fellin, Gianni; Rancati, Tiziana

2008-03-15

Purpose: To assess the predictors of late rectal toxicity in a prospectively investigated group of patients treated at 70-80 Gy for prostate cancer (1.8-2 Gy fractions) with three-dimensional conformal radiotherapy. Methods and Materials: A total of 1,132 patients were entered into the study between 2002 and 2004. Three types of rectal toxicity, evaluated by a self-administered questionnaire, mainly based on the subjective objective management, analytic late effects of normal tissue system, were considered: stool frequency/tenesmus/pain, fecal incontinence, and bleeding. The data from 506 patients with a follow-up of 24 months were analyzed. The correlation between a number of clinical andmore » dosimetric parameters and Grade 2 or greater toxicity was investigated by univariate and multivariate (MVA) logistic analyses. Results: Of the 1,132 patients, 21, 15, and 30 developed stool frequency/tenesmus/pain, fecal incontinence, and bleeding, respectively. Stool frequency/tenesmus/pain correlated with previous abdominal/pelvic surgery (MVA, p = 0.05, odds ratio [OR], 3.3). With regard to incontinence, MVA showed the volume receiving {>=}40 Gy (V{sub 40}) (p = 0.035, OR, 1.037) and surgery (p = 0.02, OR, 4.4) to be the strongest predictors. V{sub 40} to V{sub 70} were highly predictive of bleeding; V{sub 70} showed the strongest impact on MVA (p = 0.03), together with surgery (p = 0.06, OR, 2.5), which was also the main predictor of Grade 3 bleeding (p = 0.02, OR, 4.2). Conclusions: The predictive value of the dose-volume histogram was confirmed for bleeding, consistent with previously suggested constraints (V{sub 50} <55%, V{sub 60} <40%, V{sub 70} <25%, and V{sub 75} <5%). A dose-volume histogram constraint for incontinence can be suggested (V{sub 40} <65-70%). Previous abdominal/pelvic surgery correlated with all toxicity types; thus, a modified constraint for bleeding (V{sub 70} <15%) can be suggested for patients with a history of abdominal/pelvis surgery, although further validation on a larger population with longer follow-up is needed.« less

Increased population density of neurosurgeons associated with decreased risk of death from motor vehicle accidents in the United States.

PubMed

Desai, Atman; Bekelis, Kimon; Zhao, Wenyan; Ball, Perry A

2012-09-01

Motor vehicle accidents (MVAs) are a leading cause of death and disability in young people. Given that a major cause of death from MVAs is traumatic brain injury, and neurosurgeons hold special expertise in this area relative to other members of a trauma team, the authors hypothesized that neurosurgeon population density would be related to reduced mortality from MVAs across US counties. The Area Resource File (2009-2010), a national health resource information database, was retrospectively analyzed. The primary outcome variable was the 3-year (2004-2006) average in MVA deaths per million population for each county. The primary independent variable was the density of neurosurgeons per million population in the year 2006. Multiple regression analysis was performed, adjusting for population density of general practitioners, urbanicity of the county, and socioeconomic status of the county. The median number of annual MVA deaths per million population, in the 3141 counties analyzed, was 226 (interquartile range [IQR] 151-323). The median number of neurosurgeons per million population was 0 (IQR 0-0), while the median number of general practitioners per million population was 274 (IQR 175-410). Using an unadjusted analysis, each increase of 1 neurosurgeon per million population was associated with 1.90 fewer MVA deaths per million population (p < 0.001). On multivariate adjusted analysis, each increase of 1 neurosurgeon per million population was associated with 1.01 fewer MVA deaths per million population (p < 0.001), with a respective decrease in MVA deaths of 0.03 per million population for an increase in 1 general practitioner (p = 0.007). Rural location, persistent poverty, and low educational level were all associated with significant increases in the rate of MVA deaths. A higher population density of neurosurgeons is associated with a significant reduction in deaths from MVAs, a major cause of death nationally. This suggests that the availability of local neurosurgeons is an important factor in the overall likelihood of survival from an MVA, and therefore indicates the importance of promoting neurosurgical education and practice throughout the country.

Detectable end of radiation prostate specific antigen assists in identifying men with unfavorable intermediate-risk prostate cancer at high risk of distant recurrence and cancer-specific mortality.

PubMed

Hayman, Jonathan; Phillips, Ryan; Chen, Di; Perin, Jamie; Narang, Amol K; Trieu, Janson; Radwan, Noura; Greco, Stephen; Deville, Curtiland; McNutt, Todd; Song, Daniel Y; DeWeese, Theodore L; Tran, Phuoc T

2018-06-01

Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS (P = 0.008 and P = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS (P = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR-PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS (P = 0.021) and PCSS (P = 0.033), while RT dose also predicted PCSS (P = 0.013). EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men. © 2018 Wiley Periodicals, Inc.

The application of near infrared (NIR) spectroscopy to inorganic preservative-treated wood

Treesearch

Chi-Leung So; Stan T. Lebow; Leslie H. Groom; Timothy G. Rials

2004-01-01

There is a growing need to find a rapid, inexpensive, and reliable method to distinguish between treated and untreated waste wood. This paper evaluates the ability of near infrared (NIR) spectroscopy with multivariate analysis (MVA) to distinguish preservative types and retentions. It is demonstrated that principal component analysis (PCA) can differentiate lumber...

Three-dimensional transesophageal echocardiography for determination of the mitral valve area after mitral valve repair surgery for mitral stenosis.

PubMed

Kang, Woon S; Ko, Sung M; Lee, Younsuk; Oh, Chung S; Kwon, Mi Y; Muhammad, Hasmizy; Kim, Seong H; Kim, Tae Y

2016-08-01

Pressure half-time (PHT) method is usually unreliable for accurate determination of mitral valve area (MVA) immediately after surgical intervention of mitral stenosis (MS). The planimetry method using three-dimensional (3D) transesophageal echocardiography (3D-planimetery method) could enhance accurate determination of the intraoperative MVA. Authors investigated the efficacy of 3D-planimetry method in determining MVA immediately after mitral valve repair procedure (MVRep) for severe mitral stenosis (MS). In severe MS patients undergoing elective MVRep (N.=41), intraoperative MVAs were determined by using PHT-method and 3D-planimetry method before and immediately after cardiopulmonary bypass (pre- and post-MVAPHT, and -MVA3D-planimetry). MVAs were also determined by using multi-detector computed tomographic scan (MDCT) before MVRep and within 7 days after MVRep (pre- and post-MVACT). MVAs determined by using three different methods were analysed. Mitral inflow pressure gradient (median [25th-75th percentile]) was significantly reduced after MVRep (3.0 [2.0-4.0] vs. 7.0 [6.0-9.0] mmHg; P<0.001). Pre-MVAPHT, pre-MVA3D-planimetry and preop-MVACT (mean [95% confidence interval]) did not differ significantly (1.08 [1.00-1.05], 1.08 [0.98-1.08], and 1.14 [1.07-1.22] cm2, respectively), but post-MVA3D-planimetry and post-MVACT (2.22 [2.07-2.36] and 2.31 [2.07-2.36] cm2, respectively) were significantly larger than post-MVAPHT (1.98 [1.83-2.13] cm2; P=0.007 and P<0.001, respectively). The correlation coefficient between post-MVA3D-planimetry and post-MVACT (0.59, P<0.01) was greater than that between post-MVAPHT and post-MVACT (0.39, P=0.01). These results support the clinical efficacy of 3D-planimetry for accurate evaluation of the MVA immediately after MVRep for severe MS, as a valuable alternative to PHT-method which usually underestimates MVA during this period.

Use of near infared spectroscopy to measure the chemical and mechanical properties of solid wood

Treesearch

Stephen S. Kelley; Timothy G. Rials; Rebecca Snell; Leslie H. Groom; Amie Sluiter

2004-01-01

Near infrared (NIR) spectroscopy (500 nm-2400 nm), coupled with multivariate analytic (MVA) statistical techniques, have been used to predict the chemical and mechanical properties of solid loblolly pine wood. The samples were selected from different radial locations and heights of three loblolly pine trees grown in Arkansas. The chemical composition and mechanical...

Use of near infrared spectroscopy to measure the chemical and mechanical properties of solid wood

Treesearch

Stephen S. Kelley; Timothy G. Rials; Rebecca Snell; Leslie H. Groom; Amie Sluiter

2004-01-01

Near infrared (NIR) spectroscopy (500 nm-2400 nm), coupled with multivariate analytic (MVA) statistical techniques, have been used to predict the chemical and mechanical properties of solid loblolly pine wood. The samples were selected from different radial locations and heights of three loblolly pine trees grown in Arkansas. The chemical composition and mechanical...

Vergleich von rekombinanten Vaccinia- und DNA-Vektoren zur Tumorimmuntherapie im C57BL/6-Mausmodell

NASA Astrophysics Data System (ADS)

Johnen, Heiko

2002-10-01

In der vorliegenden Arbeit wurden Tumorimpfstoffe auf der Basis des Plasmid-Vektors pCI, modified vaccinia virus Ankara (MVA) und MVA-infizierten dendritischen Zellen entwickelt und durch Sequenzierung, Western blotting und durchflußzytometrische Analyse überprüft. Die in vivo Wirksamkeit der Vakzinen wurde in verschiedenen Tumormodellen in C57BL/6 Mäusen verglichen. Die auf dem eukaryotischen Expressionsvektor pCI basierende DNA-Vakzinierung induzierte einen sehr wirksamen, antigenspezifischen und langfristigen Schutz vor Muzin, CEA oder beta-Galactosidase exprimierenden Tumoren. Eine MVA-Vakzinierung bietet in den in dieser Arbeit durchgeführten Tumormodellen keinen signifikanten Schutz vor Muzin oder beta-Galactosidase exprimierenden Tumoren. Sowohl humane, als auch murine in vitro generierte dendritische Zellen lassen sich mit MVA – im Vergleich zu anderen viralen Vektoren – sehr gut infizieren. Die Expressionsrate der eingefügten Gene ist aber gering im Vergleich zur Expression in permissiven Wirtszellen des Virus (embryonale Hühnerfibroblasten). Es konnte gezeigt werden, daß eine MVA-Infektion dendritischer Zellen ähnliche Auswirkungen auf den Reifezustand humaner und muriner dendritischer Zellen hat, wie eine Infektion mit replikationskompetenten Vakzinia-Stämmen, und außerdem die Hochregulation von CD40 während der terminalen Reifung von murinen dendritischen Zellen inhibiert wird. Die während der langfristigen in vitro Kultur auf CEF-Zellen entstandenen Deletionen im MVA Genom führten zu einer starken Attenuierung und dem Verlust einiger Gene, die immunmodulatorische Proteine kodieren, jedoch nicht zu einer Verminderung des zytopathischen Effekts in dendritischen Zellen. Die geringe Expressionsrate und die beobachtete Inhibition der Expression kostimulatorischer Moleküle auf dendritischen Zellen kann für eine wenig effektive Induktion einer Immunantwort in MVA vakzinierten Tieren durch cross priming oder die direkte Infektion antigenpräsentierender Zellen verantwortlich sein. Durch die Modifikation einer Methode zur intrazellulären IFN-gamma Färbung konnten in vakzinierten Mäusen tumorantigenspezifische CTL sensitiv und quantitativ detektiert werden. Die so bestimmte CTL-Frequenz, nicht jedoch die humorale Antwort, korrelierte mit der in vivo Wirksamkeit der verschiedenen Vakzinen: DNA vakzinierte Tiere entwickeln starke tumorantigenspezifische CTL-Antworten, wohingegen in MVA-vakzinierten Tieren überwiegend gegen virale Epitope gerichtete CD4 und CD8-T-Zellen detektiert wurden. Die Wirksamkeit der pCI-DNA-Vakzine spricht für die Weiterentwicklung in weiteren präklinischen Mausmodellen, beispielsweise unter Verwendung von MUC1 oder HLA-A2 transgenen Mäusen. Die Methoden zur Detektion Tumorantigen-spezifischer CTL in 96-Loch-Mikrotiterplatten können dabei zur systematischen Suche nach im Menschen immundominanten T-Zell-Epitopen im Muzin-Molekül genutzt werden. Der durchgeführte Vergleich der auf den Vektoren pCI und MVA basierenden Vakzinen und die Analyse neuerer Publikationen führen zu dem Ergebniss, daß vor allem DNA-Vakzinen in Zukunft eine wichtige Rolle bei der Entwicklung von aktiven Tumorimpfstoffen spielen werden. Rekombinante MVA-Viren, eventuell in Kombination mit DNA- oder anderen Vektoren, haben sich dagegen in zahlreichen Studien als wirksame Impfstoffe zur Kontrolle von durch Pathogene hervorgerufenen Infektionserkrankungen erwiesen. In this study, tumor vaccines based on the plasmid pCI, the attenuated vaccinia virus strain modified vaccinia virus Ankara (MVA) and MVA-infected dendritic cells were constructed and characterized by sequencing, Western blot and flow cytometric analysis. The efficiency to induce tumor immunity in vivo was compared in several C57BL/6 mouse tumor models. Naked DNA Vaccination based on the eukaryotic expression vector pCI did induce very effective, antigen-specific and long-term protection against tumor cell lines expressing mucin, CEA or beta-Gal whereas MVA vaccination did not elicit protective immunity against Mucin or beta-Gal expressing tumors. MVA does infect human or murine in vitro generated dendritic cells very efficiently compared to other viral vectors, however expression levels of the inserted antigens in dendritic cells are significantly lower than in permissive host cells (chicken embryo fibroblasts). It could be shown that the effect of MVA infection on the maturation status of dendritic cells is similar to the effects described for dendritic cells infected with replication competent vaccinia strains. In addition it was shown that the upregulation of the important costimulatory molecule CD40 through LPS stimulation is strongly inhibited in MVA infected cells. During passage in tissue culture, MVA has accumulated a number of large deletions, including a number of immunomodulatory molecules and resulting in a strong attenuation. However the strong cytopathic effect on dendritic cells is maintained. The low level of expression and the effect on dendritic cell maturation may be responsible for the failure of MVA to induce tumor immunity through either cross presentation or direct infection of antigen presenting cells. To detect and quantify tumor-antigen-specific CTL a method based on intracellular IFN-gamma staining was modified and it could be shown that the cellular – but not the humoral – response does correlate with in vivo protection: DNA but not MVA vaccines do induce high levels of tumorantigen-specific CTL whereas MVA-vaccines do induce strong and long lasting CD4 and CD8-T-cell responses against vaccinia antigens. The excellent protection induced by pCI-DNA-vaccination in different tumor models does encourage us to further investigate the elicitation of tumor immunity in MUC1 or HLA-A2 transgenic mice. In mice transgenic for human MHC-I, the IFN-gamma staining protocol could be used to systematically screen for mucin T-cell epitopes that are relevant in humans.

Modified Vaccinia Virus Ankara Vector Induces Specific Cellular and Humoral Responses in the Female Reproductive Tract, the Main HIV Portal of Entry.

PubMed

Marlin, Romain; Nugeyre, Marie-Thérèse; Tchitchek, Nicolas; Parenti, Matteo; Hocini, Hakim; Benjelloun, Fahd; Cannou, Claude; Dereuddre-Bosquet, Nathalie; Levy, Yves; Barré-Sinoussi, Françoise; Scarlatti, Gabriella; Le Grand, Roger; Menu, Elisabeth

2017-09-01

The female reproductive tract (FRT) is one of the major mucosal invasion sites for HIV-1. This site has been neglected in previous HIV-1 vaccine studies. Immune responses in the FRT after systemic vaccination remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized specific immune responses in all compartments of the FRT of nonhuman primates after systemic vaccination. Memory T cells were preferentially found in the lower tract (vagina and cervix), whereas APCs and innate lymphoid cells were mainly located in the upper tract (uterus and fallopian tubes). This compartmentalization of immune cells in the FRT was supported by transcriptomic analyses and a correlation network. Polyfunctional MVA-specific CD8 + T cells were detected in the blood, lymph nodes, vagina, cervix, uterus, and fallopian tubes. Anti-MVA IgG and IgA were detected in cervicovaginal fluid after a second vaccine dose. Thus, systemic vaccination with an MVA vector elicits cellular and Ab responses in the FRT. Copyright © 2017 by The American Association of Immunologists, Inc.

HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine.

PubMed

Shen, Xiaoying; Basu, Rahul; Sawant, Sheetal; Beaumont, David; Kwa, Sue Fen; LaBranche, Celia; Seaton, Kelly E; Yates, Nicole L; Montefiori, David C; Ferrari, Guido; Wyatt, Linda S; Moss, Bernard; Alam, S Munir; Haynes, Barton F; Tomaras, Georgia D; Robinson, Harriet L

2017-12-15

An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4 + T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4 + T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4 + T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses. Copyright © 2017 Shen et al.

Survival benefit of local versus no local treatment for metastatic prostate cancer-Impact of baseline PSA and metastatic substages.

PubMed

Pompe, Raisa S; Tilki, Derya; Preisser, Felix; Leyh-Bannurah, Sami-Ramzi; Bandini, Marco; Marchioni, Michele; Gild, Philipp; Tian, Zhe; Fossati, Nicola; Cindolo, Luca; Shariat, Shahrokh F; Huland, Hartwig; Graefen, Markus; Briganti, Alberto; Karakiewicz, Pierre I

2018-07-01

To test whether local treatment (LT), namely radical prostatectomy (RP) or brachytherapy (BT) still confers a survival benefit versus no local treatment (NLT), when adjusted for baseline PSA (bPSA). To further examine whether the effect of LT might be modulated according to bPSA and M1 substages. Of 13 906 mPCa patients within the SEER (2004-2014), 375 underwent RP, 175 BT, and 13 356 NLT. Multivariable competing risks regression (MVA CRR) analyses after 1:2 propensity score matching assessed the impact of LT versus NLT on cancer specific mortality (CSM). Interaction analyses tested the association between treatment type and bPSA within different M1 substages. MVA CRR analyses revealed lower CSM rates for LT (RP [HR: 0.55, CI: 0.44-0.70, P < 0.001] and BT [HR: 0.63, CI: 0.49-0.83, P < 0.001]) compared to NLT. A significant interaction existed between bPSA and treatment type, in M1b patients only. Here, LT conferred a survival benefit when bPSA was <60 ng/mL with maximum benefit when bPSA was <40 ng/mL. No survival benefit existed for M1b patients above the 60 ng/mL bPSA threshold and for M1c patients, regardless of bPSA. For M1a patients, LT conferred a survival benefit compared to NLT. However, dose-response according to bPSA could not be tested, due to insufficient sample size. Our observations provide new insight regarding the pivotal effect of bPSA and M1 substages on CSM, when LT is contemplated. While M1a patients benefited from LT, the survival benefit was modulated by bPSA in M1b patients and no survival benefit existed in M1c patients. © 2018 Wiley Periodicals, Inc.

Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

PubMed Central

Okeke, Malachy I.; Okoli, Arinze S.; Offor, Collins; Oludotun, Taiwo G.; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

2017-01-01

Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines. PMID:29109380

Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

PubMed

Okeke, Malachy I; Okoli, Arinze S; Diaz, Diana; Offor, Collins; Oludotun, Taiwo G; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

2017-10-29

Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines.

An analysis of risk factors for pancreatic fistula after robotic pancreaticoduodenectomy: outcomes from a consecutive series of standardized pancreatic reconstructions.

PubMed

Polanco, Patricio M; Zenati, Mazen S; Hogg, Melissa E; Shakir, Murtaza; Boone, Brian A; Bartlett, David L; Zeh, Herbert J; Zureikat, Amer H

2016-04-01

Proponents of the robotic platform site its potential advantages in complex reconstructions such as the pancreaticojejunal anastomosis; however, the incidence and risk factors for postoperative pancreatic fistula (POPF) after robotic pancreaticoduodenectomy (RPD) have not been characterized. To identify independent risk factors for POPF after RPD. A prospectively maintained database of patients that underwent RPD (2008-2013) with a standardized pancreaticojejunostomy was analyzed. Univariate and multivariate analyses (UVA/MVA) were used to identify independent predictors for POPF. The POPF prognostic scores developed by Braga and Callery for open pancreaticoduodenectomy were then applied with logistic regression analysis on this RPD cohort. One hundred and fifty consecutive RPDs were analyzed. POPF occurred in 26 (17.3%); 13 (8.6%) of which were ISGPF category B and C. On UVA, patients with POPF had larger body mass index (BMI), smaller pancreatic duct diameter, smaller tumor size, longer OR time, larger estimated blood loss (EBL) and RBC transfusion (all p < 0.05). Higher EBL, duct size <4 mm, larger BMI and small tumor size remained the best independent risk factors for POPF on MVA. Increased Callery (OR 1.46, 95% CI, p = 0.001) and Braga (OR 1.2, 95% CI, p = 0.005) scores predicted an increased risk of POPF in this RPD cohort. Larger BMI, higher EBL, smaller tumor size and smaller duct diameter are the main predictors of POPF in RPD.

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

PubMed Central

Tomasini, Pascale; Serdjebi, Cindy; Khobta, Nataliya; Metellus, Philippe; Ouafik, L’Houcine; Nanni, Isabelle; Greillier, Laurent; Loundou, Anderson; Fina, Frederic; Mascaux, Celine; Barlesi, Fabrice

2016-01-01

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. PMID:27999344

Support vector machines and generalisation in HEP

NASA Astrophysics Data System (ADS)

Bevan, Adrian; Gamboa Goñi, Rodrigo; Hays, Jon; Stevenson, Tom

2017-10-01

We review the concept of Support Vector Machines (SVMs) and discuss examples of their use in a number of scenarios. Several SVM implementations have been used in HEP and we exemplify this algorithm using the Toolkit for Multivariate Analysis (TMVA) implementation. We discuss examples relevant to HEP including background suppression for H → τ + τ - at the LHC with several different kernel functions. Performance benchmarking leads to the issue of generalisation of hyper-parameter selection. The avoidance of fine tuning (over training or over fitting) in MVA hyper-parameter optimisation, i.e. the ability to ensure generalised performance of an MVA that is independent of the training, validation and test samples, is of utmost importance. We discuss this issue and compare and contrast performance of hold-out and k-fold cross-validation. We have extended the SVM functionality and introduced tools to facilitate cross validation in TMVA and present results based on these improvements.

Real-time 3D transesophageal echocardiography for the evaluation of rheumatic mitral stenosis.

PubMed

Schlosshan, Dominik; Aggarwal, Gunjan; Mathur, Gita; Allan, Roger; Cranney, Greg

2011-06-01

The aims of this study were: 1) to assess the feasibility and reliability of performing mitral valve area (MVA) measurements in patients with rheumatic mitral valve stenosis (RhMS) using real-time 3-dimensional transesophageal echocardiography (3DTEE) planimetry (MVA(3D)); 2) to compare MVA(3D) with conventional techniques: 2-dimensional (2D) planimetry (MVA(2D)), pressure half-time (MVA(PHT)), and continuity equation (MVA(CON)); and 3) to evaluate the degree of mitral commissural fusion. 3DTEE is a novel technique that provides excellent image quality of the mitral valve. Real-time 3DTEE is a relatively recent enhancement of this technique. To date, there have been no feasibility studies investigating the utility of real-time 3DTEE in the assessment of RhMS. Forty-three consecutive patients referred for echocardiographic evaluation of RhMS and suitability for percutaneous mitral valvuloplasty were assessed using 2D transthoracic echocardiography and real-time 3DTEE. MVA(3D), MVA(2D), MVA(PHT), MVA(CON), and the degree of commissural fusion were evaluated. MVA(3D) assessment was possible in 41 patients (95%). MVA(3D) measurements were significantly lower compared with MVA(2D) (mean difference: -0.16 ± 0.22; n=25, p<0.005) and MVA(PHT) (mean difference: -0.23 ± 0.28 cm(2); n=39, p<0.0001) but marginally greater than MVA(CON) (mean difference: 0.05 ± 0.22 cm(2); n=24, p=0.82). MVA(3D) demonstrated best agreement with MVA(CON) (intraclass correlation coefficient [ICC] 0.83), followed by MVA(2D) (ICC 0.79) and MVA(PHT) (ICC 0.58). Interobserver and intraobserver agreement was excellent for MVA(3D), with ICCs of 0.93 and 0.96, respectively. Excellent commissural evaluation was possible in all patients using 3DTEE. Compared with 3DTEE, underestimation of the degree of commissural fusion using 2D transthoracic echocardiography was observed in 19%, with weak agreement between methods (κ<0.4). MVA planimetry is feasible in the majority of patients with RhMS using 3DTEE, with excellent reproducibility, and compares favorably with established methods. Three-dimensional transesophageal echocardiography allows excellent assessment of commissural fusion. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice.

PubMed

Bohnen, C; Wangorsch, A; Schülke, S; Nakajima-Adachi, H; Hachimura, S; Burggraf, M; Süzer, Y; Schwantes, A; Sutter, G; Waibler, Z; Reese, G; Toda, M; Scheurer, S; Vieths, S

2013-08-01

Modified vaccinia virus Ankara (MVA)-encoding antigens are considered as safe vaccine candidates for various infectious diseases in humans. Here, we investigated the immune-modulating properties of MVA-encoding ovalbumin (MVA-OVA) on the allergen-specific immune response. The immune-modulating properties of MVA-OVA were investigated using GM-CSF-differentiated BMDCs from C57BL/6 mice. OVA expression upon MVA-OVA infection of BMDCs was monitored. Activation and maturation markers on viable MVA-OVA-infected mDCs were analyzed by flow cytometry. Secretion of INF-γ, IL-2, and IL-10 was determined in a co-culture of BMDCs infected with wtMVA or MVA-OVA and OVA-specific OT-I CD8(+) and OT-II CD4(+ ) T cells. BALB/c mice were vaccinated with wtMVA, MVA-OVA, or PBS, sensitized to OVA/alum and challenged with a diet containing chicken egg white. OVA-specific IgE, IgG1, and IgG2a and cytokine secretion from mesenteric lymph node (MLN) cells were analyzed. Body weight, body temperature, food uptake, intestinal inflammation, and health condition of mice were monitored. Infection with wtMVA and MVA-OVA induced comparable activation of mDCs. MVA-OVA-infected BMDCs expressed OVA and induced enhanced IFN-γ and IL-2 secretion from OVA-specific CD8(+ ) T cells in comparison with OVA, wtMVA, or OVA plus wtMVA. Prophylactic vaccination with MVA-OVA significantly repressed OVA-specific IgE, whereas OVA-specific IgG2a was induced. MVA-OVA vaccination suppressed TH 2 cytokine production in MLN cells and prevented the onset of allergic symptoms and inflammation in a mouse model of OVA-induced intestinal allergy. Modified vaccinia virus Ankara-ovalbumin (MVA-OVA) vaccination induces a strong OVA-specific TH 1- immune response, likely mediated by the induction of IFN-γ and IgG2a. Finally, MVA-based vaccines need to be evaluated for their therapeutic potential in established allergy models. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A novel method to measure mitral valve area in patients with rheumatic mitral stenosis using three-dimensional transesophageal echocardiography: Feasibility and validation.

PubMed

Mahmoud Elsayed, Hani M; Hassan, Mohamed; Nagy, Michael; Amin, Alaaeldin; Elguindy, Ahmed; Wagdy, Kerolos; Yacoub, Magdi

2018-03-01

Neither two- nor three-dimensional (3D) planimetry of the mitral valve (MV) orifice takes the mitral commissures into account. Thus, if the commissures are not completely fused, the MV orifice will not be planar, and MV area (MVA) will be underestimated. The study aimed to validate a novel method for measurement of the MVA using a software that traces the MV orifice including the commissures. The study included 30 patients undergoing percutaneous balloon mitral valvuloplasty for severe rheumatic mitral stenosis. All performed 3D transesophageal echocardiography (TEE) immediately before the procedure. MVA was measured using the mitral valve navigation (MVN) software of the Philips Q-Lab 10.2 in a diastolic frame with maximum diastolic opening of the MV. Regular 3D planimetry of the MV orifice was also performed. Before balloon dilation, the MVA was calculated invasively using the Gorlin's formula. No significant difference was detected between MVN-derived MVA and Gorlin-derived MVA (0.98 cm 2 vs. 1.0 cm 2 , P = .33). A statistically significant difference was detected between Planimetry-derived MVA and Gorlin-derived MVA (0.8 cm 2 vs. 1.0 cm 2 , P < .001). There were significant linear correlations between MVN-derived MVA and Gorlin-derived MVA (r = .84, P < .001). Using Bland-Altman analysis, Gorlin-derived MVA showed better and relatively narrower limits of agreement with MVN-derived MVA than planimetry-derived MVA. Measurement of the MVA using the MVN method is feasible and is more correlated to the invasively measured MVA than the 3D planimetry method. This is the most accurate method of measuring the MVA that takes MV commissures into account. © 2017, Wiley Periodicals, Inc.

Predictors of Long-Term Outcomes of Percutaneous Mitral Valvuloplasty in Patients with Rheumatic Mitral Stenosis.

PubMed

Kim, Darae; Chung, Hyemoon; Nam, Jong Ho; Park, Dong Hyuk; Shim, Chi Young; Kim, Jung Sun; Chang, Hyuk Jae; Hong, Geu Ru; Ha, Jong Won

2018-03-01

We determined factors associated with long-term outcomes of patients who underwent successful percutaneous mitral balloon valvuloplasty (PMV). Between August 1980 and May 2013, 1187 patients underwent PMV at Severance Hospital, Seoul, Korea. A total of 742 patients who underwent regular clinic visits for more than 10 years were retrospectively analyzed. The endpoints consisted of repeated PMV, mitral valve (MV) surgery, and cardiovascular-related death. The optimal result, defined as a post-PMV mitral valve area (MVA) >1.5 cm² and mitral regurgitation ≤Grade II, was obtained in 631 (85%) patients. Over a mean follow up duration of 214±50 months, 54 (7.3%) patients underwent repeat PMV, 4 (0.5%) underwent trido-PMV, and 248 (33.4%) underwent MV surgery. A total of 33 patients (4.4%) had stroke, and 35 (4.7%) patients died from cardiovascular-related reasons. In a multivariate analysis, echocardiographic score [p=0.003, hazard ratio=1.56, 95% confidence interval (CI): 1.01-2.41] and post-MVA cut-off (p<0.001, relative risk=0.39, 95% CI: 0.37-0.69) were the only significant predictors of long-term clinical outcomes after adjusting for confounding variables. A post-MVA cut-off value of 1.76 cm² showed satisfactory predictive power for poor long-term clinical outcomes. In this long-term follow up study (up to 20 years), an echocardiographic score >8 and post-MVA ≤1.76 cm² were independent predictors of poor long-term clinical outcomes after PMV, including MV reintervention, stroke, and cardiovascular-related death. © Copyright: Yonsei University College of Medicine 2018

E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox.

PubMed

Volz, Asisa; Jany, Sylvia; Freudenstein, Astrid; Lantermann, Markus; Ludwig, Holger; Sutter, Gerd

2018-01-04

The highly attenuated Modified Vaccinia virus Ankara (MVA) lacks most of the known vaccinia virus (VACV) virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L . Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV) challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins.

A Multi-institutional Analysis of Trimodality Therapy for Esophageal Cancer in Elderly Patients.

PubMed

Lester, Scott C; Lin, Steven H; Chuong, Michael; Bhooshan, Neha; Liao, Zhongxing; Arnett, Andrea L; James, Sarah E; Evans, Jaden D; Spears, Grant M; Komaki, Ritsuko; Haddock, Michael G; Mehta, Minesh P; Hallemeier, Christopher L; Merrell, Kenneth W

2017-07-15

The therapeutic gains of neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy may be offset by increased incidences of morbidity and mortality in elderly patients. This study aimed to determine the impact of age on the risks and benefits of trimodality therapy for esophageal cancer. We evaluated 571 patients treated with trimodality therapy at 3 high-volume tertiary cancer centers in the United States from 2007 to 2013. Two hundred two of 571 (35%) patients were 65 years or older at diagnosis and were classified as elderly. Toxicity and treatment parameters for the elderly cohort were compared with the younger cohort (ages 22-64) by the use of univariate (UVA) and multivariable (MVA) logistic analyses. Age was analyzed as a continuous hazard for cardiac and pulmonary toxicities. Survival was assessed by the Kaplan-Meier method. Elderly patients had a higher risk for postoperative cardiac toxicities (UVA: odds ratio [OR] 2.2, P<.001; MVA: OR 2.07, P=.004) and pulmonary toxicities (UVA: OR 2.0, P<.001; MVA: OR 2.03, P<.001) and a higher 90-day postoperative mortality (5.4% vs 2.2%, P=.049). Of the elderly patients, 6.9% experienced acute respiratory distress syndrome compared with 3.8% of younger patients (P=.11). Cardiac toxicity was linearly associated with age, and the relative risk increased by 61% for every additional decade of age. There was no difference in postoperative gastrointestinal or wound adverse events or in length of hospital stay. Grade 3+ acute toxicities from nCRT were infrequent and were clinically similar regardless of age. Freedom from esophageal cancer and disease-free survival were similar, but overall survival was significantly shorter in the elderly cohort. Elderly patients experienced more postoperative cardiopulmonary toxicities and mortality than did younger patients after nCRT. Compared with contemporary outcomes for trimodality therapy, both cohorts had acceptable rates for adverse events and disease control. For appropriately selected elderly patients, trimodality therapy for esophageal cancer is a reasonable treatment option. Copyright © 2017 Elsevier Inc. All rights reserved.

A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

PubMed Central

Minhinnick, Alice; Satti, Iman; Harris, Stephanie; Wilkie, Morven; Sheehan, Sharon; Stockdale, Lisa; Thomas, Zita-Rose Manjaly; Lopez-Ramon, Raquel; Poulton, Ian; Lawrie, Alison; Vermaak, Samantha; Le Vert, Alexandre; Del Campo, Judith; Hill, Fergal; Moss, Paul; McShane, Helen

2016-01-01

Introduction There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. Methods In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. Results The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. Conclusion MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163. PMID:26854906

Mitral Annular Calcium and Mitral Stenosis Determined by Multidetector Computed Tomography in Patients Referred for Aortic Stenosis.

PubMed

Mejean, Simon; Bouvier, Erik; Bataille, Vincent; Seknadji, Patrick; Fourchy, Dominique; Tabet, Jean-Yves; Lairez, Olivier; Cormier, Bertrand

2016-10-15

Mitral annular calcium (MAC) is a common finding in older patients referred for transcatheter aortic valve implantation (TAVI). Multidetector computed tomography (MDCT) allows fine quantification of the calcific deposits. Our objective was to estimate the prevalence of MAC and associated mitral stenosis (MS) in patients referred for TAVI using MDCT. A cohort of 346 consecutive patients referred for TAVI evaluation was screened by MDCT for MAC: 174 had MAC (50%). Of these patients, 165 patients (95%) had mitral valve area (MVA) assessable by MDCT planimetry (age 83.8 ± 5.9 years). Median mitral calcium volume and MVA were 545 mm 3 (193 to 1,253 mm 3 ) and 234 mm 2 (187 to 297 mm 2 ), respectively. The MS was very severe, severe, and moderate in 2%, 22%, and 10% patients, respectively. By multivariate analysis, MVA was independently correlated to mitral calcium volume, aortic annular area, and some specific patterns of mitral leaflet calcium. Based on these findings, a formula was elaborated to predict the presence of a significant MS. In conclusion, MDCT allows detailed assessment of MAC in TAVI populations, demonstrating a high prevalence. Mitral analysis should become routine during MDCT screening before TAVI as it may alter therapeutic strategy. Copyright © 2016 Elsevier Inc. All rights reserved.

A statistical study of magnetopause structures: Tangential versus rotational discontinuities

NASA Astrophysics Data System (ADS)

Chou, Y.-C.; Hau, L.-N.

2012-08-01

A statistical study of the structure of Earth's magnetopause is carried out by analyzing two-year AMPTE/IRM plasma and magnetic field data. The analyses are based on the minimum variance analysis (MVA), the deHoffmann-Teller (HT) frame analysis and the Walén relation. A total of 328 magnetopause crossings are identified and error estimates associated with MVA and HT frame analyses are performed for each case. In 142 out of 328 events both MVA and HT frame analyses yield high quality results which are classified as either tangential-discontinuity (TD) or rotational-discontinuity (RD) structures based only on the Walén relation: Events withSWA ≤ 0.4 (SWA ≥ 0.5) are classified as TD (RD), and rest (with 0.4 < SWA < 0.5) is classified as "uncertain," where SWA refers to the Walén slope. With this criterion, 84% of 142 events are TDs, 12% are RDs, and 4% are uncertain events. There are a large portion of TD events which exhibit a finite normal magnetic field component Bnbut have insignificant flow as compared to the Alfvén velocity in the HT frame. Two-dimensional Grad-Shafranov reconstruction of forty selected TD and RD events show that single or multiple X-line accompanied with magnetic islands are common feature of magnetopause current. A survey plot of the HT velocity associated with TD structures projected onto the magnetopause shows that the flow is diverted at the subsolar point and accelerated toward the dawn and dusk flanks.

Discrimination of high-Z materials in concrete-filled containers using muon scattering tomography

NASA Astrophysics Data System (ADS)

Frazão, L.; Velthuis, J.; Thomay, C.; Steer, C.

2016-07-01

An analysis method of identifying materials using muon scattering tomography is presented, which uses previous knowledge of the position of high-Z objects inside a container and distinguishes them from similar materials. In particular, simulations were performed in order to distinguish a block of Uranium from blocks of Lead and Tungsten of the same size, inside a concrete-filled drum. The results show that, knowing the shape and position from previous analysis, it is possible to distinguish 5 × 5 × 5 cm3 blocks of these materials with about 4h of muon exposure, down to 2 × 2 × 2 cm3 blocks with 70h of data using multivariate analysis (MVA). MVA uses several variables, but it does not benefit the discrimination over a simpler method using only the scatter angles. This indicates that the majority of discrimination is provided by the angular information. Momentum information is shown to provide no benefits in material discrimination.

Advanced qualification of pharmaceutical excipient suppliers by multiple analytics and multivariate analysis combined.

PubMed

Hertrampf, A; Müller, H; Menezes, J C; Herdling, T

2015-11-10

Pharmaceutical excipients have different functions within a drug formulation, consequently they can influence the manufacturability and/or performance of medicinal products. Therefore, critical to quality attributes should be kept constant. Sometimes it may be necessary to qualify a second supplier, but its product will not be completely equal to the first supplier product. To minimize risks of not detecting small non-similarities between suppliers and to detect lot-to-lot variability for each supplier, multivariate data analysis (MVA) can be used as a more powerful alternative to classical quality control that uses one-parameter-at-a-time monitoring. Such approach is capable of supporting the requirements of a new guideline by the European Parliament and Council (2015/C-95/02) demanding appropriate quality control strategies for excipients based on their criticality and supplier risks in ensuring quality, safety and function. This study compares calcium hydrogen phosphate from two suppliers. It can be assumed that both suppliers use different manufacturing processes. Therefore, possible chemical and physical differences were investigated by using Raman spectroscopy, laser diffraction and X-ray powder diffraction. Afterwards MVA was used to extract relevant information from each analytical technique. Both CaHPO4 could be discriminated by their supplier. The gained knowledge allowed to specify an enhanced strategy for second supplier qualification. Copyright © 2015 Elsevier B.V. All rights reserved.

Does educational status affect a patient's behavior toward erectile dysfunction?

PubMed

Salonia, Andrea; Abdollah, Firas; Gallina, Andrea; Pellucchi, Federico; Castillejos Molina, Ricardo Alonso; Maccagnano, Carmen; Rocchini, Lorenzo; Zanni, Giuseppe; Rigatti, Patrizio; Montorsi, Francesco

2008-08-01

Educational status has been investigated rarely as a potential factor affecting the behavior of patients with new onset erectile dysfunction (ED) toward seeking first medical help and subsequent compliance with prescribed phosphodiesterase type 5 inhibitor (PDE5) therapy. To test whether the educational status of patients with new onset ED and naïve to PDE5 therapy may have a significant impact on the delay before seeking first medical help (DSH) and compliance with the suggested PDE5. Assessing DSH and compliance with PDE5 in new onset ED patients according to their educational status by means of detailed logistic regression analyses. Data from 302 consecutive patients with new onset ED and naïve to PDE5s were comprehensively analyzed. Patients were segregated according to their educational status into low (elementary and/or secondary school education) and high (high school and/or university degrees) educational levels. Complete data were available for 231 assessable patients. Univariate (UVA) and multivariate (MVA) logistic regression analyses addressed the association between educational status and DSH after adjusting for age, relationship status, and Sexual Health Inventory for Men score. Likewise, UVA and MVA were performed to test the association between educational status and patient compliance with PDE5 at the 9-month median follow-up. Median DSH was 24 months (range 1-350; mean 38.1 +/- 42.8). The lower the educational status, the shorter the DSH (P = 0.03). In contrast, a significantly (P < 0.0001) greater proportion of patients with a higher educational status showed compliance with the suggested PDE5 at the 9-month follow-up. Overall, educational status was not an independent predictor of either DSH or patient compliance with PDE5 therapy. After adjusting for other variables, our findings suggest that in new onset ED patients, educational status does not independently affect the DSH and patient compliance with PDE5 therapy.

Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers.

PubMed

Joachim, Agricola; Munseri, Patricia J; Nilsson, Charlotta; Bakari, Muhammad; Aboud, Said; Lyamuya, Eligius F; Tecleab, Teghesti; Liakina, Valentina; Scarlatti, Gabriella; Robb, Merlin L; Earl, Patricia L; Moss, Bernard; Wahren, Britta; Mhalu, Fred; Ferrari, Guido; Sandstrom, Eric; Biberfeld, Gunnel

2017-08-01

We explored the duration of immune responses and the effect of a late third HIV-modified vaccinia virus Ankara (MVA) boost in HIV-DNA primed and HIV-MVA boosted Tanzanian volunteers. Twenty volunteers who had previously received three HIV-DNA and two HIV-MVA immunizations were given a third HIV-MVA immunization 3 years after the second HIV-MVA boost. At the time of the third HIV-MVA, 90% of the vaccinees had antibodies to HIV-1 subtype C gp140 (median titer 200) and 85% to subtype B gp160 (median titer 100). The majority of vaccinees had detectable antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, 70% against CRF01_AE virus-infected cells (median titer 239) and 84% against CRF01_AE gp120-coated cells (median titer 499). A high proportion (74%) of vaccinees had IFN-γ ELISpot responses, 63% to Gag and 42% to Env, 3 years after the second HIV-MVA boost. After the third HIV-MVA, there was an increase in Env-binding antibodies and ADCC-mediating antibodies relative to the response seen at the time of the third HIV-MVA vaccination, p < .0001 and p < .05, respectively. The frequency of IFN-γ ELISpot responses increased to 95% against Gag or Env and 90% to both Gag and Env, p = .064 and p = .002, respectively. In conclusion, the HIV-DNA prime/HIV-MVA boost regimen elicited potent antibody and cellular immune responses with remarkable durability, and a third HIV-MVA immunization significantly boosted both antibody and cellular immune responses relative to the levels detected at the time of the third HIV-MVA, but not to higher levels than after the second HIV-MVA.

Percutaneous Vaccination as an Effective Method of Delivery of MVA and MVA-Vectored Vaccines.

PubMed

Meseda, Clement A; Atukorale, Vajini; Kuhn, Jordan; Schmeisser, Falko; Weir, Jerry P

2016-01-01

The robustness of immune responses to an antigen could be dictated by the route of vaccine inoculation. Traditional smallpox vaccines, essentially vaccinia virus strains, that were used in the eradication of smallpox were administered by percutaneous inoculation (skin scarification). The modified vaccinia virus Ankara is licensed as a smallpox vaccine in Europe and Canada and currently undergoing clinical development in the United States. MVA is also being investigated as a vector for the delivery of heterologous genes for prophylactic or therapeutic immunization. Since MVA is replication-deficient, MVA and MVA-vectored vaccines are often inoculated through the intramuscular, intradermal or subcutaneous routes. Vaccine inoculation via the intramuscular, intradermal or subcutaneous routes requires the use of injection needles, and an estimated 10 to 20% of the population of the United States has needle phobia. Following an observation in our laboratory that a replication-deficient recombinant vaccinia virus derived from the New York City Board of Health strain elicited protective immune responses in a mouse model upon inoculation by tail scarification, we investigated whether MVA and MVA recombinants can elicit protective responses following percutaneous administration in mouse models. Our data suggest that MVA administered by percutaneous inoculation, elicited vaccinia-specific antibody responses, and protected mice from lethal vaccinia virus challenge, at levels comparable to or better than subcutaneous or intramuscular inoculation. High titers of specific neutralizing antibodies were elicited in mice inoculated with a recombinant MVA expressing the herpes simplex type 2 glycoprotein D after scarification. Similarly, a recombinant MVA expressing the hemagglutinin of attenuated influenza virus rgA/Viet Nam/1203/2004 (H5N1) elicited protective immune responses when administered at low doses by scarification. Taken together, our data suggest that MVA and MVA-vectored vaccines inoculated by scarification can elicit protective immune responses that are comparable to subcutaneous vaccination, and may allow for antigen sparing when vaccine supply is limited.

Myristoylation increases the CD8+T-cell response to a GFP prototype antigen delivered by modified vaccinia virus Ankara.

PubMed

Marr, Lisa; Lülf, Anna-Theresa; Freudenstein, Astrid; Sutter, Gerd; Volz, Asisa

2016-04-01

Activation of CD8(+)T-cells is an essential part of immune responses elicited by recombinant modified vaccinia virus Ankara (MVA). Strategies to enhance T-cell responses to antigens may be particularly necessary for broadly protective immunization against influenza A virus infections or for candidate vaccines targeting chronic infections and cancer. Here, we tested recombinant MVAs that targeted a model antigen, GFP, to different localizations in infected cells. In vitro characterization demonstrated that GFP accumulated in the nucleus (MVA-nls-GFP), associated with cellular membranes (MVA-myr-GFP) or was equally distributed throughout the cell (MVA-GFP). On vaccination, we found significantly higher levels of GFP-specific CD8(+)T-cells in MVA-myr-GFP-vaccinated BALB/c mice than in those immunized with MVA-GFP or MVA-nls-GFP. Thus, myristoyl modification may be a useful strategy to enhance CD8(+)T-cell responses to MVA-delivered target antigens.

Enhancing Production of Bio-Isoprene Using Hybrid MVA Pathway and Isoprene Synthase in E. coli

PubMed Central

Yang, Jianming; Xian, Mo; Su, Sizheng; Zhao, Guang; Nie, Qingjuan; Jiang, Xinglin; Zheng, Yanning; Liu, Wei

2012-01-01

The depleting petroleum reserve, increasingly severe energy crisis, and global climate change are reigniting enthusiasm for seeking sustainable technologies to replace petroleum as a source of fuel and chemicals. In this paper, the efficiency of the MVA pathway on isoprene production has been improved as follows: firstly, in order to increase MVA production, the source of the “upper pathway” which contains HMG-CoA synthase, acetyl-CoA acetyltransferase and HMG-CoA reductase to covert acetyl-CoA into MVA has been changed from Saccharomyces cerevisiae to Enterococcus faecalis; secondly, to further enhance the production of MVA and isoprene, a alanine 110 of the mvaS gene has been mutated to a glycine. The final genetic strain YJM25 containing the optimized MVA pathway and isoprene synthase from Populus alba can accumulate isoprene up to 6.3 g/L after 40 h of fed-batch cultivation. PMID:22558074

Efficacy and safety of a modified vaccinia Ankara (MVA) vectored plague vaccine in mice

PubMed Central

Brewoo, Joseph N.; Powell, Tim D.; Stinchcomb, Dan T.; Osorio, Jorge E.

2010-01-01

The efficacy and safety of plague vaccines based on the modified vaccinia Ankara (MVA) viral vector was evaluated. MVA recombinants were constructed expressing Yersinia pestis antigens under the translational control of the encephalomyocarditis virus (EMCV) internal ribosomal entry site (IRES) and/or fused to the tissue plasminogen activator (tPA) secretory signal. A MVA/Y. pestis recombinant that expressed a truncated version of the low-calcium response V antigen (MVA/IRES/tPA/V307), conferred significant protection (87.5%–100%) against intranasal or intraperitoneal challenge with CO92 (encapsulated) or Java 9 (non-encapsulated) strains of Y pestis, respectively. In contrast, a MVA/Y. pestis recombinant that expressed the full-length V antigen provided only 37.5% protection against challenge with CO92 or Java 9 strains, respectively. Interestingly, a MVA/Y. pestis recombinant that expressed the capsular protein (F1) did not elicit significant antibody titers but still conferred 50% and 25% protection against CO92 or Java 9 challenge, respectively. The MVA/Y. pestis recombinant viruses did not demonstrate any mortality or morbidity in SCID mice. Based on their safety and efficacy in mice, these MVA/Y. pestis recombinants are candidates for further development as biodefense and public health vaccines. PMID:20638759

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

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

Morris, W. James, E-mail: jmorris@bccancer.bc.ca; BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398more » trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.« less

Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein.

PubMed

Parra, Marcela; Liu, Xia; Derrick, Steven C; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D; Waldmann, Thomas A; Kumar, Sanjai; Morris, Sheldon L; Perera, Liyanage P

2015-01-01

Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies.

Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

PubMed Central

Climent, Núria; Guerra, Susana; García, Felipe; Rovira, Cristina; Miralles, Laia; Gómez, Carmen Elena; Piqué, Núria; Gil, Cristina; Gatell, José María; Esteban, Mariano; Gallart, Teresa

2011-01-01

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B. PMID:21625608

Diabetes and driving safety: science, ethics, legality and practice.

PubMed

Cox, Daniel J; Singh, Harsimran; Lorber, Daniel

2013-04-01

Diabetes affects over 25 million people in the United States, most of whom are over the age of 16 and many of whom are licensed to drive a motor vehicle. Safe operation of a motor vehicle requires complex interactions of cognitive and motor functions and medical conditions that affect these functions often will increase the risk of motor vehicle accidents (MVA). In the case of diabetes, hypoglycemia is the most common factor that has been shown to increase MVA rates. When people with diabetes are compared with nondiabetic controls, systematic analyses show that the relative risk of MVA is increased by between 12% and 19% (Relative Risk Ratio 1.12-1.19). In comparison, the RRR for attention deficit hyperactivity disorder is 4.4 and for sleep apnea is 2.4. Epidemiologic research suggests that patients at risk for hypoglycemia-related MVAs may have some characteristics in common, including a history of severe hypoglycemia or of hypoglycemia-related driving mishaps. Experimental studies also have shown that people with a history of hypoglycemia-related driving mishaps have abnormal counter-regulatory responses to hypoglycemia and greater cognitive impairments during moderate hypoglycemia.

Internal and external generalizability of temporal dose-response relationships for xerostomia following IMRT for head and neck cancer

PubMed Central

Thor, Maria; Owosho, Adepitan A; Clark, Haley D; Oh, Jung Hun; Riaz, Nadeem; Hovan, Allan; Tsai, Jillian; Thomas, Steven D; Yom, Sae Hee K; Wu, Jonn S; Huryn, Joseph M; Moiseenko, Vitali; Lee, Nancy Y; Estilo, Cherry L; Deasy, Joseph O

2016-01-01

Background and Purpose To study internal and external generalizability of temporal dose-response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Material and Methods Objective xerostomia was assessed in 121 patients (nCohort1=55; nCohort2=66) treated to 70Gy@2Gy in 2006–2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1, and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p-values, and Hosmer-Lemeshow p-values (pHL)). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmeancontra, Dmeanipsi) were estimated from the generated dose-response curves. Results The observed xerostomia rate was 38%/47% (3 months) and 19%/23% (11–12 months) in Cohort1/Cohort2. Risk of xerostomia at 3 months increased for higher Dmeancontra and Dmeanipsi (Cohort1: 0.17•Dmeancontra+0.11•Dmeanipsi−8.13; AUC=0.90±0.05; p=0.0002±0.002; pHL=0.22±0.23; Cohort2: AUC=0.81; p<0.0001; pHL=0.27). The identified minimum Dmeancontra thresholds were lower than in the QUANTEC guidelines (Cohort1/Cohort2: Dmeancontra=12/19 Gy; Dmeancontra, Dmeanipsi=16, 25/20, 26 Gy). Conclusions Increased Dmeancontra and Dmeanipsi explain short-term xerostomia following IMRT. Our results also suggest decreasing Dmeancontra to below 20 Gy, while keeping Dmeanipsi to around 25 Gy. Long-term xerostomia was less frequent, and no dose-response relationship was established for this follow-up time. PMID:27890427

Internal and external generalizability of temporal dose-response relationships for xerostomia following IMRT for head and neck cancer.

PubMed

Thor, Maria; Owosho, Adepitan A; Clark, Haley D; Oh, Jung Hun; Riaz, Nadeem; Hovan, Allan; Tsai, Jillian; Thomas, Steven D; Yom, Sae Hee K; Wu, Jonn S; Huryn, Joseph M; Moiseenko, Vitali; Lee, Nancy Y; Estilo, Cherry L; Deasy, Joseph O

2017-02-01

To study internal and external generalizability of temporal dose-response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Objective xerostomia was assessed in 121 patients (n Cohort1 =55; n Cohort2 =66) treated to 70Gy@2Gy in 2006-2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1, and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p-values, and Hosmer-Lemeshow p-values (p HL )). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmean contra , Dmean ipsi ) were estimated from the generated dose-response curves. The observed xerostomia rate was 38%/47% (3months) and 19%/23% (11-12months) in Cohort1/Cohort2. Risk of xerostomia at 3months increased for higher Dmean contra and Dmean ipsi (Cohort1: 0.17·Dmean contra +0.11·Dmean ipsi -8.13; AUC=0.90±0.05; p=0.0002±0.002; p HL =0.22±0.23; Cohort2: AUC=0.81; p<0.0001; p HL =0.27). The identified minimum Dmean contra thresholds were lower than in the QUANTEC guidelines (Cohort1/Cohort2: Dmean contra =12/19Gy; Dmean contra , Dmean ipsi =16, 25/20, 26Gy). Increased Dmean contra and Dmean ipsi explain short-term xerostomia following IMRT. Our results also suggest decreasing Dmean contra to below 20Gy, while keeping Dmean ipsi to around 25Gy. Long-term xerostomia was less frequent, and no dose-response relationship was established for this follow-up time. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A mitral annulus tracking approach for navigation of off-pump beating heart mitral valve repair.

PubMed

Li, Feng P; Rajchl, Martin; Moore, John; Peters, Terry M

2015-01-01

To develop and validate a real-time mitral valve annulus (MVA) tracking approach based on biplane transesophageal echocardiogram (TEE) data and magnetic tracking systems (MTS) to be used in minimally invasive off-pump beating heart mitral valve repair (MVR). The authors' guidance system consists of three major components: TEE, magnetic tracking system, and an image guidance software platform. TEE provides real-time intraoperative images to show the cardiac motion and intracardiac surgical tools. The magnetic tracking system tracks the TEE probe and the surgical tools. The software platform integrates the TEE image planes and the virtual model of the tools and the MVA model on the screen. The authors' MVA tracking approach, which aims to update the MVA model in near real-time, comprises of three steps: image based gating, predictive reinitialization, and registration based MVA tracking. The image based gating step uses a small patch centered at each MVA point in the TEE images to identify images at optimal cardiac phases for updating the position of the MVA. The predictive reinitialization step uses the position and orientation of the TEE probe provided by the magnetic tracking system to predict the position of the MVA points in the TEE images and uses them for the initialization of the registration component. The registration based MVA tracking step aims to locate the MVA points in the images selected by the image based gating component by performing image based registration. The validation of the MVA tracking approach was performed in a phantom study and a retrospective study on porcine data. In the phantom study, controlled translations were applied to the phantom and the tracked MVA was compared to its "true" position estimated based on a magnetic sensor attached to the phantom. The MVA tracking accuracy was 1.29 ± 0.58 mm when the translation distance is about 1 cm, and increased to 2.85 ± 1.19 mm when the translation distance is about 3 cm. In the study on porcine data, the authors compared the tracked MVA to a manually segmented MVA. The overall accuracy is 2.37 ± 1.67 mm for single plane images and 2.35 ± 1.55 mm for biplane images. The interoperator variation in manual segmentation was 2.32 ± 1.24 mm for single plane images and 1.73 ± 1.18 mm for biplane images. The computational efficiency of the algorithm on a desktop computer with an Intel(®) Xeon(®) CPU @3.47 GHz and an NVIDIA GeForce 690 graphic card is such that the time required for registering four MVA points was about 60 ms. The authors developed a rapid MVA tracking algorithm for use in the guidance of off-pump beating heart transapical mitral valve repair. This approach uses 2D biplane TEE images and was tested on a dynamic heart phantom and interventional porcine image data. Results regarding the accuracy and efficiency of the authors' MVA tracking algorithm are promising, and fulfill the requirements for surgical navigation.

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells.

PubMed

Dai, Peihong; Wang, Weiyi; Yang, Ning; Serna-Tamayo, Cristian; Ricca, Jacob M; Zamarin, Dmitriy; Shuman, Stewart; Merghoub, Taha; Wolchok, Jedd D; Deng, Liang

2017-05-19

Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA sensing and Batf3-dependent CD103 + /CD8α + DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as an immunotherapeutic agent for human cancers. Copyright © 2017, American Association for the Advancement of Science.

Vaccination with Combination DNA and Virus-Like Particles Enhances Humoral and Cellular Immune Responses upon Boost with Recombinant Modified Vaccinia Virus Ankara Expressing Human Immunodeficiency Virus Envelope Proteins.

PubMed

Gangadhara, Sailaja; Kwon, Young-Man; Jeeva, Subbiah; Quan, Fu-Shi; Wang, Baozhong; Moss, Bernard; Compans, Richard W; Amara, Rama Rao; Jabbar, M Abdul; Kang, Sang-Moo

2017-12-19

Heterologous prime boost with DNA and recombinant modified vaccinia virus Ankara (rMVA) vaccines is considered as a promising vaccination approach against human immunodeficiency virus (HIV-1). To further enhance the efficacy of DNA-rMVA vaccination, we investigated humoral and cellular immune responses in mice after three sequential immunizations with DNA, a combination of DNA and virus-like particles (VLP), and rMVA expressing HIV-1 89.6 gp120 envelope proteins (Env). DNA prime and boost with a combination of VLP and DNA vaccines followed by an rMVA boost induced over a 100-fold increase in Env-specific IgG antibody titers compared to three sequential immunizations with DNA and rMVA. Cellular immune responses were induced by VLP-DNA and rMVA vaccinations at high levels in CD8 T cells, CD4 T cells, and peripheral blood mononuclear cells secreting interferon (IFN)-γ, and spleen cells producing interleukin (IL)-2, 4, 5 cytokines. This study suggests that a DNA and VLP combination vaccine with MVA is a promising strategy in enhancing the efficacy of DNA-rMVA vaccination against HIV-1.

Secondary ion mass spectrometry imaging and multivariate data analysis reveal co-aggregation patterns of Populus trichocarpa leaf surface compounds on a micrometer scale.

PubMed

Kulkarni, Purva; Dost, Mina; Bulut, Özgül Demir; Welle, Alexander; Böcker, Sebastian; Boland, Wilhelm; Svatoš, Aleš

2018-01-01

Spatially resolved analysis of a multitude of compound classes has become feasible with the rapid advancement in mass spectrometry imaging strategies. In this study, we present a protocol that combines high lateral resolution time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging with a multivariate data analysis (MVA) approach to probe the complex leaf surface chemistry of Populus trichocarpa. Here, epicuticular waxes (EWs) found on the adaxial leaf surface of P. trichocarpa were blotted on silicon wafers and imaged using TOF-SIMS at 10 μm and 1 μm lateral resolution. Intense M +● and M -● molecular ions were clearly visible, which made it possible to resolve the individual compound classes present in EWs. Series of long-chain aliphatic saturated alcohols (C 21 -C 30 ), hydrocarbons (C 25 -C 33 ) and wax esters (WEs; C 44 -C 48 ) were clearly observed. These data correlated with the 7 Li-chelation matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, which yielded mostly molecular adduct ions of the analyzed compounds. Subsequently, MVA was used to interrogate the TOF-SIMS dataset for identifying hidden patterns on the leaf's surface based on its chemical profile. After the application of principal component analysis (PCA), a small number of principal components (PCs) were found to be sufficient to explain maximum variance in the data. To further confirm the contributions from pure components, a five-factor multivariate curve resolution (MCR) model was applied. Two distinct patterns of small islets, here termed 'crystals', were apparent from the resulting score plots. Based on PCA and MCR results, the crystals were found to be formed by C 23 or C 29 alcohols. Other less obvious patterns observed in the PCs revealed that the adaxial leaf surface is coated with a relatively homogenous layer of alcohols, hydrocarbons and WEs. The ultra-high-resolution TOF-SIMS imaging combined with the MVA approach helped to highlight the diverse patterns underlying the leaf's surface. Currently, the methods available to analyze the surface chemistry of waxes in conjunction with the spatial information related to the distribution of compounds are limited. This study uses tools that may provide important biological insights into the composition of the wax layer, how this layer is repaired after mechanical damage or insect feeding, and which transport mechanisms are involved in deploying wax constituents to specific regions on the leaf surface. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

(S)-3-hydroxy-3-methylglutaryl coenzyme A reductase, a product of the mva operon of Pseudomonas mevalonii, is regulated at the transcriptional level.

PubMed Central

Wang, Y L; Beach, M J; Rodwell, V W

1989-01-01

We have cloned and sequenced a 505-base-pair (bp) segment of DNA situated upstream of mvaA, the structural gene for (S)-3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) of Pseudomonas mevalonii. The DNA segment that we characterized includes the promoter region for the mva operon. Nuclease S1 mapping and primer extension analysis showed that mvaA is the promoter-proximal gene of the mva operon. Transcription initiates at -56 bp relative to the first A (+1) of the translation start site. Transcription in vivo was induced by mevalonate. Structural features of the mva promoter region include an 80-bp A + T-rich region, and -12, -24 consensus sequences that resemble sequences of sigma 54 promoters in enteric organisms. The relative amplitudes of catalytic activity, enzyme protein, and mvaA mRNA are consistent with a model of regulation of this operon at the transcriptional level. Images PMID:2477360

Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo.

PubMed

Altenburg, Arwen F; van de Sandt, Carolien E; Li, Bobby W S; MacLoughlin, Ronan J; Fouchier, Ron A M; van Amerongen, Geert; Volz, Asisa; Hendriks, Rudi W; de Swart, Rik L; Sutter, Gerd; Rimmelzwaan, Guus F; de Vries, Rory D

2017-08-17

Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies.

Recombinant Modified Vaccinia Virus Ankara Generating Ebola Virus-Like Particles.

PubMed

Schweneker, Marc; Laimbacher, Andrea S; Zimmer, Gert; Wagner, Susanne; Schraner, Elisabeth M; Wolferstätter, Michael; Klingenberg, Marieken; Dirmeier, Ulrike; Steigerwald, Robin; Lauterbach, Henning; Hochrein, Hubertus; Chaplin, Paul; Suter, Mark; Hausmann, Jürgen

2017-06-01

There are currently no approved therapeutics or vaccines to treat or protect against the severe hemorrhagic fever and death caused by Ebola virus (EBOV). Ebola virus-like particles (EBOV VLPs) consisting of the matrix protein VP40, the glycoprotein (GP), and the nucleoprotein (NP) are highly immunogenic and protective in nonhuman primates against Ebola virus disease (EVD). We have constructed a modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN) recombinant coexpressing VP40 and GP of EBOV Mayinga and the NP of Taï Forest virus (TAFV) (MVA-BN-EBOV-VLP) to launch noninfectious EBOV VLPs as a second vaccine modality in the MVA-BN-EBOV-VLP-vaccinated organism. Human cells infected with either MVA-BN-EBOV-VLP or MVA-BN-EBOV-GP showed comparable GP expression levels and transport of complex N-glycosylated GP to the cell surface. Human cells infected with MVA-BN-EBOV-VLP produced large amounts of EBOV VLPs that were decorated with GP spikes but excluded the poxviral membrane protein B5, thus resembling authentic EBOV particles. The heterologous TAFV NP enhanced EBOV VP40-driven VLP formation with efficiency similar to that of the homologous EBOV NP in a transient-expression assay, and both NPs were incorporated into EBOV VLPs. EBOV GP-specific CD8 T cell responses were comparable between MVA-BN-EBOV-VLP- and MVA-BN-EBOV-GP-immunized mice. The levels of EBOV GP-specific neutralizing and binding antibodies, as well as GP-specific IgG1/IgG2a ratios induced by the two constructs, in mice were also similar, raising the question whether the quality rather than the quantity of the GP-specific antibody response might be altered by an EBOV VLP-generating MVA recombinant. IMPORTANCE The recent outbreak of Ebola virus (EBOV), claiming more than 11,000 lives, has underscored the need to advance the development of safe and effective filovirus vaccines. Virus-like particles (VLPs), as well as recombinant viral vectors, have proved to be promising vaccine candidates. Modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN) is a safe and immunogenic vaccine vector with a large capacity to accommodate multiple foreign genes. In this study, we combined the advantages of VLPs and the MVA platform by generating a recombinant MVA-BN-EBOV-VLP that would produce noninfectious EBOV VLPs in the vaccinated individual. Our results show that human cells infected with MVA-BN-EBOV-VLP indeed formed and released EBOV VLPs, thus producing a highly authentic immunogen. MVA-BN-EBOV-VLP efficiently induced EBOV-specific humoral and cellular immune responses in vaccinated mice. These results are the basis for future advancements, e.g., by including antigens from various filoviral species to develop multivalent VLP-producing MVA-based filovirus vaccines. Copyright © 2017 American Society for Microbiology.

Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins.

PubMed

Lázaro-Frías, Adrián; Gómez-Medina, Sergio; Sánchez-Sampedro, Lucas; Ljungberg, Karl; Ustav, Mart; Liljeström, Peter; Muñoz-Fontela, César; Esteban, Mariano; García-Arriaza, Juan

2018-06-01

Zaire and Sudan ebolavirus species cause a severe disease in humans and nonhuman primates (NHPs) characterized by a high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013 to 2016 outbreak in West Africa highlighted the need for EVD-specific medical countermeasures. Here, we generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs). In a human monocytic cell line, the different MVA vectors (termed MVA-EBOVs and MVA-SUDVs) triggered robust innate immune responses, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. Additionally, several innate immune cells, such as dendritic cells, neutrophils, and natural killer cells, were differentially recruited in the peritoneal cavity of mice inoculated with MVA-EBOVs. After immunization of mice with a homologous prime/boost protocol (MVA/MVA), total IgG antibodies against GP or VP40 from Zaire and Sudan ebolavirus were differentially induced by these vectors, which were mainly of the IgG1 and IgG3 isotypes. Remarkably, an MVA-EBOV construct coexpressing GP and VP40 protected chimeric mice challenged with EBOV to a greater extent than a vector expressing GP alone. These results support the consideration of MVA-EBOVs and MVA-SUDVs expressing GP and VP40 and producing VLPs as best-in-class potential vaccine candidates against EBOV and SUDV. IMPORTANCE EBOV and SUDV cause a severe hemorrhagic fever affecting humans and NHPs. Since their discovery in 1976, they have caused several sporadic epidemics, with the recent outbreak in West Africa from 2013 to 2016 being the largest and most severe, with more than 11,000 deaths being reported. Although some vaccines are in advanced clinical phases, less expensive, safer, and more effective licensed vaccines are desirable. We generated and characterized head-to-head the immunogenicity and efficacy of five novel vaccines against EBOV and SUDV based on the poxvirus MVA expressing GP or GP and VP40. The expression of GP and VP40 leads to the formation of VLPs. These MVA-EBOV and MVA-SUDV recombinants triggered robust innate and humoral immune responses in mice. Furthermore, MVA-EBOV recombinants expressing GP and VP40 induced high protection against EBOV in a mouse challenge model. Thus, MVA expressing GP and VP40 and producing VLPs is a promising vaccine candidate against EBOV and SUDV. Copyright © 2018 American Society for Microbiology.

Hydrochemistry of the Mahomet Bedrock Valley Aquifer, East-Central Illinois: indicators of recharge and ground-water flow

USGS Publications Warehouse

Panno, S.V.; Hackley, Keith C.; Cartwright, K.; Liu, Chao-Li

1994-01-01

A conceptual model of the ground-water flow and recharge to the Mahomet Bedrock Valley Aquifer (MVA), east-central Illinois, was developed using major ion chemistry and isotope geochemistry. The MVA is a 'basal' fill in the east-west trending buried bedrock valley composed of clean, permeable sand and gravel to thicknesses of up to 61 m. It is covered by a thick sequence of glacial till containing thinner bodies of interbedded sand and gravel. Ground water from the MVA was found to be characterized by clearly defined geochemical regions with three distinct ground-water types. A fourth ground-water type was found at the confluence of the MVA and the Mackinaw Bedrock Valley Aquifer (MAK) to the west. Ground water in the Onarga Valley, a northeastern tributary of the MVA, is of two types, a mixed cation-SO42- type and a mixed cation-HCO3- type. The ground water is enriched in Na+, Ca2+, Mg2+, and SO42- which appears to be the result of an upward hydraulic gradient and interaction of deeper ground water with oxidized pyritic coals and shale. We suggest that recharge to the Onarga Valley and overlying aquifers is 100% from bedrock (leakage) and lateral flow from the MVA to the south. The central MVA (south of the Onarga Valley) is composed of relatively dilute ground water of a mixed cation-HCO3- type, with low total dissolved solids, and very low concentrations of Cl- and SO42-. Stratigraphic relationships of overlying aquifers and ground-water chemistry of these and the MVA suggest recharge to this region of the MVA (predominantly in Champaign County) is relatively rapid and primarily from the surface. Midway along the westerly flow path of the MVA (western MVA), ground water is a mixed cation-HCO3- type with relatively high Cl-, where Cl- increases abruptly by one to ??? two orders of magnitude. Data suggest that the increase in Cl- is the result of leakage of saline ground water from bedrock into the MVA. Mass-balance calculations indicate that approximately 9.5% of recharge in this area is from bedrock. Concentrations of Na+, HCO3-, As, and TDS also increase in the western MVA. Ground water in the MAK is of a Ca2+-HCO3- type. Mass-balance calculations, using Cl- as a natural, conservative tracer, indicate that approximately 17% of the ground water flowing from the confluence area is derived from the MVA.

Comparison of tissue adequacy for histologic examination from Ipas MVA plus and Wallach Endocell in women with abnormal uterine bleeding.

PubMed

Wanijasombutti, Paphada; Imruetaicharoenchok, Arinporn; Tangjitgamol, Siriwan; Loharamtaweethong, Kongsak; Phuriputt, Napaporn; Phaloprakarn, Chadakarn

2015-08-01

The aim of this study was to compare endometrial tissue adequacy sampling by Wallach Endocell and manual vacuum aspiration (Ipas MVA plus) in women with abnormal uterine bleeding. Pain and immediate complications from each method were also compared. Two hundred and forty women with abnormal uterine bleeding were randomly assigned to two methods of endometrial sampling: MVA (n = 122) and Endocell (n = 118). The basic characteristic features of the women, the difficulty of the procedure, pain score by visual analogue scale, immediate complications, and treatment were recorded. Endometrial tissue adequacy and histopathologic diagnoses were evaluated. The adequacy of tissue samples was 81.1% in the MVA group and 85.6% in the Endocell group (P = 0.356). There was a significant difference in the rates of difficult procedure between the two groups (27.0% in MVA vs 14.4% in Endocell; P = 0.016). Moderate to severe pain was significantly higher in the MVA group compared to the Endocell group: 60.7% and 19.5%, respectively (P < 0.001). Other immediate minor complications were also observed to be significantly higher in the MVA group (44.3%) than in the Endocell group (30.5%) (P = 0.028). Although medication required for pain was higher in the MVA group (23.0%) than in the Endocell group (12.0%), the difference was not significant (P = 0.130). The two most common histopathologic findings obtained from MVA and Endocell specimens were proliferative endometrium (32.4%) and atrophic endometrium (27.1%). MVA was comparable to Endocell in terms of tissue adequacy. Moderate to severe pain was experienced significantly more in the MVA group; however, the requirement of pain treatment was not significantly different between the groups. © 2015 The Authors Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model

PubMed Central

Sridharan, Vijayalakshmi; Seawright, John W.; Antonawich, Francis J.; Garnett, Merrill; Cao, Maohua; Singh, Preeti; Boerma, Marjan

2017-01-01

Exposure of the heart to ionizing radiation can cause adverse myocardial remodeling. In small animal models, local heart irradiation causes persistent alterations in cardiac mitochondrial function and swelling. POLY-MVA is a dietary supplement that contains a palladium lipoic acid complex that targets mitochondrial complex I and has been demonstrated to have greater redox potential than lipoic acid alone. POLY-MVA improves mitochondrial function and anti-oxidant enzyme activity in the aged rat heart. In this study, we tested whether POLY-MVA can mitigate cardiac effects of ionizing radiation. Adult male rats were exposed to local heart X rays with a daily dose of 9 Gy for 5 consecutive days. Eighteen weeks after irradiation, POLY-MVA was administered orally at 1 ml/kg bodyweight per day during weekdays, for 6 weeks. Alterations in cardiac function as measured with echocardiography coincided with enhanced mitochondrial swelling, a reduction in mitochondrial expression of complex II, manifestations of adverse remodeling such as a reduction in myocardial microvessel density and an increase in collagen deposition and mast cell numbers. POLY-MVA enhanced left ventricular expression of superoxide dismutase 2, but only in sham-irradiated animals. In irradiated animals, POLY-MVA caused a reduction in markers of inflammatory infiltration, CD2 and CD68. Moreover, POLY-MVA mitigated the effects of radiation on mitochondria. Nonetheless, POLY-MVA did not mitigate adverse cardiac remodeling, suggesting that this tissue remodeling may not be alleviated by altering cardiac mitochondria alone. However, we cannot exclude the possibility that an earlier onset of POLY-MVA administration may have more profound effects on radiation-induced cardiac remodeling. PMID:28231026

Adjuvant radiation therapy and lymphadenectomy in esophageal cancer: a SEER database analysis.

PubMed

Shridhar, Ravi; Weber, Jill; Hoffe, Sarah E; Almhanna, Khaldoun; Karl, Richard; Meredith, Kenneth

2013-08-01

This study seeks to determine the effects of postoperative radiation therapy and lymphadenectomy on survival in esophageal cancer. An analysis of patients with surgically resected esophageal cancer from the SEER database between 2004 and 2008 was performed to determine association of adjuvant radiation and lymph node dissection on survival. Survival curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. We identified 2109 patients who met inclusion criteria. Radiation was associated with increased survival in stage III patients (p = 0.005), no benefit in stage II (p = 0.075) and IV (p = 0.913) patients, and decreased survival in stage I patients (p < 0.0001). Univariate analysis revealed that radiation therapy was associated with a survival benefit node positive (N1) patients while it was associated with a detriment in survival for node negative (N0) patients. Removing >12 and >15 lymph nodes was associated with increased survival in N0 patients, while removing >8, >10, >12, >15, and >20 lymph nodes was associated with a survival benefit in N1 patients. MVA revealed that age, gender, tumor and nodal stage, tumor location, and number of lymph nodes removed were prognostic for survival in N0 patients. In N1 patients, MVA showed the age, tumor stage, number of lymph nodes removed, and radiation were prognostic for survival. The number of lymph nodes removed in esophageal cancer is associated with increased survival. The benefit of adjuvant radiation therapy on survival in esophageal cancer is limited to N1 patients.

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

Murphy, Colin; Anderson, Penny R.; Li Tianyu

Purpose: We examined the impact of radiation tumor bed boost parameters in early-stage breast cancer on local control and cosmetic outcomes. Methods and Materials: A total of 3,186 women underwent postlumpectomy whole-breast radiation with a tumor bed boost for Tis to T2 breast cancer from 1970 to 2008. Boost parameters analyzed included size, energy, dose, and technique. Endpoints were local control, cosmesis, and fibrosis. The Kaplan-Meier method was used to estimate actuarial incidence, and a Cox proportional hazard model was used to determine independent predictors of outcomes on multivariate analysis (MVA). The median follow-up was 78 months (range, 1-305 months).more » Results: The crude cosmetic results were excellent in 54%, good in 41%, and fair/poor in 5% of patients. The 10-year estimate of an excellent cosmesis was 66%. On MVA, independent predictors for excellent cosmesis were use of electron boost, lower electron energy, adjuvant systemic therapy, and whole-breast IMRT. Fibrosis was reported in 8.4% of patients. The actuarial incidence of fibrosis was 11% at 5 years and 17% at 10 years. On MVA, independent predictors of fibrosis were larger cup size and higher boost energy. The 10-year actuarial local failure was 6.3%. There was no significant difference in local control by boost method, cut-out size, dose, or energy. Conclusions: Likelihood of excellent cosmesis or fibrosis are associated with boost technique, electron energy, and cup size. However, because of high local control and rare incidence of fair/poor cosmesis with a boost, the anatomy of the patient and tumor cavity should ultimately determine the necessary boost parameters.« less

Calibrating the ChemCam LIBS for Carbonate Minerals on Mars

DOE R&D Accomplishments Database

Wiens, Roger C.; Clegg, Samuel M.; Ollila, Ann M.; Barefield, James E.; Lanza, Nina; Newsom, Horton E.

2009-01-01

The ChemCam instrument suite on board the NASA Mars Science Laboratory (MSL) rover includes the first LIBS instrument for extraterrestrial applications. Here we examine carbonate minerals in a simulated martian environment using the LIDS technique in order to better understand the in situ signature of these materials on Mars. Both chemical composition and rock type are determined using multivariate analysis (MVA) techniques. Composition is confirmed using scanning electron microscopy (SEM) techniques. Our initial results suggest that ChemCam can recognize and differentiate between carbonate materials on Mars.

Effects of pre-existing orthopoxvirus-specific immunity on the performance of Modified Vaccinia virus Ankara-based influenza vaccines.

PubMed

Altenburg, Arwen F; van Trierum, Stella E; de Bruin, Erwin; de Meulder, Dennis; van de Sandt, Carolien E; van der Klis, Fiona R M; Fouchier, Ron A M; Koopmans, Marion P G; Rimmelzwaan, Guus F; de Vries, Rory D

2018-04-24

The replication-deficient orthopoxvirus modified vaccinia virus Ankara (MVA) is a promising vaccine vector against various pathogens and has an excellent safety record. However, pre-existing vector-specific immunity is frequently suggested to be a drawback of MVA-based vaccines. To address this issue, mice were vaccinated with MVA-based influenza vaccines in the presence or absence of orthopoxvirus-specific immunity. Importantly, protective efficacy of an MVA-based influenza vaccine against a homologous challenge was not impaired in the presence of orthopoxvirus-specific pre-existing immunity. Nonetheless, orthopoxvirus-specific pre-existing immunity reduced the induction of antigen-specific antibodies under specific conditions and completely prevented induction of antigen-specific T cell responses by rMVA-based vaccination. Notably, antibodies induced by vaccinia virus vaccination, both in mice and humans, were not capable of neutralizing MVA. Thus, when using rMVA-based vaccines it is important to consider the main correlate of protection induced by the vaccine, the vaccine dose and the orthopoxvirus immune status of vaccine recipients.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

PubMed

Walsh, Stephen R; Wilck, Marissa B; Dominguez, David J; Zablowsky, Elise; Bajimaya, Shringkhala; Gagne, Lisa S; Verrill, Kelly A; Kleinjan, Jane A; Patel, Alka; Zhang, Ying; Hill, Heather; Acharyya, Aruna; Fisher, David C; Antin, Joseph H; Seaman, Michael S; Dolin, Raphael; Baden, Lindsey R

2013-06-15

Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. NCT00565929.

Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development.

PubMed

Volz, A; Sutter, G

2017-01-01

Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology. © 2017 Elsevier Inc. All rights reserved.

Intraoperative assessment of mitral valve area after mitral valve repair: comparison of different methods.

PubMed

Maslow, Andrew; Gemignani, Anthony; Singh, Arun; Mahmood, Feroze; Poppas, Athena

2011-04-01

In the present study, 3 different methods to measure the mitral valve area (MVA) after mitral valve repair (MVRep) were studied. Data obtained immediately after repair were compared with postoperative data. The objective was to determine the feasibility and correlation between intraoperative and postoperative MVA data. A prospective study. A tertiary care medical center. Twenty-five elective adult surgical patients scheduled for MVRep. Echocardiographic data included MVAs obtained using the pressure half-time (PHT), 2-dimensional planimetry (2D-PLAN), and the continuity equation (CE). These data were obtained immediately after cardiopulmonary bypass and were compared with data obtained before hospital discharge (transthoracic echocardiogram 1) and 6 to 12 months after surgery (transthoracic echocardiogram 2). Intraoperative care was guided by hemodynamic goals designed to optimize cardiac function. The data show good agreement and correlation between MVA obtained with PHT and 2D-PLAN within and between each time period. MVA data obtained with the CE in the postoperative period were lower than and did not correlate or agree as well with other MVA data. The MVA recorded immediately after valve repair, using PHT, correlated and agreed with MVA data obtained in the postoperative period. These results contrast with previously published data and could highlight the impact of hemodynamic function during the assessment of MVA. Copyright © 2011 Elsevier Inc. All rights reserved.

Protective immunity against influenza in HLA-A2 transgenic mice by modified vaccinia virus Ankara vectored vaccines containing internal influenza proteins.

PubMed

Di Mario, Giuseppina; Sciaraffia, Ester; Facchini, Marzia; Gubinelli, Francesco; Soprana, Elisa; Panigada, Maddalena; Bernasconi, Valentina; Garulli, Bruno; Siccardi, Antonio; Donatelli, Isabella; Castrucci, Maria R

2017-03-01

The emergence of novel strains of influenza A viruses with hemagglutinins (HAs) that are antigenically distinct from those circulating in humans, and thus have pandemic potential, pose concerns and call for the development of more broadly protective influenza vaccines. In the present study, modified vaccinia virus Ankara (MVA) encoding internal influenza antigens were evaluated for their immunogenicity and ability to protect HLA-A2.1 transgenic (AAD) mice from infection with influenza viruses. MVAs expressing NP (MVA-NP), M1 (MVA-M1) or polymerase PB1 (MVA-PB1) of A/California/4/09 (CA/09) virus were generated and used to immunize AAD mice. Antibodies and CD8+T cell responses were assessed by ELISA and ELISPOT, respectively, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus. CD8+T cells specific to immunodominant and subdominant epitopes on the internal influenza proteins were elicited by MVA-based vectors in AAD mice, whereas influenza-specific antibodies were detected only in MVA-NP-immunized mice. Both M1- and NP-based MVA vaccines, regardless of whether they were applied individually or in combination, conferred protection against lethal influenza virus challenge. Our data further emphasize the promising potential of MVA vector expressing internal antigens toward the development of a universal influenza vaccine.

Evaluation of initial posttrauma cardiovascular levels in association with acute PTSD symptoms following a serious motor vehicle accident.

PubMed

Buckley, Beth; Nugent, Nicole; Sledjeski, Eve; Raimonde, A Jay; Spoonster, Eileen; Bogart, Laura M; Delahanty, Douglas L

2004-08-01

The present study examined the relationship between heart rate (HR) and blood pressure (BP) levels assessed at multiple time points posttrauma and subsequent acute posttraumatic stress disorder (PTSD) symptoms present at a 1-month follow-up. HR and BP levels were measured in 65 motor vehicle accident (MVA) survivors during Emergency Medical Service transport, upon admission to the trauma unit, for the first 20 min postadmission and on the day of discharge. Hierarchical linear modeling analyses revealed no significant relationships between cardiovascular levels and acute PTSD symptoms. Given the small sample size, these results should be interpreted with caution. However, the present results question the use of initial cardiovascular levels as predictors of subsequent acute PTSD in seriously injured MVA victims.

Regression of Human Papillomavirus Intraepithelial Lesions Is Induced by MVA E2 Therapeutic Vaccine

PubMed Central

López-Contreras, Mario; Rosales, Carlos; Magallanes-Molina, Jose-Roberto; Gonzalez-Vergara, Roberto; Arroyo-Cazarez, Jose Martin; Ricardez-Arenas, Antonio; del Follo-Valencia, Armando; Padilla-Arriaga, Santiago; Guerrero, Miriam Veronica; Pirez, Miguel Angel; Arellano-Fiore, Claudia; Villarreal, Freddy

2014-01-01

Abstract Human papilloma viruses can induce warts, condylomas, and other intraepithelial cervical lesions that can progress to cancer. Cervical cancer is a serious problem in developing countries because early detection is difficult, and thus proper early treatment is many times missing. In this phase III clinical trial, we evaluated the potential use of MVA E2 recombinant vaccinia virus to treat intraepithelial lesions associated with papillomavirus infection. A total of 1176 female and 180 male patients with intraepithelial lesions were studied. They were injected with 107 MVA E2 virus particles directly into their uterus, urethra, vulva, or anus. Patients were monitored by colposcopy and cytology. Immune response was determined by measuring the antibody titer against MVA E2 virus and by analyzing the cytotoxic activity against cancer cells bearing papillomavirus DNA. Papillomavirus was determined by the Hybrid Capture method or by polymerase chain reaction analysis. By histology, 1051 (89.3%) female patients showed complete elimination of lesions after treatment with MVA E2. In 28 (2.4%) female patients, the lesion was reduced to CIN 1. Another 97 (8.3%) female patients presented isolated koilocytes after treatment. In men, all lesions were completely eliminated. All MVA E2–treated patients developed antibodies against the MVA E2 vaccine and generated a specific cytotoxic response against papilloma-transformed cells. Papillomavirus DNA was not detected after treatment in 83% of total patients treated. MVA E2 did not generate any apparent side effects. These data suggest that therapeutic vaccination with MVA E2 vaccine is an excellent candidate to stimulate the immune system and generate regression in intraepithelial lesions when applied locally. PMID:25275724

A survey of manual vacuum aspiration’s experiences among the new medical graduates in Thailand

PubMed Central

2013-01-01

Background Despite Thai laws permitting abortion conducted by registered medical practitioners, unsafe abortion still kills and maims Thai women as a result of inadequate access to safe abortion services. Surgical evacuation of the uterus by manual vacuum aspirator (MVA) is a safe and effective technique recommended by the World Health Organization (WHO) guidelines. This study assessed new medical graduates’ MVA experiences during their clinical years in medical schools. Methods Cross-sectional questionnaire surveys on all new medical graduates participating in the annual assembly arranged by the Ministry of Public Health in 2010 and 2012 were applied. Descriptive and inferential statistics were employed for data analysis. Results The significant minority of new graduates (44% and 43% in 2010 and 2012 batches) had seen but never used MVA. The proportion of graduates who had ‘never seen’ reduced from 32% in 2010 to 23% in 2012 while the proportion of ‘ever used’ had noticeably increased from 24% to 34% in corresponding years. Graduates from medical schools outside Bangkok and vicinity and those reporting confidence in their surgical skills tended to have more MVA experience. The 2012 graduation year was also positively related to higher experience on MVA. Conclusion Though the proportion of graduates who had ever used MVA was still low in 2012, a positive change from that in 2010 was observed. Medical schools outside Bangkok and vicinity provided more opportunities for learning MVA. It is recommended that medical schools, especially in Bangkok and vicinity should provide more MVA learning opportunities for students. Adequate training and regular hands-on MVA practice should be incorporated into a wide range of clinical practice. PMID:24025699

Generation and Production of Modified Vaccinia Virus Ankara (MVA) as a Vaccine Vector.

PubMed

Pavot, Vincent; Sebastian, Sarah; Turner, Alison V; Matthews, Jake; Gilbert, Sarah C

2017-01-01

The smallpox vaccine based on the vaccinia virus was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one to two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is an attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. MVA can encode one or more foreign antigens and thus can function as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant properties, and induces humoral and cellular immune responses. Many clinical trials of these new vaccines have been conducted, and the safety of MVA is now well documented. Immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate. In this chapter, we provide protocols for generation, isolation, amplification, and purification of recombinant MVA for preclinical and clinical evaluation.

[Construction and Function Verification of a Novel Shuttle Vector Containing a Marker Gene Self-deletion System].

PubMed

Li, Lili; Wang, Zhan; Zhou, Yubai; Zhang, Fang; Shen, Sisi; Li, Zelin; Zeng, Yi

2015-09-01

For rapid and accurate screening of recombinant modified vaccinia virus Ankara (rMVA) that satisfied the quality standards of clinical trials, a novel shuttle vector that can delete the marker gene automatically during virus propagation was construted: pZL-EGFP. To construct the pZL-EGFP, the original shuttle vector pSC11 was modified by replacing the LacZ marker gene with enhanced green fluorescent protein (EGFP) and then inserting homologous sequences of TKL into the flank regions of EGFP. Baby hamster kidney (BHK)-21 cells were cotransfected with pZL-EGFP and MVA, and underwent ten passages and one plaque screening to obtain the EGFP-free rMVA carrying the exogenous gene. Resulting rMVA was tested by polymerase chain reaction and western blotting to verify pZL-EGFP function. A novel shuttle vector pZL-EGFP containing an EGFP marker gene which could be deleted automatically was constructed. This gene deletion had no effect on the activities of rMVA, and the exogenous gene could be expressed stably. These results suggest that rMVA can be packaged efficiently by homologous recombination between pZL-EGFP and MVA in BHK-21 cells, and that the carried EGFP gene can be removed automatically by intramolecular homologous recombination during virus passage. Meanwhile, the gene deletion had no influence on the activities of rMVA and the expression of exogenous target gene. This study lays a solid foundation for the future research.

Anatomical considerations of percutaneous transvenous mitral annuloplasty: a novel procedure for treatment of functional mitral regurgitation.

PubMed

Mehra, Lalit; Raheja, Shashi; Agarwal, Sneh; Rani, Yashoda; Kaur, Kulwinder; Tuli, Anita

2016-03-01

Percutaneous transvenous mitral annuloplasty (PTMA) has evolved as a latest procedure for the treatment of functional mitral regurgitation. It reduces mitral valve annulus (MVA) size and increases valve leaflet coaptation via compression of coronary sinus (CS). Anatomical considerations for this procedure were elucidated in the present study. In 40 formalin fixed adult cadaveric human hearts, relation of the venous channel formed by CS and great cardiac vein (GCV) to MVA and the adjacent arteries was described, at 6 points by making longitudinal sections perpendicular to the plane of MVA, numbered 1-6 starting from CS ostium. CS/GCV formed a semicircular venous channel on the atrial side of MVA. Based on the distance of CS/GCV from MVA, two patterns were identified. In 37 hearts, the venous channel at point 2 was widely separated from the MVA compared to the two ends and in three hearts a nonconsistent pattern was observed. GCV crossed circumflex artery superficially. GCV or CS crossed the left marginal artery and ventricular branches of circumflex artery superficially in 17 and 23 hearts, respectively. As the venous channel was related more to the left atrial wall, PTMA devices probably exert an indirect traction on MVA. The arteries crossing deep to the venous channel may be compressed by PTMA device leading to myocardial ischemia. Knowledge of the spatial relations of MVA and a preoperative and postoperative angiogram may help to reduce such complications during PTMA.

Can vaccinia virus be replaced by MVA virus for testing virucidal activity of chemical disinfectants?

PubMed

Rabenau, Holger F; Rapp, Ingrid; Steinmann, Jochen

2010-06-23

Vaccinia virus strain Lister Elstree (VACV) is a test virus in the DVV/RKI guidelines as representative of the stable enveloped viruses. Since the potential risk of laboratory-acquired infections with VACV persists and since the adverse effects of vaccination with VACV are described, the replacement of VACV by the modified vaccinia Ankara strain (MVA) was studied by testing the activity of different chemical biocides in three German laboratories. The inactivating properties of different chemical biocides (peracetic acid, aldehydes and alcohols) were tested in a quantitative suspension test according to the DVV/RKI guideline. All tests were performed with a protein load of 10% fetal calf serum with both viruses in parallel using different concentrations and contact times. Residual virus was determined by endpoint dilution method. The chemical biocides exhibited similar virucidal activity against VACV and MVA. In three cases intra-laboratory differences were determined between VACV and MVA - 40% (v/v) ethanol and 30% (v/v) isopropanol are more active against MVA, whereas MVA seems more stable than VACV when testing with 0.05% glutardialdehyde. Test accuracy across the three participating laboratories was high. Remarkably inter-laboratory differences in the reduction factor were only observed in two cases. Our data provide valuable information for the replacement of VACV by MVA for testing chemical biocides and disinfectants. Because MVA does not replicate in humans this would eliminate the potential risk of inadvertent inoculation with vaccinia virus and disease in non-vaccinated laboratory workers.

Relationship of Various Open Quotients With Acoustic Property, Phonation Types, Fundamental Frequency, and Intensity.

PubMed

Yokonishi, Hisayuki; Imagawa, Hiroshi; Sakakibara, Ken-Ichi; Yamauchi, Akihito; Nito, Takaharu; Yamasoba, Tatsuya; Tayama, Niro

2016-03-01

In the present study, we examined the relationship between various open quotients (Oqs) and phonation types, fundamental frequency (F0), and intensity by multivariate linear regression analysis (MVA) to determine which Oq best reflects vocal fold vibratory characteristics. Using high-speed digital imaging (HSDI), a sustained vowel /e/ at different phonation types, F0s, and intensities was recorded from six vocally healthy male volunteers: the types of phonation included modal, falsetto, modal breathy, and modal pressed phonations; and each phonation was performed at different F0s and intensities. Electroglottography (EGG) and sound signals were simultaneously recorded with HSDI. From the obtained data, 10 conventional Oqs (four Oqs from the glottal area function, four kymographic Oqs, and two EGG-derived Oqs) and two newly introduced Oqs (Oq(edge)+ and Oq(edge)) were evaluated. And, relationships between various Oqs and phonation types, F0, and intensity were evaluated by MVA. Among the various Oqs, Oq(edge)+ and Oq(edge) revealed the strongest correlations with an acoustic property and could best describe changes in phonation types: Oq(edge) was found to be better than Oq(edge)¯. Oq(MLK), the average of five Oqs from five-line multiline kymography was a very good alternative to Oq(edge)¯. EGG-derived Oqs were able to differentiate between modal phonation and falsetto phonation, but it was necessary to consider the change of F0 simultaneously. MVA showed the changes in Oq values between modal and other phonation types, the degree of involvement of intensity, and no relationship between F0 and Oqs. Among Oqs evaluated in this study, Oq(edge)+ and Oq(edge) were considered to best reflect the vocal fold vibratory characteristics. Copyright © 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial.

PubMed

Overton, Edgar Turner; Lawrence, Steven J; Wagner, Eva; Nopora, Katrin; Rösch, Siegfried; Young, Philip; Schmidt, Darja; Kreusel, Christian; De Carli, Sonja; Meyer, Thomas P; Weidenthaler, Heinz; Samy, Nathaly; Chaplin, Paul

2018-01-01

Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts. The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637. Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment. The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA. ClinicalTrials.gov NCT01144637.

Genetic Adjuvantation of Recombinant MVA with CD40L Potentiates CD8 T Cell Mediated Immunity

PubMed Central

Lauterbach, Henning; Pätzold, Juliane; Kassub, Ronny; Bathke, Barbara; Brinkmann, Kay; Chaplin, Paul; Suter, Mark; Hochrein, Hubertus

2013-01-01

Modified vaccinia Ankara (MVA) is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetically adjuvanted MVA with the coding sequence of murine CD40L, a member of the tumor necrosis factor superfamily. Immunization of mice with this new vector led to strongly enhanced primary and memory CD8 T cell responses. Concordant with the enhanced CD8 T cell response, we could detect stronger activation of dendritic cells and higher systemic levels of innate cytokines (including IL-12p70) early after immunization. Interestingly, acquisition of memory characteristics (i.e., IL-7R expression) was accelerated after immunization with MVA-CD40L in comparison to non-adjuvanted MVA. Furthermore, the generated cytotoxic T-lymphocytes (CTLs) also showed improved functionality as demonstrated by intracellular cytokine staining and in vivo killing activity. Importantly, the superior CTL response after a single MVA-CD40L immunization was able to protect B cell deficient mice against a fatal infection with ectromelia virus. Taken together, we show that genetic adjuvantation of MVA can change strength, quality, and functionality of innate and adaptive immune responses. These data should facilitate a rational vaccine design with a focus on rapid induction of large numbers of CD8 T cells able to protect against specific diseases. PMID:23986761

Using Multimedia Vocabulary Annotations in L2 Reading and Listening Activities

ERIC Educational Resources Information Center

Jing Xu

2010-01-01

This paper reviews the role of multimedia vocabulary annotation (MVA) in facilitating second language (L2) reading and listening activities. It examines the multimedia learning and multimedia language learning theories that underlie the MVA research, synthesizes the findings on MVA in the last decade, and identifies three underresearched areas on…

Modal Vibration Analysis of Large Castings

NASA Technical Reports Server (NTRS)

Werlink, Rudolph J.; Margasahayam, Ravi N.

2009-01-01

The art of experimental modal vibration analysis (MVA) has been extended to apply to large castings. This extension was made to enable the use of experimental MVA as a relatively inexpensive, simple means of assessing the internal structural integrity of tread shoes of crawler transporters used to move spacecraft to the launch pad at Kennedy Space Center. Each tread shoe is made from cast iron and weighs about a ton (has a mass .907 kg). The present extended version of experimental MVA could also be applied to other large castings. It could be especially useful to manufacturers as a means of rapidly discriminating against large castings that contain unacceptably large concentrations of internal defects. The use of experimental MVA to assess structural integrity is not new. What are new here are those aspects of the extension of experimental MVA that pertain to the application of MVA to objects so massive that it may not be practical or cost effective to mount them in special test fixtures that impose special test boundary conditions to test them in place under normal conditions of use.

CORRELATION OF CERVICAL LORDOSIS MEASUREMENT WITH INCIDENCE OF MOTOR VEHICLE ACCIDENTS

PubMed Central

Marshall, Dorothy L.; Tuchin, Peter J.

1996-01-01

A retrospective analysis of 500 patient radiographs was conducted to measure the clinical correlation of cervical lordosis measurements and incidence of motor vehicle accident (MVA). Five hundred lateral cervical radiographs were selected at random from the practice of one of the authors (DLM). The C1-7 angle of the cervical curve was then measured by two blinded examiners. Inter-examiner reliability had a confidence interval of 95%. Eighty-two percent of patients who have had a MVA had an abnormal lordosis. The mean lordosis of patients who had been involved in a MVA was 26.1 degrees (SD 11.4), compared with 36.4 (SD 8.4) for those who had not been involved in a MVA. The results suggest a correlation of reduced cervical lordosis measurements following motor vehicle accident (MVA). PMID:17987143

High doses of granulocyte-macrophage colony stimulating factor inhibit antibody responses in rectal secretions and diminish MVA/SIV vaccine protection in TRIM5α restrictive macaques

PubMed Central

Kannanganat, Sunil; Wyatt, Linda S; Gangadhara, Sailaja; Chamcha, Venkateswarlu; Chea, Lynette S.; Kozlowski, Pamela A; LaBranche, Celia C; Chennareddi, Lakshmi; Lawson, Benton; Reddy, Pradeep B. J.; Styles, Tiffany M.; Vanderford, Thomas H; Montefiori, David C; Moss, Bernard; Robinson, Harriet L; Amara, Rama Rao

2016-01-01

Here, we test in rhesus macaques the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/simian immunodeficiency macaque 239 (SIVmac239) vaccine. High doses of the MVA/GM-CSF did not affect the levels of systemic Env-specific Ab but did decrease the expression of the gut homing receptor α4β7 on plasmacytoid dendritic cells (p<0.01) and the magnitudes of Env-specific IgA (p=0.01) and IgG (p<0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus, SIVsmE660. Eight of 9 TRIM5α-restrictive animals receiving no, or the lowest dose [1×105 plaque forming units (pfu)] of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group only 1 of 12 animals resisted all 12 challenges. In the TRIM5α restrictive, but not permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r=0.6) and IgA (r=0.6), the avidity of Env-specific serum IgG (r=0.5), and antibody dependent cell-mediated virus inhibition (r=0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that (i) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of the TRIM5α restriction, (ii) in TRIM5α restrictive animals, non-neutralizing Ab responses contribute to protection against SIVsmE660, and (iii) high doses of co-expressed MVA/GM-CSF inhibit mucosal Ab responses and MVA/SIV239-elicited protection. PMID:27683750

Comparison of homologous and heterologous prime-boost vaccine approaches using Modified Vaccinia Ankara and soluble protein to induce neutralizing antibodies by the human cytomegalovirus pentamer complex in mice.

PubMed

Chiuppesi, Flavia; Wussow, Felix; Scharf, Louise; Contreras, Heidi; Gao, Han; Meng, Zhuo; Nguyen, Jenny; Barry, Peter A; Bjorkman, Pamela J; Diamond, Don J

2017-01-01

Since neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) pentamer complex (PC) potently block HCMV host cell entry, anti-PC NAb induction is thought to be important for a vaccine formulation to prevent HCMV infection. By developing a vaccine strategy based on soluble PC protein and using a previously generated Modified Vaccinia Ankara vector co-expressing all five PC subunits (MVA-PC), we compared HCMV NAb induction by homologous immunization using prime-boost vaccine regimen employing only PC protein or MVA-PC and heterologous immunization using prime-boost combinations of PC protein and MVA-PC. Utilizing a recently isolated anti-PC NAb, we produced highly pure soluble PC protein that displayed conformational and linear neutralizing epitopes, interfered with HCMV entry, and was recognized by antibodies induced by HCMV during natural infection. Mice vaccinated by different immunization routes with the purified PC protein in combination with a clinically approved adjuvant formulation elicited high-titer and durable HCMV NAb. While MVA-PC and soluble PC protein either alone or in combination elicited robust HCMV NAb, significantly different potencies of these vaccine approaches were observed in dependence on immunization schedule. Using only two immunizations, vaccination with MVA-PC alone or prime-boost combinations of MVA-PC and PC protein was significantly more effective in stimulating HCMV NAb than immunization with PC protein alone. In contrast, with three immunizations, NAb induced by soluble PC protein either alone or combined with two boosts of MVA-PC increased to levels that exceeded NAb titer stimulated by MVA-PC alone. These results provide insights into the potency of soluble protein and MVA to elicit NAb by the HCMV PC via homologous and heterologous prime-boost immunization, which may contribute to develop clinically deployable vaccine strategies to prevent HCMV infection.

Impact of HIV knowledge and stigma on the uptake of HIV testing – Results from a community-based participatory research survey among migrants from sub-Saharan Africa in Germany

PubMed Central

Koschollek, Carmen; Santos-Hövener, Claudia; Thorlie, Adama; Müllerschön, Johanna; Mputu Tshibadi, Christina; Mayamba, Pierre; Batemona-Abeke, Helene; Amoah, Stephen; Wangare Greiner, Virginia; Dela Bursi, Taty; Bremer, Viviane

2018-01-01

Background In 2015, 3,674 new HIV diagnoses were notified in Germany; 16% of those newly diagnosed cases originated from sub-Saharan Africa (sSA). One quarter of the newly diagnosed cases among migrants from sSA (MisSA) are notified as having acquired the HIV infection in Germany. In order to reach MisSA with HIV testing opportunities, we aimed to identify which determinants influence the uptake of HIV testing among MisSA in Germany. Methods To identify those determinants, we conducted a quantitative cross-sectional survey among MisSA in Germany. The survey was designed in a participatory process that included MisSA and other stakeholders in HIV-prevention. Peer researchers recruited participants to complete standardized questionnaires on HIV knowledge and testing. We conducted multivariable analyses (MVA) to identify determinants associated with ever having attended voluntary HIV testing; and another MVA to identify determinant associated with having had the last voluntary HIV test in Germany. Results Peer researchers recruited 2,782 participants eligible for inclusion in the MVA. Of these participants, 59.9% (1,667/2,782) previously had an HIV test. For each general statement about HIV that participants knew prior to participation in the study, the odds of having been tested increased by 19% (OR 1.19; 95%-CI: 1.11–1.27). Participants reporting that HIV is a topic that is discussed in their community had 92% higher odds of having been tested for HIV (OR 1.92; 95%-CI: 1.60–2.31). Migrants living in Germany for less than a year had the lowest odds of having had their last HIV test in Germany (OR 0.17; 95%-CI: 0.11–0.27). Additionally, MisSA 18 to 25 years (OR 0.55; 95%-CI: 0.42–0.73) and participants with varied sexual partners and inconsistent condom use (OR 0.75; 95%-CI: 0.44–0.97) had significantly lower odds of having had their last HIV test in Germany. Discussion Through participatory research, we were able to show that knowledge about HIV and discussing HIV in communities increased the odds of having attended HIV testing among MisSA. However, recent migrants and young sexually active people are among the least reached by testing offers in Germany. Community-based interventions may present opportunities to reach such migrants and improve knowledge and increase discussion about HIV. PMID:29641527

"Right tool," wrong "job": Manual vacuum aspiration, post-abortion care and transnational population politics in Senegal.

PubMed

Suh, Siri

2015-06-01

The "rightness" of a technology for completing a particular task is negotiated by medical professionals, patients, state institutions, manufacturing companies, and non-governmental organizations. This paper shows how certain technologies may challenge the meaning of the "job" they are designed to accomplish. Manual vacuum aspiration (MVA) is a syringe device for uterine evacuation that can be used to treat complications of incomplete abortion, known as post-abortion care (PAC), or to terminate pregnancy. I explore how negotiations over the rightness of MVA as well as PAC unfold at the intersection of national and global reproductive politics during the daily treatment of abortion complications at three hospitals in Senegal, where PAC is permitted but induced abortion is legally prohibited. Although state health authorities have championed MVA as the "preferred" PAC technology, the primary donor for PAC, the United States Agency for International Development, does not support the purchase of abortifacient technologies. I conducted an ethnography of Senegal's PAC program between 2010 and 2011. Data collection methods included interviews with 49 health professionals, observation of PAC treatment and review of abortion records at three hospitals, and a review of transnational literature on MVA and PAC. While MVA was the most frequently employed form of uterine evacuation in hospitals, concerns about off-label MVA practices contributed to the persistence of less effective methods such as dilation and curettage (D&C) and digital curettage. Anxieties about MVA's capacity to induce abortion have constrained its integration into routine obstetric care. This capacity also raises questions about what the "job," PAC, represents in Senegalese hospitals. The prioritization of MVA's security over women's access to the preferred technology reinforces gendered inequalities in health care. Copyright © 2015 Elsevier Ltd. All rights reserved.

Microarray Analysis Reveals Characteristic Changes of Host Cell Gene Expression in Response to Attenuated Modified Vaccinia Virus Ankara Infection of Human HeLa Cells

PubMed Central

Guerra, Susana; López-Fernández, Luis A.; Conde, Raquel; Pascual-Montano, Alberto; Harshman, Keith; Esteban, Mariano

2004-01-01

The potential use of the modified vaccinia virus Ankara (MVA) strain as a live recombinant vector to deliver antigens and elicit protective immune responses against infectious diseases demands a comprehensive understanding of the effect of MVA infection on human host gene expression. We used microarrays containing more than 15,000 human cDNAs to identify gene expression changes in human HeLa cell cultures at 2, 6, and 16 h postinfection. Clustering of the 410 differentially regulated genes identified 11 discrete gene clusters with altered expression patterns after MVA infection. Clusters 1 and 2 (accounting for 16.59% [68 of 410] of the genes) contained 68 transcripts showing a robust induction pattern that was maintained during the course of infection. Changes in cellular gene transcription detected by microarrays after MVA infection were confirmed for selected genes by Northern blot analysis and by real-time reverse transcription-PCR. Upregulated transcripts in clusters 1 and 2 included 20 genes implicated in immune responses, including interleukin 1A (IL-1A), IL-6, IL-7, IL-8, and IL-15 genes. MVA infection also stimulated the expression of NF-κB and components of the NF-κB signal transduction pathway, including p50 and TRAF-interacting protein. A marked increase in the expression of histone family members was also induced during MVA infection. Expression of the Wiskott-Aldrich syndrome family members WAS, WASF1, and the small GTP-binding protein RAC-1, which are involved in actin cytoskeleton reorganization, was enhanced after MVA infection. This study demonstrates that MVA infection triggered the induction of groups of genes, some of which may be involved in host resistance and immune modulation during virus infection. PMID:15140980

“Right tool,” wrong “job”: Manual vacuum aspiration, post-abortion care and transnational population politics in Senegal

PubMed Central

Suh, Siri

2015-01-01

The “rightness” of a technology for completing a particular task is negotiated by medical professionals, patients, state institutions, manufacturing companies, and non-governmental organizations. This paper shows how certain technologies may challenge the meaning of the “job” they are designed to accomplish. Manual vacuum aspiration (MVA) is a syringe device for uterine evacuation that can be used to treat complications of incomplete abortion, known as post-abortion care (PAC), or to terminate pregnancy. I explore how negotiations over the rightness of MVA as well as PAC unfold at the intersection of national and global reproductive politics during the daily treatment of abortion complications at three hospitals in Senegal, where PAC is permitted but induced abortion is legally prohibited. Although state health authorities have championed MVA as the “preferred” PAC technology, the primary donor for PAC, the United States Agency for International Development, does not support the purchase of abortifacient technologies. I conducted an ethnography of Senegal's PAC program between 2010 and 2011. Data collection methods included interviews with 49 health professionals, observation of PAC treatment and review of abortion records at three hospitals, and a review of transnational literature on MVA and PAC. While MVA was the most frequently employed form of uterine evacuation in hospitals, concerns about off-label MVA practices contributed to the persistence of less effective methods such as dilation and curettage (D&C) and digital curettage. Anxieties about MVA's capacity to induce abortion have constrained its integration into routine obstetric care. This capacity also raises questions about what the “job,” PAC, represents in Senegalese hospitals. The prioritization of MVA's security over women's access to the preferred technology reinforces gendered inequalities in health care. PMID:25948127

Synoptic analysis of heat waves in the Barcelona city (Catalonia, Spain) during 21st century

NASA Astrophysics Data System (ADS)

Amaro, Jéssica; Peña, Juan Carlos; Miró, Josep Ramon; Aran, Montserrat

2017-04-01

The impact of extremely warm episodes on health has been analysed by a large number of studies conducted in different countries and cities, showing that heat waves events (HWE) can cause an abrupt increase in mortality. A HWE was defined as a 7-day sequence following a key-day labelled by the 95th percentile of Barcelona daily mortality (see Peña et al., 2015). The aim of this study is to identify synoptic patterns associated to HWE in Barcelona over the 21st century and evaluate the impact and possible mitigations. To achieve it, a multivariate analysis (MVA) integrating different atmospheric levels (sea level pressure, temperature at 850 hPa and geopotential at 500 hPa) was undertaken. The observed data used for this study was the 20th Century Reanalysis. The Max Planck Institute Earth system model was used to study two scenarios (RCP 4.5 and RCP 8.5) during the 21st century. The model was calibrated given the variability in the climate scenario, using the Quantile-Quantile mapping transformation (Q-Q). The MVA applied to the observed period (1990-2015) distinguish three main synoptic patterns: two dynamic configurations produced by southern fluxes related to an Atlantic low, associated with HWE recorded in southern Europe, and a third pattern identified by a stagnation situation related to persistent anticyclone periods. These patterns were also detected in the control simulated period (1961-2005) after the Q-Q calibration, preserving, therefore, the climatic variability: the number of HWE during the warm period (1990-2005) is twice more than during the cold period (1976-1989) due to an intensification of the warm masses. In the RCP 4.5 scenario (2006-2100 period) a positive and significant trend is shown in synoptic patterns which provoke HWE in Barcelona, especially during August; in the RCP 8.5 scenario there is no significant trend, but the intensification of the warm masses is higher.

Survival benefit of postoperative radiation in papillary meningioma: Analysis of the National Cancer Data Base.

PubMed

Sumner, Whitney A; Amini, Arya; Hankinson, Todd C; Foreman, Nicholas K; Gaspar, Laurie E; Kavanagh, Brian D; Karam, Sana D; Rusthoven, Chad G; Liu, Arthur K

2017-01-01

Papillary meningioma represents a rare subset of World Health Organization (WHO) Grade III meningioma that portends an overall poor prognosis. There is relatively limited data regarding the benefit of postoperative radiation therapy (PORT). We used the National Cancer Data Base (NCDB) to compare overall survival (OS) outcomes of surgically resected papillary meningioma cases undergoing PORT compared to post-operative observation. The NCDB was queried for patients with papillary meningioma, diagnosed between 2004 and 2013, who underwent upfront surgery with or without PORT. Overall survival (OS) was determined using the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) analyses were performed. In total, 190 patients were identified; 89 patients underwent PORT, 101 patients were observed. Eleven patients received chemotherapy (6 with PORT, 5 without). 2-Year OS was significantly improved with PORT vs. no PORT (93.0% vs. 74.4%), as was 5-year OS (78.5% vs. 62.5%) (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27-0.85; p  = 0.01). On MVA, patients receiving PORT had improved OS compared to observation (HR, 0.41; 95% CI, 0.22-0.76; p  = 0.005). On subset analysis by age group, the benefit of PORT vs. no PORT was significant in patients ≤18 years ( n  = 13), with 2-year OS of 85.7% vs. 50.0% (HR, 0.08; 95% CI, 0.01-0.80; p  = 0.032) and for patients >18 years ( n  = 184), with 2-year OS of 94.7% vs. 76.1% (HR, 0.55; 95% CI, 0.31-1.00; p  = 0.049), respectively. In this large contemporary analysis, PORT was associated with improved survival for both adult and pediatric patients with papillary meningioma. PORT should be considered in those who present with this rare, aggressive tumor.

Ultra-sensitive PSA Following Prostatectomy Reliably Identifies Patients Requiring Post-Op Radiotherapy

PubMed Central

Kang, Jung Julie; Reiter, Robert; Steinberg, Michael; King, Christopher R.

2015-01-01

PURPOSE Integrating ultra-sensitive PSA (uPSA) into surveillance of high-risk patients following radical prostatectomy (RP) potentially optimizes management by correctly identifying actual recurrences, promoting an early salvage strategy and minimizing overtreatment. The power of uPSA following surgery to identify eventual biochemical failures is tested. PATIENTS AND METHODS From 1991–2013, 247 high-risk patients with a median follow-up was 44 months after RP were identified (extraprostatic extension and/or positive margin). Surgical technique, initial PSA (iPSA), pathology and post-op PSA were analyzed. The uPSA assay threshold was 0.01 ng/mL. Conventional biochemical relapse (cBCR) was defined as PSA ≥0.2 ng/mL. Kaplan Meier and Cox multivariate analyses (MVA) compared uPSA recurrence vs. cBCR rates. RESULTS Sensitivity analysis identified uPSA ≥0.03 as the optimal threshold identifying recurrence. First post-op uPSA ≥0.03, Gleason grade, T-stage, iPSA, and margin status predicted cBCR. On MVA, only first post-op uPSA ≥0.03, Gleason grade, and T-stage independently predicted cBCR. First post-op uPSA ≥0.03 conferred the highest risk (HR 8.5, p<0.0001) and discerned cBCR with greater sensitivity than undetectable first conventional PSA (70% vs. 46%). Any post-op PSA ≥0.03 captured all failures missed by first post-op value (100% sensitivity) with accuracy (96% specificity). Defining failure at uPSA ≥0.03 yielded a median lead-time advantage of 18 months (mean 24 months) over the conventional PSA ≥0.2 definition. CONCLUSION uPSA ≥0.03 is an independent factor, identifies BCR more accurately than any traditional risk factors, and confers a significant lead-time advantage. uPSA enables critical decisions regarding timing and indication for post-op RT among high-risk patients following RP. PMID:25463990

Iron overload in lower international prognostic scoring system risk patients with myelodysplastic syndrome receiving red blood cell transfusions: Relation to infections and possible benefit of iron chelation therapy.

PubMed

Wong, Colleen A C; Wong, Shannon A Y; Leitch, Heather A

2018-04-01

An increased incidence of infections and infectious mortality has been reported in myelodysplastic syndromes (MDS) patients receiving red blood cell (RBC) transfusions. We examined incidence of infections requiring antibiotics, antifungal or antiviral medications in transfused lower International Prognostic Scoring System (IPSS) risk MDS patients and whether this differed with iron chelation therapy (ICT). 138 transfused MDS patients were lower IPSS risk. 59 received ICT; median duration was 13 months. There was no significant difference between groups in neutrophil count at first RBC transfusion or first infection. Infections included: bacterial, n = 88; viral; fungal; and mycobacterial; n = 2 each. In ICT and non-ICT patients, respectively, infections were (number [%]): patients, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and deaths, 0 (0%) and 1 (1.3%), p = NS for all. Median overall survival (OS) from first RBC transfusion was superior in ICT patients, p = 0.01, and remained significant in a multivariate analysis (MVA), p = 0.003. Median time to first infection (TTI) was 27 and 7.8 months, respectively, p < 0.0001, and ICT remained significant for TTI in an MVA, p = 0.02, hazard ratio 0.3. For ICT patients with blast count <5%, TTI was significantly superior (p = 0.004). In this retrospective analysis, for lower IPSS risk MDS patients receiving RBC transfusions, though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients (p < 0.0001). These results should be confirmed in larger, prospective analyses. Copyright © 2018 Elsevier Ltd. All rights reserved.

Multi-institutional evaluation of the prognostic significance of EZH2 expression in high-grade upper tract urothelial carcinoma.

PubMed

Singla, Nirmish; Krabbe, Laura-Maria; Aydin, Ahmet M; Panwar, Vandana; Woldu, Solomon L; Freifeld, Yuval; Wood, Christopher G; Karam, Jose A; Weizer, Alon Z; Raman, Jay D; Remzi, Mesut; Rioux-Leclercq, Nathalie; Haitel, Andrea; Roscigno, Marco; Bolenz, Christian; Bensalah, Karim; Sagalowsky, Arthur I; Shariat, Shahrokh F; Lotan, Yair; Bagrodia, Aditya; Kapur, Payal; Margulis, Vitaly

2018-07-01

Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC. We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05. A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21-3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06-2.24], P = 0.024), while significance was lost for RFS. Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated. Copyright © 2018 Elsevier Inc. All rights reserved.

The Effect of Radiation on Complication Rates and Patient Satisfaction in Breast Reconstruction using Temporary Tissue Expanders and Permanent Implants.

PubMed

Anker, Christopher J; Hymas, Richard V; Ahluwalia, Ravinder; Kokeny, Kristine E; Avizonis, Vilija; Boucher, Kenneth M; Neumayer, Leigh A; Agarwal, Jayant P

2015-01-01

The optimal method of reconstruction following mastectomy for breast cancer patients receiving radiation therapy (RT) is controversial. This study evaluated patient satisfaction and complication rates among patients who received implant-based breast reconstruction. The specific treatment algorithm analyzed included patients receiving mastectomy and immediate temporary tissue expander (TE), followed by placement of a permanent breast implant (PI). If indicated, RT was delivered to the fully expanded TE. Records of 218 consecutive patients with 222 invasive (85%) or in situ (15%) breast lesions from the Salt Lake City region treated between 1998 and 2009 were retrospectively reviewed, 28% of whom received RT. Median RT dose was 50.4 Gy, and 41% received a scar boost at a median dose of 10 Gy. Kaplan-Meier analyses were performed to evaluate the cumulative incidence of surgical complications, including permanent PI removal. Risk factors associated with surgical events were analyzed. To evaluate cosmetic results and patient satisfaction, an anonymous survey was administered. Mean follow-up was 44 months (range 6-144). Actuarial 5-year PI removal rates for non-RT and RT patients were 4% and 22%, respectively. On multivariate analysis (MVA), the only factor associated with PI removal was RT (p = 0.009). Surveys were returned describing the outcomes of 149 breasts. For the non-RT and RT groups, those who rated their breast appearance as good or better were 63% versus 62%, respectively. Under 1/3 of each group was dissatisfied with their reconstruction. RT did not significantly affect patient satisfaction scores, but on MVA RT was the only factor associated with increased PI removal. This reconstruction technique may be considered an acceptable option even if RT is needed, but the increased complication risk with RT must be recognized. © 2015 Wiley Periodicals, Inc.

Induction of Both Local Immune Response in Mice and Protection in a Rabbit Model by Intranasal Immunization with Modified Vaccinia Ankara Virus Expressing a Secreted Form of Bovine Herpesvirus 1 Glycoprotein D.

PubMed

Del Medico Zajac, María Paula; Zanetti, Flavia Adriana; Esusy, María Soledad; Federico, Carlos Rodolfo; Zabal, Osvaldo; Valera, Alejandro Rafael; Calamante, Gabriela

In this study, we evaluated the immunogenicity and efficacy of mucosal delivery of a recombinant modified vaccinia Ankara virus (MVA) expressing the secreted version of bovine herpesvirus type 1 (BoHV-1) glycoprotein D (MVA-gDs) without addition of adjuvant in two animal models. First, we demonstrated the capability of MVA-gDs of inducing both local and systemic anti-gD humoral immune response after intranasal immunization of mice. Then, we confirmed that two doses of MVA-gDs administered intranasally to rabbits induced systemic anti-gD antibodies and conferred protection against BoHV-1 challenge. Our results show the potential of using MVA as a vector for the rational design of veterinary vaccines capable of inducing specific and protective immune responses both at local and systemic level.

Poly-MVA attenuates 7,12- dimethylbenz[a]anthracene initiated and croton oil promoted skin papilloma formation on mice skin.

PubMed

Veena, Ravindran K; Ajith, Thekkuttuparambil A; Janardhanan, Kainoor K; Antonawich, Francis

2017-09-01

Chemopreventive agents which exhibit activities such as anti-inflammation, inhibition of carcinogen induced mutagenesis and scavenging of free radical might play a decisive role in the inhibition of chemical carcinogenesis either at the initiation or promotion stage. Many synthesized palladium (Pd) complexes tested experimentally for antitumor activity are found effective. Poly-MVA is a liquid blend preparation containing B complex vitamins, ruthenium with Pd complexed with alpha lipoic acid as the major ingredients. The antitumor effect of Poly-MVA was evaluated against 7,12-dimethylbenz[a] anthracene-initiated croton oil-promoted papilloma formation on mice skin. Skin tumor was initiated with a single application of 390 nmol of DMBA in 20 µl acetone. The effect of Poly-MVA against croton oil- induced inflammation and lipid peroxidation on the mice skin was also evaluated. Topical application of Poly-MVA (100 µl, twice weekly for 18 weeks) 30 minutes prior to each croton oil application, significantly decreased the tumor incidence (11%) and the average number of tumor per animals. Application of Poly-MVA (100 µl) before croton oil significantly (p &#60; 0.05) protected the mouse skin from inflammation (36%) and lipid peroxidation (14%) when compared to the croton oil alone treated group. Experimental results indicate that Poly-MVA attenuate the tumor promoting effects of croton oil and the effect may probably be due to its anti-inflammatory and antioxidant activity.

Vaccination with recombinant Modified Vaccinia Ankara (MVA) viruses expressing single African horse sickness virus VP2 antigens induced cross-reactive virus neutralising antibodies (VNAb) in horses when administered in combination.

PubMed

Manning, Nicola Mary; Bachanek-Bankowska, Katarzyna; Mertens, Peter Paul Clement; Castillo-Olivares, Javier

2017-10-20

African horse sickness is a lethal viral disease of equids transmitted by biting midges of the Genus Culicoides. The disease is endemic to sub-Saharan Africa but outbreaks of high mortality and economic impact have occurred in the past in non-endemic regions of Africa, Asia and Southern Europe. Vaccination is critical for the control of this disease but only live attenuated vaccines are currently available. However, there are bio-safety concerns over the use of this type of vaccines, especially in non-endemic countries, and live attenuated vaccines do not have DIVA (Differentiation of Infected from Vaccinated Animals) capacity. In addition, large scale manufacturing of live attenuated vaccines of AHSV represents a significant environmental and health risk and level 3 bio-safety containment facilities are required for their production. A variety of different technologies have been investigated over the years to develop alternative AHSV vaccines, including the use of viral vaccine vectors such Modified Vaccinia Ankara virus (MVA). In previous studies we demonstrated that recombinant MVA expressing outer capsid protein AHSV-VP2 induced virus neutralising antibodies and protection against virulent challenge both in a mouse model and in the horse. However, AHSV-VP2 is antigenically variable and determines the existence of 9 different AHSV serotypes. Immunity against AHSV is serotype-specific and there is limited cross-reactivity between certain AHSV serotypes: 1 and 2, 3 and 7, 5 and 8, 6 and 9. In Africa, multiple serotypes circulate simultaneously and a polyvalent attenuated vaccine comprising different AHSV serotypes is used. We investigated the potential of a polyvalent AHSV vaccination strategy based on combinations of MVA-VP2 viruses each expressing a single VP2 antigen from a specific serotype. We showed that administration of 2 different recombinant MVA viruses, each expressing a single VP2 protein from AHSV serotype 4 or 9, denoted respectively as MVA-VP2(4) and MVA-VP2(9), induced virus neutralising antibodies against the homologous AHSV serotypes. Vaccination was more efficient when vaccines were administered simultaneously than when they were administered sequentially. A third and fourth dose of a different MVA expressing VP2 of AHSV serotype 5, given 4months later to ponies previously vaccinated with MVA-VP2(4) and MVA-VP2(9), resulted in the induction of VNAb against serotypes 4, 5, 6, 8 and 9. The anamnestic antibody response against AHSV 9 and AHSV 4 following the MVA-VP2(5) boost suggests that it is possible some shared epitopes exist between different serotypes. In conclusion this study showed that it is feasible to develop a polyvalent AHSV vaccination regime based on the use of combinations of MVA-VP2 viruses. Copyright © 2017. Published by Elsevier Ltd.

Modified Vaccinia Ankara Virus Vaccination Provides Long-Term Protection against Nasal Rabbitpox Virus Challenge.

PubMed

Jones, Dorothy I; McGee, Charles E; Sample, Christopher J; Sempowski, Gregory D; Pickup, David J; Staats, Herman F

2016-07-01

Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. This study was performed to determine if MVA vaccination provides long-term protection against rabbitpox virus (RPXV) challenge, an animal model of smallpox. Two doses of MVA provided 100% protection against a lethal intranasal RPXV challenge administered 9 months after vaccination. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A novel MVA-mediated pathway for isoprene production in engineered E. coli.

PubMed

Yang, Jianming; Nie, Qingjuan; Liu, Hui; Xian, Mo; Liu, Huizhou

2016-01-20

To deal with the increasingly severe energy crisis and environmental consequences, biofuels and biochemicals generated from renewable resources could serve as a promising alternative for replacing petroleum as a source of fuel and chemicals, among which isoprene (2-methyl-1,3-butadiene) in particular is of great significance in that it is an important platform chemical, which has been used in industrial production of synthetic rubber for tires and coatings or aviation fuel. We firstly introduced fatty acid decarboxylase (OleTJE) from Jeotgalicoccus species into E. coli to directly convert MVA(mevalonate) into 3-methy-3-buten-1-ol. And then to transform 3-methy-3-buten-1-ol to isoprene, oleate hydratase (OhyAEM) from Elizabethkingia meningoseptica was overexpressed in E. coli. A novel biosynthetic pathway of isoprene in E. coli was established by co-expressing the heterologous mvaE gene encoding acetyl-CoA acetyltransferase/HMG-CoA reductase and mvaS gene encoding HMG-CoA synthase from Enterococcus faecalis, fatty acid decarboxylase (OleTJE) and oleate hydratase (OhyAEM). Furthermore, to enhance isoprene production, a further optimization of expression level of OleTJE, OhyAEM was carried out by using different promoters and copy numbers of plasmids. Thereafter, the fermentation process was also optimized to improve the production of isoprene. The final engineered strain, YJM33, bearing the innovative biosynthetic pathway of isoprene, was found to produce isoprene up to 2.2 mg/L and 620 mg/L under flask and fed-batch fermentation conditions, respectively. In this study, by using metabolic engineering techniques, the novel MVA-mediated biosynthetic pathway of isoprene was successfully assembled in E. coli BL21(DE3) with the heterologous MVA upper pathway, OleTJE from Jeotgalicoccus species and OhyAEM from Elizabethkingia meningoseptica. Compared with traditional MVA pathway, the novel pathway is shortened by 3 steps. In addition, this is the first report on the reaction of converting MVA into 3-methy-3-buten-1-ol by fatty acid decarboxylase (OleTJE) from Jeotgalicoccus species. In brief, this study provided an alternative method for isoprene biosynthesis, which is largely different from the well-developed MEP pathway or MVA pathway.

Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

PubMed

Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

2015-12-04

Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.

Quantitative assessment of copper proteinates used as animal feed additives using ATR-FTIR spectroscopy and powder X-ray diffraction (PXRD) analysis.

PubMed

Cantwell, Caoimhe A; Byrne, Laurann A; Connolly, Cathal D; Hynes, Michael J; McArdle, Patrick; Murphy, Richard A

2017-08-01

The aim of the present work was to establish a reliable analytical method to determine the degree of complexation in commercial metal proteinates used as feed additives in the solid state. Two complementary techniques were developed. Firstly, a quantitative attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopic method investigated modifications in vibrational absorption bands of the ligand on complex formation. Secondly, a powder X-ray diffraction (PXRD) method to quantify the amount of crystalline material in the proteinate product was developed. These methods were developed in tandem and cross-validated with each other. Multivariate analysis (MVA) was used to develop validated calibration and prediction models. The FTIR and PXRD calibrations showed excellent linearity (R 2  > 0.99). The diagnostic model parameters showed that the FTIR and PXRD methods were robust with a root mean square error of calibration RMSEC ≤3.39% and a root mean square error of prediction RMSEP ≤7.17% respectively. Comparative statistics show excellent agreement between the MVA packages assessed and between the FTIR and PXRD methods. The methods can be used to determine the degree of complexation in complexes of both protein hydrolysates and pure amino acids.

DNA and modified vaccinia virus Ankara vaccines encoding multiple cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) are safe but weakly immunogenic in HIV-1-uninfected, vaccinia virus-naive adults.

PubMed

Gorse, Geoffrey J; Newman, Mark J; deCamp, Allan; Hay, Christine Mhorag; De Rosa, Stephen C; Noonan, Elizabeth; Livingston, Brian D; Fuchs, Jonathan D; Kalams, Spyros A; Cassis-Ghavami, Farah L

2012-05-01

We evaluated a DNA plasmid-vectored vaccine and a recombinant modified vaccinia virus Ankara vaccine (MVA-mBN32), each encoding cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) in a randomized, double-blinded, placebo-controlled trial in 36 HIV-1-uninfected adults using a heterologous prime-boost schedule. HIV-1-specific cellular immune responses, measured as interleukin-2 and/or gamma interferon production, were induced in 1 (4%) of 28 subjects after the first MVA-mBN32 immunization and in 3 (12%) of 25 subjects after the second MVA-mBN32 immunization. Among these responders, polyfunctional T-cell responses, including the production of tumor necrosis factor alpha and perforin, were detected. Vaccinia virus-specific antibodies were induced to the MVA vector in 27 (93%) of 29 and 26 (93%) of 28 subjects after the first and second immunizations with MVA-mBN32. These peptide-based vaccines were safe but were ineffective at inducing HIV-1-specific immune responses and induced much weaker responses than MVA vaccines expressing the entire open reading frames of HIV-1 proteins.

Masked Visual Analysis: Minimizing Type I Error in Visually Guided Single-Case Design for Communication Disorders

PubMed Central

Hitchcock, Elaine R.; Ferron, John

2017-01-01

Purpose Single-case experimental designs are widely used to study interventions for communication disorders. Traditionally, single-case experiments follow a response-guided approach, where design decisions during the study are based on participants' observed patterns of behavior. However, this approach has been criticized for its high rate of Type I error. In masked visual analysis (MVA), response-guided decisions are made by a researcher who is blinded to participants' identities and treatment assignments. MVA also makes it possible to conduct a hypothesis test assessing the significance of treatment effects. Method This tutorial describes the principles of MVA, including both how experiments can be set up and how results can be used for hypothesis testing. We then report a case study showing how MVA was deployed in a multiple-baseline across-subjects study investigating treatment for residual errors affecting rhotics. Strengths and weaknesses of MVA are discussed. Conclusions Given their important role in the evidence base that informs clinical decision making, it is critical for single-case experimental studies to be conducted in a way that allows researchers to draw valid inferences. As a method that can increase the rigor of single-case studies while preserving the benefits of a response-guided approach, MVA warrants expanded attention from researchers in communication disorders. PMID:28595354

Elements in the Development of a Production Process for Modified Vaccinia Virus Ankara

PubMed Central

Jordan, Ingo; Lohr, Verena; Genzel, Yvonne; Reichl, Udo; Sandig, Volker

2013-01-01

The production of several viral vaccines depends on chicken embryo fibroblasts or embryonated chicken eggs. To replace this logistically demanding substrate, we created continuous anatine suspension cell lines (CR and CR.pIX), developed chemically-defined media, and established production processes for different vaccine viruses. One of the processes investigated in greater detail was developed for modified vaccinia virus Ankara (MVA). MVA is highly attenuated for human recipients and an efficient vector for reactogenic expression of foreign genes. Because direct cell-to-cell spread is one important mechanism for vaccinia virus replication, cultivation of MVA in bioreactors is facilitated if cell aggregates are induced after infection. This dependency may be the mechanism behind our observation that a novel viral genotype (MVA-CR) accumulates with serial passage in suspension cultures. Sequencing of a major part of the genomic DNA of the new strain revealed point mutations in three genes. We hypothesize that these changes confer an advantage because they may allow a greater fraction of MVA-CR viruses to escape the host cells for infection of distant targets. Production and purification of MVA-based vaccines may be simplified by this combination of designed avian cell line, chemically defined media and the novel virus strain. PMID:27694766

Elements in the Development of a Production Process for Modified Vaccinia Virus Ankara.

PubMed

Jordan, Ingo; Lohr, Verena; Genzel, Yvonne; Reichl, Udo; Sandig, Volker

2013-11-01

The production of several viral vaccines depends on chicken embryo fibroblasts or embryonated chicken eggs. To replace this logistically demanding substrate, we created continuous anatine suspension cell lines (CR and CR.pIX), developed chemically-defined media, and established production processes for different vaccine viruses. One of the processes investigated in greater detail was developed for modified vaccinia virus Ankara (MVA). MVA is highly attenuated for human recipients and an efficient vector for reactogenic expression of foreign genes. Because direct cell-to-cell spread is one important mechanism for vaccinia virus replication, cultivation of MVA in bioreactors is facilitated if cell aggregates are induced after infection. This dependency may be the mechanism behind our observation that a novel viral genotype (MVA-CR) accumulates with serial passage in suspension cultures. Sequencing of a major part of the genomic DNA of the new strain revealed point mutations in three genes. We hypothesize that these changes confer an advantage because they may allow a greater fraction of MVA-CR viruses to escape the host cells for infection of distant targets. Production and purification of MVA-based vaccines may be simplified by this combination of designed avian cell line, chemically defined media and the novel virus strain.

Masked Visual Analysis: Minimizing Type I Error in Visually Guided Single-Case Design for Communication Disorders.

PubMed

Byun, Tara McAllister; Hitchcock, Elaine R; Ferron, John

2017-06-10

Single-case experimental designs are widely used to study interventions for communication disorders. Traditionally, single-case experiments follow a response-guided approach, where design decisions during the study are based on participants' observed patterns of behavior. However, this approach has been criticized for its high rate of Type I error. In masked visual analysis (MVA), response-guided decisions are made by a researcher who is blinded to participants' identities and treatment assignments. MVA also makes it possible to conduct a hypothesis test assessing the significance of treatment effects. This tutorial describes the principles of MVA, including both how experiments can be set up and how results can be used for hypothesis testing. We then report a case study showing how MVA was deployed in a multiple-baseline across-subjects study investigating treatment for residual errors affecting rhotics. Strengths and weaknesses of MVA are discussed. Given their important role in the evidence base that informs clinical decision making, it is critical for single-case experimental studies to be conducted in a way that allows researchers to draw valid inferences. As a method that can increase the rigor of single-case studies while preserving the benefits of a response-guided approach, MVA warrants expanded attention from researchers in communication disorders.

Isopentenyl diphosphate (IPP)-bypass mevalonate pathways for isopentenol production

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

Kang, Aram; George, Kevin W.; Wang, George

Branched C 5 alcohols are promising biofuels with excellent combustion properties. A mevalonate (MVA)-based isoprenoid biosynthetic pathway for C 5 alcohols was constructed in Escherichia coli using genes from several organisms, and the pathway was optimized to achieve over 50% theoretical yield. Although the MVA pathway is energetically less efficient than the native methylerythritol 4-phosphate (MEP) pathway, implementing the MVA pathway in bacterial hosts such as E. coli is advantageous due to its lack of endogenous regulation. The MVA and MEP pathways intersect at isopentenyl diphosphate (IPP), the direct precursor to isoprenoid-derived C 5 alcohols and initial precursor to longermore » chain terpenes, which makes independent regulation of the pathways difficult. In pursuit of the complete "decoupling" of the MVA pathway from native cellular regulation, we designed novel IPP-bypass MVA pathways for C 5 alcohol production by utilizing promiscuous activities of two enzymes, phosphomevalonate decarboxylase (PMD) and an E. coli-endogenous phosphatase (AphA). These bypass pathways have reduced energetic requirements, are further decoupled from intrinsic regulation, and are free from IPP-related toxicity. In addition to these benefits, we demonstrate that reduced aeration rate has less impact on the bypass pathway than the original MVA pathway. Finally, we showed that performance of the bypass pathway was primarily determined by the activity of PMD. We designed PMD mutants with improved activity and demonstrated titer increases in the mutant strains. These modified pathways would be a good platform for industrial production of isopentenol and related chemicals such as isoprene.« less

Isopentenyl diphosphate (IPP)-bypass mevalonate pathways for isopentenol production

DOE PAGES

Kang, Aram; George, Kevin W.; Wang, George; ...

2015-12-17

Branched C 5 alcohols are promising biofuels with excellent combustion properties. A mevalonate (MVA)-based isoprenoid biosynthetic pathway for C 5 alcohols was constructed in Escherichia coli using genes from several organisms, and the pathway was optimized to achieve over 50% theoretical yield. Although the MVA pathway is energetically less efficient than the native methylerythritol 4-phosphate (MEP) pathway, implementing the MVA pathway in bacterial hosts such as E. coli is advantageous due to its lack of endogenous regulation. The MVA and MEP pathways intersect at isopentenyl diphosphate (IPP), the direct precursor to isoprenoid-derived C 5 alcohols and initial precursor to longermore » chain terpenes, which makes independent regulation of the pathways difficult. In pursuit of the complete "decoupling" of the MVA pathway from native cellular regulation, we designed novel IPP-bypass MVA pathways for C 5 alcohol production by utilizing promiscuous activities of two enzymes, phosphomevalonate decarboxylase (PMD) and an E. coli-endogenous phosphatase (AphA). These bypass pathways have reduced energetic requirements, are further decoupled from intrinsic regulation, and are free from IPP-related toxicity. In addition to these benefits, we demonstrate that reduced aeration rate has less impact on the bypass pathway than the original MVA pathway. Finally, we showed that performance of the bypass pathway was primarily determined by the activity of PMD. We designed PMD mutants with improved activity and demonstrated titer increases in the mutant strains. These modified pathways would be a good platform for industrial production of isopentenol and related chemicals such as isoprene.« less

Immunogenicity and Protection Against Influenza H7N3 in Mice by Modified Vaccinia Virus Ankara Vectors Expressing Influenza Virus Hemagglutinin or Neuraminidase.

PubMed

Meseda, Clement A; Atukorale, Vajini; Soto, Jackeline; Eichelberger, Maryna C; Gao, Jin; Wang, Wei; Weiss, Carol D; Weir, Jerry P

2018-03-29

Influenza subtypes such as H7 have pandemic potential since they are able to infect humans with severe consequences, as evidenced by the ongoing H7N9 infections in China that began in 2013. The diversity of H7 viruses calls for a broadly cross-protective vaccine for protection. We describe the construction of recombinant modified vaccinia virus Ankara (MVA) vectors expressing the hemagglutinin (HA) or neuraminidase (NA) from three H7 viruses representing both Eurasian and North American H7 lineages - A/mallard/Netherlands/12/2000 (H7N3), A/Canada/rv444/2004 (H7N3), and A/Shanghai/02/2013 (H7N9). These vectors were evaluated for immunogenicity and protective efficacy against H7N3 virus in a murine model of intranasal challenge. High levels of H7-, N3-, and N9-specific antibodies, including neutralizing antibodies, were induced by the MVA-HA and MVA-NA vectors. Mice vaccinated with MVA vectors expressing any of the H7 antigens were protected, suggesting cross-protection among H7 viruses. In addition, MVA vectors expressing N3 but not N9 elicited protection against H7N3 virus challenge. Similar outcomes were obtained when immune sera from MVA vector-immunized mice were passively transferred to naïve mice prior to challenge with the H7N3 virus. The results support the further development of an MVA vector platform as a candidate vaccine for influenza strains with pandemic potential.

Efficacy assessment of an MVA vectored Rift Valley Fever vaccine in lambs.

PubMed

Busquets, Núria; Lorenzo, Gema; López-Gil, Elena; Rivas, Raquel; Solanes, David; Galindo-Cardiel, Iván; Abad, F Xavier; Rodríguez, Fernando; Bensaid, Albert; Warimwe, George; Gilbert, Sarah C; Domingo, Mariano; Brun, Alejandro

2014-08-01

The present study has evaluated the protection conferred by a single subcutaneous dose of a modified vaccinia virus Ankara (MVA) vectored vaccine encoding the Rift Valley Fever virus (RVFV) glycoproteins Gn and Gc in lambs. Three groups of six to seven lambs were immunized as follows: one group received the vaccine (termed rMVA-GnGc), a second group received an MVA vector (vector control) and a third group received saline solution (non-vaccinated control). Fourteen days later, all animals were subcutaneously challenged with 10(5) TCID50 of the virulent RVFV isolate 56/74 and vaccine efficacy assessed using standard endpoints. Two lambs (one from the vaccine group and one from the vector control group) succumbed to RVFV challenge, showing characteristic liver lesions. Lambs from both the vector control and non-vaccinated groups were febrile from days 2 to 5 post challenge (pc) while those in the rMVA-GnGc group showed a single peak of pyrexia at day 3 pc. RVFV RNA was detected in both nasal and oral swabs from days 3 to 7 pc in some lambs from the vector control and non-vaccinated groups, but no viral shedding could be detected in the surviving lambs vaccinated with rMVA-GnGc. Together, the data suggest that a single dose of the rMVA-GnGc vaccine may be sufficient to reduce RVFV shedding and duration of viremia but does not provide sterile immunity nor protection from disease. Further optimization of this vaccine approach in lambs is warranted. Copyright © 2014 Elsevier B.V. All rights reserved.

DNA-MVA-protein vaccination of rhesus macaques induces HIV-specific immunity in mucosal-associated lymph nodes and functional antibodies.

PubMed

Chege, Gerald K; Burgers, Wendy A; Müller, Tracey L; Gray, Clive M; Shephard, Enid G; Barnett, Susan W; Ferrari, Guido; Montefiori, David; Williamson, Carolyn; Williamson, Anna-Lise

2017-02-07

Successful future HIV vaccines are expected to generate an effective cellular and humoral response against the virus in both the peripheral blood and mucosal compartments. We previously reported the development of DNA-C and MVA-C vaccines based on HIV-1 subtype C and demonstrated their immunogenicity when given in a DNA prime-MVA boost combination in a nonhuman primate model. In the current study, rhesus macaques previously vaccinated with a DNA-C and MVA-C vaccine regimen were re-vaccinated 3.5years later with MVA-C followed by a protein vaccine based on HIV-1 subtype C envelope formulated with MF59 adjuvant (gp140Env/MF59), and finally a concurrent boost with both vaccines. A single MVA-C re-vaccination elicited T cell responses in all animals similar to previous peak responses, with 4/7 demonstrating responses >1000 SFU/10 6 PBMC. In contrast to an Env/MF59-only vaccine, concurrent boosting with MVA-C and Env/MF59 induced HIV-specific cellular responses in multiple mucosal associated lymph nodes in 6/7 animals, with high magnitude responses in some animals. Both vaccine regimens induced high titer Env-specific antibodies with ADCC activity, as well as neutralization of Tier 1 viruses and modest Tier 2 neutralization. These data demonstrate the feasibility of inducing HIV-specific immunity in the blood and mucosal sites of viral entry by means of DNA and poxvirus-vectored vaccines, in combination with a HIV envelope-based protein vaccine. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Mental health status of drivers--Motor vehicle accidents perpetrators].

PubMed

Merecz-Kot, Dorota; Waszkowska, Malgorzata; Wężyk, Agata

2015-01-01

This study aimed at exploring the phenomenon of motor vehicle accidents (MVA). The following research questions were addressed: what are the immediate reactions to accidents among MVA perpetrators, do MVA perpetrators develop posttraumatic stress symptoms, and what are the differences between high and low symptomatic signs in terms of socio-demographics and accident features? Post-traumatic stress disorder (PTSD) questionnaire by Watson et al. in the Polish adaptation was applied to assess PTSD and its subclinical symptoms. The information on the MVA nature, declared MVA causes, drivers' reactions after MVA, as well as on the age, education and history of driving in the study group was collected. The results of psychological examination obtained from 209 MVA perpetrators were analyzed. The examination took place at least 1 month after the accident. In 1/3 of the study group no physiological reactions were observed directly after the accident, while 46% of respondents experienced trembling and shaking and about 30% of subjects were crying or having tears in their eyes. Compassion for the injured and victims, guilt, helplessness and fear were the most common among immediate psychological reactions related to the accident. On the day of psychological examination 11.2% of drivers met diagnostic criteria for PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV). Drivers showing low and high PTSD symptoms did not differ in terms of age, education, and subjective perception of accident cause. Women were significantly overrepresented it the group meeting the diagnostic criteria for PTSD. The results of the study indicate the need to carry on systematic screening for mental health problems in drivers involved in serious MVA as a part of strategy for improving road safety. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects.

PubMed

Greenberg, Richard N; Hay, Christine M; Stapleton, Jack T; Marbury, Thomas C; Wagner, Eva; Kreitmeir, Eva; Röesch, Siegfried; von Krempelhuber, Alfred; Young, Philip; Nichols, Richard; Meyer, Thomas P; Schmidt, Darja; Weigl, Josef; Virgin, Garth; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

2016-01-01

Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56-80 years old population. MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56-80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group MM were 804.1 and 605.8 for Group PM (with ratio of GMTs of 1.33 with 95% CI of [0.96, 1.84]). Similarly, GMTs measured by PRNT were 210.3 for Group MM and 126.7 for Group PM (with ratio 1.66 and 95% CI [0.95, 2.90]). One or two doses of MVA were safe and immunogenic in a 56-80 years old vaccinia-experienced population. No cases of myopericarditis were observed following vaccinations with MVA. The safety, reactogenicity and immunogenicity were similar to that seen in younger (18-55 year old) healthy populations as investigated in other MVA trials. The results suggest that a single dose of MVA in a 56-80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine. ClinicalTrials.gov NCT00857493.

Recombinant modified vaccinia virus Ankara-based malaria vaccines.

PubMed

Sebastian, Sarah; Gilbert, Sarah C

2016-01-01

A safe and effective malaria vaccine is a crucial part of the roadmap to malaria elimination/eradication by the year 2050. Viral-vectored vaccines based on adenoviruses and modified vaccinia virus Ankara (MVA) expressing malaria immunogens are currently being used in heterologous prime-boost regimes in clinical trials for induction of strong antigen-specific T-cell responses and high-titer antibodies. Recombinant MVA is a safe and well-tolerated attenuated vector that has consistently shown significant boosting potential. Advances have been made in large-scale MVA manufacture as high-yield producer cell lines and high-throughput purification processes have recently been developed. This review describes the use of MVA as malaria vaccine vector in both preclinical and clinical studies in the past 5 years.

HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial.

PubMed

Nilsson, Charlotta; Hejdeman, Bo; Godoy-Ramirez, Karina; Tecleab, Teghesti; Scarlatti, Gabriella; Bråve, Andreas; Earl, Patricia L; Stout, Richard R; Robb, Merlin L; Shattock, Robin J; Biberfeld, Gunnel; Sandström, Eric; Wahren, Britta

2015-01-01

We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers. HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA. The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158). The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot response rate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1β and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients. Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use. International Standard Randomised Controlled Trial Number (ISRCTN) 60284968.

HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial

PubMed Central

Nilsson, Charlotta; Hejdeman, Bo; Godoy-Ramirez, Karina; Tecleab, Teghesti; Scarlatti, Gabriella; Bråve, Andreas; Earl, Patricia L.; Stout, Richard R.; Robb, Merlin L.; Shattock, Robin J.; Biberfeld, Gunnel; Sandström, Eric; Wahren, Britta

2015-01-01

Background We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers. Methods HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA. Results The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158). The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot response rate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1β and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients. Conclusion Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use. Trial Registration International Standard Randomised Controlled Trial Number (ISRCTN) 60284968 PMID:26121679

Market implementation of the MVA platform for pre-pandemic and pandemic influenza vaccines: A quantitative key opinion leader analysis

PubMed Central

Ramezanpour, Bahar; Pronker, Esther S.; Kreijtz, Joost H.C.M.; Osterhaus, Albert D.M.E.; Claassen, E.

2015-01-01

A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT–AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available. PMID:26048779

Market implementation of the MVA platform for pre-pandemic and pandemic influenza vaccines: A quantitative key opinion leader analysis.

PubMed

Ramezanpour, Bahar; Pronker, Esther S; Kreijtz, Joost H C M; Osterhaus, Albert D M E; Claassen, E

2015-08-20

A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT-AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission.

PubMed

Page, Kristin M; Labopin, Myriam; Ruggeri, Annalisa; Michel, Gerard; Diaz de Heredia, Cristina; O'Brien, Tracey; Picardi, Alessandra; Ayas, Mouhab; Bittencourt, Henrique; Vora, Ajay J; Troy, Jesse; Bonfim, Carmen; Volt, Fernanda; Gluckman, Eliane; Bader, Peter; Kurtzberg, Joanne; Rocha, Vanderson

2017-08-01

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2 + (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer.

PubMed

Freilich, J; Hoffe, S E; Almhanna, K; Dinwoodie, W; Yue, B; Fulp, W; Meredith, K L; Shridhar, R

2015-01-01

Emerging data suggests a benefit for using intensity modulated radiation therapy (IMRT) for the management of esophageal cancer. We retrospectively reviewed patients treated at our institution who received definitive or preoperative chemoradiation with either IMRT or 3D conformal radiation therapy (3DCRT) between October 2000 and January 2012. Kaplan Meier analysis and the Cox proportional hazard model were used to evaluate survival outcomes. We evaluated a total of 232 patients (138 IMRT, 94 3DCRT) who received a median dose of 50.4 Gy (range, 44-64.8) to gross disease. Median follow up for all patients, IMRT patients alone, and 3DCRT patients alone was 18.5 (range, 2.5-124.2), 16.5 (range, 3-59), and 25.9 months (range, 2.5-124.2), respectively. We observed no significant difference based on radiation technique (3DCRT vs. IMRT) with respect to median overall survival (OS) (median 29 vs. 32 months; P = 0.74) or median relapse free survival (median 20 vs. 25 months; P = 0.66). On multivariable analysis (MVA), surgical resection resulted in improved OS (HR 0.444; P < 0.0001). Superior OS was also associated on MVA with stage I/II disease (HR 0.523; P = 0.010) and tumor length ≤5 cm (HR 0.567; P = 0.006). IMRT was also associated on univariate analysis with a significant decrease in acute weight loss (mean 6% + 4.3% vs 9% + 7.4%, P = 0.012) and on MVA with a decrease in objective grade ≥3 toxicity, defined as any hospitalization, feeding tube, or >20% weight loss (OR 0.51; P = 0.050). Our data suggest that while IMRT-based chemoradiation for esophageal cancer does not impact survival there was significantly less toxicity. In the IMRT group there was significant decrease in weight loss and grade ≥3 toxicity compared to 3DCRT. © 2014 International Society for Diseases of the Esophagus.

Association of reproductive health training on intention to provide services after residency: the family physician resident survey.

PubMed

Romero, Diana; Maldonado, Lisa; Fuentes, Liza; Prine, Linda

2015-01-01

High rates of unintended pregnancy and need for reproductive health services (RHS), including abortion, require continued efforts to train medical professionals and increase availability of these services. With US approval 12 years ago of Mifepristone, a medication abortion pill, abortion services are additionally amenable to primary care. Family physicians are a logical group to focus on given that they provide the bulk of primary care. We analyzed data from an annual survey (2007--2010) of third-year family medicine residents (n=284, response rate=48%--64%) in programs offering abortion training to examine the association between such training and self-reported competence and intentions to provide RHS (with a particular focus on abortion) upon graduation from residency. The majority of residents (75% in most cases) were trained in each of the RHS we asked about; relatively fewer trained in implant insertion (39%), electric vacuum aspiration (EVA) (58%), and manual vacuum aspiration (MVA) (69%). Perceived competence on the part of the graduating residents ranged from high levels in pregnancy options counseling (89%) and IUD insertion (85%) to lows in ultrasound and EVA (both 34%). Bivariate analysis revealed significant associations between number of procedures performed and future intentions to provide them. The association between competence and intentions persisted for all procedures in multivariate analysis, adjusting for number of procedures. Further, the total number of abortions performed during residency increased the odds of intending to provide MVA and medication abortion by 3% and 2%, respectively. Findings support augmenting training in RHS for family medicine residents, given that almost half (45%) of those trained intended to provide abortions. The volume of training should be increased so more residents feel competent, particularly in light of the fact that combined exposure to different abortion procedures has a cumulative impact on intention to provide MVA and medication abortion.

Recombinant poxviruses as mucosal vaccine vectors.

PubMed

Gherardi, M Magdalena; Esteban, Mariano

2005-11-01

The majority of infections initiate their departure from a mucosal surface, such as Human immunodeficiency virus (HIV), a sexually transmitted virus. Therefore, the induction of mucosal immunity is a high priority in the development of vaccines against mucosal pathogens. The selection of an appropriate antigen delivery system is necessary to induce an efficient mucosal immune response. Poxvirus vectors have been the most intensively studied live recombinant vector, and numerous studies have demonstrated their ability to induce mucosal immune responses against foreign expressed antigens. Previous studies have demonstrated that recombinants based on the attenuated modified vaccinia virus Ankara (MVA) vector were effective in inducing protective responses against different respiratory viruses, such as influenza and respiratory syncytial virus, following immunization via mucosal routes. Recent studies performed in the murine and macaque models have shown that recombinant MVA (rMVA) does not only stimulate HIV-specific immunity in the genital and rectal tracts following mucosal delivery, but can also control simian/human immunodeficiency viraemia and disease progression. In addition, a prime-boost vaccination approach against tuberculosis emphasized the importance of the intranasal rMVA antigen delivery to induce protective immunity against Mycobacterium tuberculosis. The aim of this review is to summarize the studies employing recombinant poxviruses, specifically rMVA as a mucosal delivery vector. The results demonstrate that rMVAs can activate specific immune responses at mucosal surfaces, and encourage further studies to characterize and improve the MVA mucosal immunogenicity of poxvirus vectors.

Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in Healthy Gambian and Kenyan Adults

PubMed Central

Kimani, Domtila; Jagne, Ya Jankey; Sheehy, Susanne H.; Bliss, Carly M.; Duncan, Christopher J. A.; Collins, Katharine A.; Garcia Knight, Miguel A.; Kimani, Eva; Anagnostou, Nicholas A.; Berrie, Eleanor; Moyle, Sarah; Gilbert, Sarah C.; Spencer, Alexandra J.; Soipei, Peninah; Mueller, Jenny; Okebe, Joseph; Colloca, Stefano; Cortese, Riccardo; Viebig, Nicola K.; Roberts, Rachel; Gantlett, Katherine; Lawrie, Alison M.; Nicosia, Alfredo; Imoukhuede, Egeruan B.; Bejon, Philip; Urban, Britta C.; Flanagan, Katie L.; Ewer, Katie J.; Chilengi, Roma; Hill, Adrian V. S.; Bojang, Kalifa

2013-01-01

Background Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI). Methodology We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns. Results ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC). Conclusions ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted. Trial Registration Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430 PMID:23526949

Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults.

PubMed

Ogwang, Caroline; Afolabi, Muhammed; Kimani, Domtila; Jagne, Ya Jankey; Sheehy, Susanne H; Bliss, Carly M; Duncan, Christopher J A; Collins, Katharine A; Garcia Knight, Miguel A; Kimani, Eva; Anagnostou, Nicholas A; Berrie, Eleanor; Moyle, Sarah; Gilbert, Sarah C; Spencer, Alexandra J; Soipei, Peninah; Mueller, Jenny; Okebe, Joseph; Colloca, Stefano; Cortese, Riccardo; Viebig, Nicola K; Roberts, Rachel; Gantlett, Katherine; Lawrie, Alison M; Nicosia, Alfredo; Imoukhuede, Egeruan B; Bejon, Philip; Urban, Britta C; Flanagan, Katie L; Ewer, Katie J; Chilengi, Roma; Hill, Adrian V S; Bojang, Kalifa

2013-01-01

Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI). We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns. ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC). ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted. Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430.

Quadriceps muscle strength and voluntary activation after polio.

PubMed

Beelen, Anita; Nollet, Frans; de Visser, Marianne; de Jong, Bareld A; Lankhorst, Gustaaf J; Sargeant, Anthony J

2003-08-01

Quadriceps strength, maximal anatomical cross-sectional area (CSA), maximal voluntary activation (MVA), and maximal relaxation rate (MRR) were studied in 48 subjects with a past history of polio, 26 with and 22 without postpoliomyelitis syndrome (PPS), and in 13 control subjects. It was also investigated whether, apart from CSA, MVA and MRR were determinants of muscle strength. Polio subjects had significantly less strength, CSA, and MRR in the more-affected quadriceps than control subjects. MVA was reduced in 18 polio subjects and normal in all controls. PPS subjects differed from non-PPS subjects only in that the MVA of the more-affected quadriceps was significantly lower. Both CSA and MVA were found to be associated with muscle strength. Quadriceps strength in polio subjects was dependent not only on muscle mass, but also on the ability to activate the muscles. Since impaired activation was more pronounced in PPS subjects, the new muscle weakness and functional decline in PPS may be due not only to a gradual loss of muscle fibers, but also to an increasing inability to activate the muscles.

Selection of recombinant MVA by rescue of the essential D4R gene.

PubMed

Ricci, Patricia S; Schäfer, Birgit; Kreil, Thomas R; Falkner, Falko G; Holzer, Georg W

2011-12-12

Modified vaccinia virus Ankara (MVA) has become a promising vaccine vector due to its immunogenicity and its proven safety in humans. As a general approach for stringent and rapid selection of recombinant MVA, we assessed marker rescue of the essential viral D4R gene in an engineered deletion mutant that is fully replication defective in wild-type cells. Recombinant, replicating virus was obtained by re-introduction of the deleted viral gene as a dominant selection marker into the deletion mutant.

The impact of cardiac rhythm on the mitral valve area and gradient in patients with mitral stenosis.

PubMed

Arı, Hasan; Arı, Selma; Karakuş, Alper; Camcı, Sencer; Doğanay, Kübra; Tütüncü, Ahmet; Melek, Mehmet; Bozat, Tahsin

2017-08-01

The aim of this study was to evaluate the effect of cardiac rhythm on the echocardiographic mitral valve area (MVA) and transmitral gradient calculation in relation to net atrioventricular compliance (Cn). Patients (n=22) with mild or moderate pure rheumatic mitral stenosis (MS) (MVA <2 cm2 and MVA >1 cm2) and atrial fibrillation (AF) were evaluated. All patients underwent transthoracic electrical DC cardioversion under amiodarone treatment. Nineteen of the 22 patients were successfully converted to sinus rhythm (SR). The patients were evaluated with transthoracic echocardiography before and two to three days after DC cardioversion. In order to deal with variable R-R intervals, the measurements were averaged on five to eight consecutive beats in AF. Cn was calculated with a previously validated equation [Cn (mL/mm Hg)=1.270 x MVA/E-wave downslope]. The Cn difference between AF and SR was calculated as follows: [(AF Cn-SR Cn)/AF Cn] x 100. The percentage gradient (mean or maximal) difference between AF and SR was calculated as follows: [AF gradient (mean or maximal) - SR gradient (mean or maximal)]/[AF gradient (mean or maximal)] x 100. The MVA was lower (MVA planimetric; 1.62±0.29 vs. 1.54±0.27; p=.003, MVA PHT; 1.66±0.30 vs. 1.59±0.26; p=0.01) but transmitral gradient (mean gradient; 6.49±2.51 vs. 8.89±3.52; p=0.001, maximal gradient: 16.94±5.11 vs. 18.57±4.54; p=0.01) and Cn values (5.37±0.77 vs. 6.26±0.64; p<0.001) were higher in the AF than SR. There was a significant correlation between Cn difference and transmitral gradient difference (mean and maximal) (Cn difference-mean gradient difference; r=0.46; p=0.05; Cn difference-maximal gradient difference; r=0.72; p=0.001). Cardiac rhythm has a significant impact on echocardiographic evaluation of MVA, transmitral gradient, and Cn in patients with MS.

High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques.

PubMed

Kannanganat, Sunil; Wyatt, Linda S; Gangadhara, Sailaja; Chamcha, Venkatesarlu; Chea, Lynette S; Kozlowski, Pamela A; LaBranche, Celia C; Chennareddi, Lakshmi; Lawson, Benton; Reddy, Pradeep B J; Styles, Tiffany M; Vanderford, Thomas H; Montefiori, David C; Moss, Bernard; Robinson, Harriet L; Amara, Rama Rao

2016-11-01

We tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/SIV macaque 239 vaccine. High doses of MVA/GM-CSF did not affect the levels of systemic envelope (Env)-specific Ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of Env-specific IgA (p = 0.01) and IgG (p < 0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus macaques subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus SIVsmE660. Eight of nine TRIM5α-restrictive animals receiving no or the lowest dose (1 × 10 5 PFU) of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group, only 1 of 12 animals resisted all 12 challenges. In the TRIM5α-restrictive animals, but not in the TRIM5α-permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r = +0.6) and IgA (r = +0.6), the avidity of Env-specific serum IgG (r = +0.5), and Ab dependent cell-mediated virus inhibition (r = +0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that 1) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of TRIM5α restriction, 2) nonneutralizing Ab responses contribute to protection against SIVsmE660 in TRIM5α-restrictive animals, and 3) high doses of codelivered MVA/GM-CSF inhibit mucosal Ab responses and the protection elicited by MVA expressing noninfectious SIV macaque 239 virus-like particles. Copyright © 2016 by The American Association of Immunologists, Inc.

Improving the MVA Vaccine Potential by Deleting the Viral Gene Coding for the IL-18 Binding Protein

PubMed Central

Pascutti, María Fernanda; Rodríguez, Ana María; Maeto, Cynthia; Perdiguero, Beatriz; Gómez, Carmen E.; Esteban, Mariano; Calamante, Gabriela; Gherardi, María Magdalena

2012-01-01

Background Modified Vaccinia Ankara (MVA) is an attenuated strain of Vaccinia virus (VACV) currently employed in many clinical trials against HIV/AIDS and other diseases. MVA still retains genes involved in host immune response evasion, enabling its optimization by removing some of them. The aim of this study was to evaluate cellular immune responses (CIR) induced by an IL-18 binding protein gene (C12L) deleted vector (MVAΔC12L). Methodology/Principal Findings BALB/c and C57BL/6 mice were immunized with different doses of MVAΔC12L or MVA wild type (MVAwt), then CIR to VACV epitopes in immunogenic proteins were evaluated in spleen and draining lymph nodes at acute and memory phases (7 and 40 days post-immunization respectively). Compared with parental MVAwt, MVAΔC12L immunization induced a significant increase of two to three-fold in CD8+ and CD4+ T-cell responses to different VACV epitopes, with increased percentage of anti-VACV cytotoxic CD8+ T-cells (CD107a/b+) during the acute phase of the response. Importantly, the immunogenicity enhancement was also observed after MVAΔC12L inoculation with different viral doses and by distinct routes (systemic and mucosal). Potentiation of MVA's CIR was also observed during the memory phase, in correlation with a higher protection against an intranasal challenge with VACV WR. Of note, we could also show a significant increase in the CIR against HIV antigens such as Env, Gag, Pol and Nef from different subtypes expressed from two recombinants of MVAΔC12L during heterologous DNA prime/MVA boost vaccination regimens. Conclusions/Significance This study demonstrates the relevance of IL-18 bp contribution in the immune response evasion during MVA infection. Our findings clearly show that the deletion of the viral IL-18 bp gene is an effective approach to increase MVA vaccine efficacy, as immunogenicity improvements were observed against vector antigens and more importantly to HIV antigens. PMID:22384183

Isoprene production by Escherichia coli through the exogenous mevalonate pathway with reduced formation of fermentation byproducts.

PubMed

Kim, Jung-Hun; Wang, Chonglong; Jang, Hui-Jung; Cha, Myeong-Seok; Park, Ju-Eon; Jo, Seon-Yeong; Choi, Eui-Sung; Kim, Seon-Won

2016-12-23

Isoprene, a volatile C5 hydrocarbon, is an important platform chemical used in the manufacturing of synthetic rubber for tires and various other applications, such as elastomers and adhesives. In this study, Escherichia coli MG1655 harboring Populus trichocarpa isoprene synthase (PtispS) and the exogenous mevalonate (MVA) pathway produced 80 mg/L isoprene. Codon optimization and optimal expression of the ispS gene via adjustment of the RBS strength and inducer concentration increased isoprene production to 199 and 337 mg/L, respectively. To augment expression of MVA pathway genes, the MVA pathway was cloned on a high-copy plasmid (pBR322 origin) with a strong promoter (P trc ), which resulted in an additional increase in isoprene production up to 956 mg/L. To reduce the formation of byproducts derived from acetyl-CoA (an initial substrate of the MVA pathway), nine relevant genes were deleted to generate the E. coli AceCo strain (E. coli MG1655 ΔackA-pta, poxB, ldhA, dld, adhE, pps, and atoDA). The AceCo strain harboring the ispS gene and MVA pathway showed enhanced isoprene production of 1832 mg/L in flask culture with reduced accumulation of byproducts. We achieved a 23-fold increase in isoprene production by codon optimization of PtispS, augmentation of the MVA pathway, and deletion of genes involved in byproduct formation.

Comparison of multivariate analysis methods for extracting the paraffin component from the paraffin-embedded cancer tissue spectra for Raman imaging

NASA Astrophysics Data System (ADS)

Meksiarun, Phiranuphon; Ishigaki, Mika; Huck-Pezzei, Verena A. C.; Huck, Christian W.; Wongravee, Kanet; Sato, Hidetoshi; Ozaki, Yukihiro

2017-03-01

This study aimed to extract the paraffin component from paraffin-embedded oral cancer tissue spectra using three multivariate analysis (MVA) methods; Independent Component Analysis (ICA), Partial Least Squares (PLS) and Independent Component - Partial Least Square (IC-PLS). The estimated paraffin components were used for removing the contribution of paraffin from the tissue spectra. These three methods were compared in terms of the efficiency of paraffin removal and the ability to retain the tissue information. It was found that ICA, PLS and IC-PLS could remove the paraffin component from the spectra at almost the same level while Principal Component Analysis (PCA) was incapable. In terms of retaining cancer tissue spectral integrity, effects of PLS and IC-PLS on the non-paraffin region were significantly less than that of ICA where cancer tissue spectral areas were deteriorated. The paraffin-removed spectra were used for constructing Raman images of oral cancer tissue and compared with Hematoxylin and Eosin (H&E) stained tissues for verification. This study has demonstrated the capability of Raman spectroscopy together with multivariate analysis methods as a diagnostic tool for the paraffin-embedded tissue section.

Calculation of Mitral Valve Area in Mitral Stenosis: Comparison of Continuity Equation and Pressure Half Time With Two-Dimensional Planimetry in Patients With and Without Associated Aortic or Mitral Regurgitation or Atrial Fibrillation.

PubMed

Sattarzadeh, Roya; Tavoosi, Anahita; Saadat, Mohammad; Derakhshan, Leila; Khosravi, Bakhtyar; Geraiely, Babak

2017-11-01

Accurate measurement of Mitral Valve Area (MVA) is essential to determining the Mitral Stenosis (MS) severity and to achieving the best management strategies for this disease. The goal of the present study is to compare mitral valve area (MVA) measurement by Continuity Equation (CE) and Pressure Half-Time (PHT) methods with that of 2D-Planimetry (PL) in patients with moderate to severe mitral stenosis (MS). This comparison also was performed in subgroups of patients with significant Aortic Insufficiency (AI), Mitral Regurgitation (MR) and Atrial Fibrillation (AF). We studied 70 patients with moderate to severe MS who were referred to echocardiography clinic. MVA was determined by PL, CE and PHT methods. The agreement and correlations between MVA's obtained from various methods were determined by kappa index, Bland-Altman analysis, and linear regression analysis. The mean values for MVA calculated by CE was 0.81 cm (±0.27) and showed good correlation with those calculated by PL (0.95 cm, ±0.26 ) in whole population (r=0.771, P<0.001) and MR subgroup (r=0.763, P<0.001) and normal sinus rhythm and normal valve subgroups (r=0.858, P<0.001 and r=0.867, P<0.001, respectively). But CE methods didn't show any correlation in AF and AI subgroups. MVA measured by PHT had a good correlation with that measured by PL in whole population (r=0.770, P<0.001) and also in NSR (r=0.814, P<0.001) and normal valve subgroup (r=0.781, P<0.001). Subgroup with significant AI and those with significant MR showed moderate correlation (r=0.625, P=0.017 and r=0.595, P=0.041, respectively). Bland Altman Analysis showed that CE would estimate MVA smaller in comparison with PL in the whole population and all subgroups and PHT would estimate MVA larger in comparison with PL in the whole population and all subgroups. The mean bias for CE and PHT are 0.14 cm and -0.06 cm respectively. In patients with moderate to severe mitral stenosis, in the absence of concomitant AF, AI or MR, the accuracy of CE or PHT method in measuring MVA is nearly equal. But in the presence of significant AI or MR, PHT method is obviously superior to CE and in the presence of AF neither have sufficient accuracy.

Biochemical and Structural Basis for Inhibition of Enterococcus faecalis Hydroxymethylglutaryl-CoA Synthase, mvaS, by Hymeglusin

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

Skaff, D. Andrew; Ramyar, Kasra X.; McWhorter, William J.

Hymeglusin (1233A, F244, L-659-699) is established as a specific {beta}-lactone inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition results from formation of a thioester adduct to the active site cysteine. In contrast, the effects of hymeglusin on bacterial HMG-CoA synthase, mvaS, have been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. After removal of the inhibitor from culture media, a growth curve inflection point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than that measured for human HMGCS. Hydroxylamine cleaves the thioester adduct;more » substantial enzyme activity is restored at a rate that is 8-fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme-inhibitor thioester adduct stability and solvent accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 {angstrom}) reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica juncea) HMGCS binds hymeglusin in a more solvent-exposed cavity.« less

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

PubMed

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

2018-01-16

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

Three-dimensional proximal flow convergence automatic calculation for determining mitral valve area in rheumatic mitral stenosis.

PubMed

Sampaio, Francisco; Ladeiras-Lopes, Ricardo; Almeida, João; Fonseca, Paulo; Fontes-Carvalho, Ricardo; Ribeiro, José; Gama, Vasco

2017-07-01

Management of patients with mitral stenosis (MS) depends heavily on the accurate quantification of mitral valve area (MVA) using echocardiography. All currently used two-dimensional (2D) methods have limitations. Estimation of MVA using the proximal isovelocity surface area (PISA) method with real time three-dimensional (3D) echocardiography may circumvent those limitations. We aimed to evaluate the accuracy of 3D direct measurement of PISA in the estimation of MVA. Twenty-seven consecutive patients (median age of 63 years; 77.8% females) with rheumatic MS were prospectively studied. Transthoracic and transesophageal echocardiography with 2D and 3D acquisitions were performed on the same day. The reference method for MVA quantification was valve planimetry after 3D-volume multiplanar reconstruction. A semi-automated software was used to calculate the 3D flow convergence volume. Compared to MVA estimation using 3D planimetry, 3D PISA showed the best correlation (rho=0.78, P<.0001), followed by pressure half-time (PHT: rho=0.66, P<.001), continuity equation (CE: rho=0.61, P=.003), and 2D PISA (rho=0.26, P=.203). Bland-Altman analysis revealed a good agreement for MVA estimation with 3D PISA (mean difference -0.03 cm 2 ; limits of agreement (LOA) -0.40-0.35), in contrast to wider LOA for 2D methods: CE (mean difference 0.02 cm 2 , LOA -0.56-0.60); PHT (mean difference 0.31 cm 2 , LOA -0.32-0.95); 2D PISA (mean difference -0.03 cm 2 , LOA -0.92-0.86). MVA estimation using 3D PISA was feasible and more accurate than 2D methods. Its introduction in daily clinical practice seems possible and may overcome technical limitations of 2D methods. © 2017, Wiley Periodicals, Inc.

Therapeutic vaccination to treat chronic infectious diseases

PubMed Central

Boukhebza, Houda; Bellon, Nadine; Limacher, Jean Marc; Inchauspé, Geneviève

2012-01-01

A famous milestone in the vaccine field has been the first successful vaccination against smallpox, in 1798, by Edward Jenner. Using the vaccinia cowpox virus, Jenner was able to protect vaccinees from variola or smallpox. The Modified Virus Ankara (MVA) poxvirus strain has been one of the vaccines subsequently developed to prevent smallpox infection and was selected by the US government in their Biodefense strategy. Progress in molecular biology and immunology associated with MVA infection has led to the development of MVA as vaccine platform, both in the field of preventive and therapeutic vaccines. This later class of therapeutics has witnessed growing interest that has translated into an increasing number of vaccine candidates reaching the clinics. Among those, MVA-based therapeutic vaccines have addressed four major chronic infections including viral hepatitis, AIDS, human papillomavirus-linked pathologies and tuberculosis. Clinical trials encompass phase 1 and 2 and have started to show significant results and promises. PMID:22894957

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

Wild, Aaron T.; Herman, Joseph M.; Dholakia, Avani S.

Purpose: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods and Materials: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariatemore » and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. Results: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm{sup 3}) than in CRT (344.6 cm{sup 3}; P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm{sup 3} vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). Conclusions: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.« less

Survival outcomes with concurrent chemoradiation for elderly patients with locally advanced head and neck cancer according to the National Cancer Data Base.

PubMed

Amini, Arya; Jones, Bernard L; McDermott, Jessica D; Serracino, Hilary S; Jimeno, Antonio; Raben, David; Ghosh, Debashis; Bowles, Daniel W; Karam, Sana D

2016-05-15

The overall survival (OS) benefit of concurrent chemoradiotherapy (CRT) for head and neck squamous cell carcinoma patients older than 70 years is debated. This study examines the outcomes of elderly patients receiving CRT versus radiotherapy (RT) alone. The National Cancer Data Base was queried for patients older than 70 years with nonmetastatic oropharyngeal, laryngeal, or hypopharyngeal cancer (T3-4 or N(+)). CRT was defined as chemotherapy started within 14 days of the initiation of RT. Univariate analysis, multivariate analysis (MVA), propensity score matching (PSM), and recursive partitioning analysis (RPA) were performed. The study included 4042 patients: 2538 (63%) received CRT. The median follow-up was 19 months. The unadjusted median OS was longer with the addition of CRT (P < .001). OS was superior with CRT in the MVA (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.58-0.68; P < .001) and PSM analyses (HR, 0.73; 95% CI, 0.66-0.80; P < .001) in comparison with RT alone. According to RPA, CRT was associated with longer OS for patients 81 years or younger with low comorbidity scores and either T1-2/N2-3 disease or T3-4/N0-3 disease. The survival benefit with CRT disappeared for 2 subgroups in the 71- to 81-year age range: those with T1-2, N1, and Charlson-Deyo 0-1 (CD0-1) disease and those with T3-4, N1+, and CD1+ disease. Patients who were older than 81 years did not have increased survival with CRT. The receipt of CRT was associated with a longer duration of RT (odds ratio, 1.74; 95% CI, 1.50-2.01; P < .001). Patients older than 70 years should not be denied concurrent chemotherapy solely on the basis of age; additional factors, including the performance status and the tumor stage, should be taken into account. Cancer 2016;122:1533-43. © 2016 American Cancer Society. © 2016 American Cancer Society.

Improved Survival With Radiation Therapy in Stage I-II Primary Mediastinal B Cell Lymphoma: A Surveillance, Epidemiology, and End Results Database Analysis

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

Jackson, Matthew W., E-mail: matthew.jackson@ucdenver.edu; Rusthoven, Chad G.; Jones, Bernard L.

Background: Primary mediastinal B cell lymphoma (PMBCL) is an uncommon lymphoma for which trials are few with small patient numbers. The role of radiation therapy (RT) after standard immunochemotherapy for early-stage disease has never been studied prospectively. We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate PMBCL and the impact of RT on outcomes. Methods and Materials: We queried the SEER database for patients with stage I-II PMBCL diagnosed from 2001 to 2011. Retrievable data included age, gender, race (white/nonwhite), stage, extranodal disease, year of diagnosis, and use of RT as a component of definitive therapy. Kaplan-Meier overallmore » survival (OS) estimates, univariate (UVA) log-rank and multivariate (MVA) Cox proportional hazards regression analyses were performed. Results: Two hundred fifty patients with stage I-II disease were identified, with a median follow-up time of 39 months (range, 3-125 months). The median age was 36 years (range, 18-89 years); 61% were female; 76% were white; 45% had stage I disease, 60% had extranodal disease, and 55% were given RT. The 5-year OS for the entire cohort was 86%. On UVA, OS was improved with RT (hazard ratio [HR] 0.446, P=.029) and decreased in association with nonwhite race (HR 2.70, P=.006). The 5-year OS was 79% (no RT) and 90% (RT). On MVA, white race and RT remained significantly associated with improved OS (P=.007 and .018, respectively). The use of RT decreased over time: 61% for the 67 patients whose disease was diagnosed from 2001 to 2005 and 53% in the 138 patients treated from 2006 to 2010. Conclusion: This retrospective population-based analysis is the largest PMBCL dataset to date and demonstrates a significant survival benefit associated with RT. Nearly half of patients treated in the United States do not receive RT, and its use appears to be declining. In the absence of phase 3 data, the use of RT should be strongly considered for its survival benefit in early-stage disease.« less

Bilateral implant reconstruction does not affect the quality of postmastectomy radiation therapy

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

Ho, Alice Y., E-mail: hoa1234@mskcc.org; Patel, Nisha; Ohri, Nisha

To determine if the presence of bilateral implants, in addition to other anatomic and treatment-related variables, affects coverage of the target volume and dose to the heart and lung in patients receiving postmastectomy radiation therapy (PMRT). A total of 197 consecutive women with breast cancer underwent mastectomy and immediate tissue expander (TE) placement, with or without exchange for a permanent implant (PI) before radiation therapy at our center. PMRT was delivered with 2 tangential beams + supraclavicular lymph node field (50 Gy). Patients were grouped by implant number: 51% unilateral (100) and 49% bilateral (97). The planning target volume (PTV)more » (defined as implant + chest wall + nodes), heart, and ipsilateral lung were contoured and the following parameters were abstracted from dose-volume histogram (DVH) data: PTV D{sub 95%} > 98%, Lung V{sub 20}Gy > 30%, and Heart V{sub 25}Gy > 5%. Univariate (UVA) and multivariate analyses (MVA) were performed to determine the association of variables with these parameters. The 2 groups were well balanced for implant type and volume, internal mammary node (IMN) treatment, and laterality. In the entire cohort, 90% had PTV D{sub 95%} > 98%, indicating excellent coverage of the chest wall. Of the patients, 27% had high lung doses (V{sub 20}Gy > 30%) and 16% had high heart doses (V{sub 25}Gy > 5%). No significant factors were associated with suboptimal PTV coverage. On MVA, IMN treatment was found to be highly associated with high lung and heart doses (both p < 0.0001), but implant number was not (p = 0.54). In patients with bilateral implants, IMN treatment was the only predictor of dose to the contralateral implant (p = 0.001). In conclusion, bilateral implants do not compromise coverage of the target volume or increase lung and heart dose in patients receiving PMRT. The most important predictor of high lung and heart doses in patients with implant-based reconstruction, whether unilateral or bilateral, is treatment of the IMNs. Refinement of radiation techniques in reconstructed patients who require comprehensive nodal irradiation is warranted.« less

Salvage Radiosurgery for Brain Metastases: Prognostic Factors to Consider in Patient Selection

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

Kurtz, Goldie; Zadeh, Gelareh; Gingras-Hill, Geneviève

2014-01-01

Purpose: Stereotactic radiosurgery (SRS) is offered to patients for recurrent brain metastases after prior brain radiation therapy (RT), but few studies have evaluated the efficacy of salvage SRS or factors to consider in selecting patients for this treatment. This study reports overall survival (OS), intracranial progression-free survival (PFS), and local control (LC) after salvage SRS, and factors associated with outcomes. Methods and Materials: This is a retrospective review of patients treated from 2009 to 2011 with salvage SRS after prior brain RT for brain metastases. Survival from salvage SRS and from initial brain metastases diagnosis (IBMD) was calculated. Univariate andmore » multivariable (MVA) analyses included age, performance status, recursive partitioning analysis (RPA) class, extracranial disease control, and time from initial RT to salvage SRS. Results: There were 106 patients included in the analysis with a median age of 56.9 years (range 32.5-82 years). A median of 2 metastases were treated per patient (range, 1-12) with a median dose of 21 Gy (range, 12-24) prescribed to the 50% isodose. With a median follow-up of 10.5 months (range, 0.1-68.2), LC was 82.8%, 60.1%, and 46.8% at 6 months, 1 year, and 3 years, respectively. Median PFS was 6.2 months (95% confidence interval [CI] = 4.9-7.6). Median OS was 11.7 months (95% CI = 8.1-13) from salvage SRS, and 22.1 months from IBMD (95% CI = 18.4-26.8). On MVA, age (P=.01; hazard ratio [HR] = 1.04; 95% CI = 1.01-1.07), extracranial disease control (P=.004; HR = 0.46; 95% CI = 0.27-0.78), and interval from initial RT to salvage SRS of at least 265 days (P=.001; HR = 2.46; 95% CI = 1.47-4.09) were predictive of OS. Conclusions: This study demonstrates that patients can have durable local control and survival after salvage SRS for recurrent brain metastases. In particular, younger patients with controlled extracranial disease and a durable response to initial brain RT are likely to benefit from salvage SRS.« less

Vaccination directed against the human endogenous retrovirus-K envelope protein inhibits tumor growth in a murine model system.

PubMed

Kraus, Benjamin; Fischer, Katrin; Büchner, Sarah M; Wels, Winfried S; Löwer, Roswitha; Sliva, Katja; Schnierle, Barbara S

2013-01-01

Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.

Modelling the cost-effectiveness of a new infant vaccine to prevent tuberculosis disease in children in South Africa

PubMed Central

2014-01-01

Background Tuberculosis remains the leading cause of death in South Africa. A number of potential new TB vaccine candidates have been identified and are currently in clinical trials. One such candidate is MVA85A. This study aimed to estimate the cost-effectiveness of adding the MVA85A vaccine as a booster to the BCG vaccine in children from the perspective of the South African government. Methods The cost-effectiveness was assessed by employing Decision Analytic Modelling, through the use of a Markov model. The model compared the existing strategy of BCG vaccination to a new strategy in which infants receive BCG and a booster vaccine, MVA85A, at 4 months of age. The costs and outcomes of the two strategies are estimated through modelling the vaccination of a hypothetical cohort of newborns and following them from birth through to 10 years of age, employing 6-monthly cycles. Results The results of the cost-effectiveness analysis indicate that the MVA85A strategy is both more costly and more effective – there are fewer TB cases and deaths from TB than BCG alone. The South African government would need to spend an additional USD 1,105 for every additional TB case averted and USD 284,017 for every additional TB death averted. The threshold analysis shows that, if the efficacy of the MVA85A vaccine was 41.3% (instead of the current efficacy of 17.3%), the two strategies would have the same cost but more cases of TB and more deaths from TB would be prevented by adding the MVA85A vaccine to the BCG vaccine. In this case, the government chould consider the MVA85A strategy. Conclusions At the current level of efficacy, the MVA85A vaccine is neither effective nor cost-effective and, therefore, not a good use of limited resources. Nevertheless, this study contributes to developing a standardized Markov model, which could be used, in the future, to estimate the potential cost-effectiveness of new TB vaccines compared to the BCG vaccine, in children between the ages of 0–10 years. It also provides an indicative threshold of vaccine efficacy, which could guide future development. PMID:25242892

Antitumor Effects of Palladium-α-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy.

PubMed

Veena, Ravindran Kalathil; Ajith, Thekkuttuparambil Ananthanarayanan; Janardhanan, Kainoor Krishnankutty; Antonawich, Francis

2016-01-01

Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body γ-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-α-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application.

Vaccination of horses with a recombinant modified vaccinia Ankara virus (MVA) expressing African horse sickness (AHS) virus major capsid protein VP2 provides complete clinical protection against challenge.

PubMed

Alberca, Berta; Bachanek-Bankowska, Katarzyna; Cabana, Marta; Calvo-Pinilla, Eva; Viaplana, Elisenda; Frost, Lorraine; Gubbins, Simon; Urniza, Alicia; Mertens, Peter; Castillo-Olivares, Javier

2014-06-17

African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant modified vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR -/-) against virulent AHSV challenge. This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection. These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pulmonary hypertension in rheumatic mitral stenosis revisited.

PubMed

Pourafkari, L; Ghaffari, S; Ahmadi, M; Tajlil, A; Aslanabadi, N; Nader, N D

2017-12-01

In patients with mitral stenosis (MS), pulmonary hypertension (PH) is a significant contributor to the associated morbidity. We aimed to study factors associated with the presence of significant PH (sPH) and whether incorporating body surface area (BSA) in the mitral valve area (MVA) would improve the predictive value of the latter. The medical records of 558 patients with severe MS undergoing percutaneous balloon mitral commissurotomy were evaluated over a period of 8 years. Factors associated with the presence of significant PH (sPH) defined as mPAP ≥ 40 mm Hg were examined. A total of 558 patients (423 women) were enrolled. Overall, 153 (27%) patients had sPH. Patients with sPH were similar to the rest of the subjects in terms of demographics, body habitus, blood group, and incidence of atrial fibrillation. Among echocardiographic findings, absolute MVA, indexed MVA, and mean transmitral valve gradient were associated with the presence of sPH. Transmitral valve gradient during right heart catheterization had the highest area under the curve for an association with sPH. Age, gender, heart rhythm, and blood group were not associated with the presence of sPH in severe MS. The predictive value of the indexed MVA for the presence of sPH was not higher than that of absolute MVA.

1H NMR Spectroscopy and MVA Analysis of Diplodus sargus Eating the Exotic Pest Caulerpa cylindracea.

PubMed

De Pascali, Sandra A; Del Coco, Laura; Felline, Serena; Mollo, Ernesto; Terlizzi, Antonio; Fanizzi, Francesco P

2015-06-05

The green alga Caulerpa cylindracea is a non-autochthonous and invasive species that is severely affecting the native communities in the Mediterranean Sea. Recent researches show that the native edible fish Diplodus sargus actively feeds on this alga and cellular and physiological alterations have been related to the novel alimentary habits. The complex effects of such a trophic exposure to the invasive pest are still poorly understood. Here we report on the metabolic profiles of plasma from D. sargus individuals exposed to C. cylindracea along the southern Italian coast, using 1H NMR spectroscopy and multivariate analysis (Principal Component Analysis, PCA, Orthogonal Partial Least Square, PLS, and Orthogonal Partial Least Square Discriminant Analysis, OPLS-DA). Fish were sampled in two seasonal periods from three different locations, each characterized by a different degree of algal abundance. The levels of the algal bisindole alkaloid caulerpin, which is accumulated in the fish tissues, was used as an indicator of the trophic exposure to the seaweed and related to the plasma metabolic profiles. The profiles appeared clearly influenced by the sampling period beside the content of caulerpin, while the analyses also supported a moderate alteration of lipid and choline metabolism related to the Caulerpa-based diet.

Diabetes and Driving Safety: Science, Ethics, Legality & Practice

PubMed Central

Cox, Daniel J.; Singh, Harsimran; Lorber, Daniel

2013-01-01

Diabetes affects over 25 million people in the United States, most of whom are over the age of 16 and many of whom are licensed to drive a motor vehicle. Safe operation of a motor vehicle requires complex interactions of cognitive and motor functions and medical conditions that affect these functions often will increase the risk of motor vehicle accidents (MVA). In the case of diabetes, hypoglycemia is the most common factor that has been shown to increase MVA rates. When people with diabetes are compared with non-diabetic controls, systematic analyses show that the relative risk of MVA is increased by between 12 and 19% (RRR 1.12-1.19). In comparison, the RRR for Attention Deficit Hyperactivity Disorder is 4.4 and for Sleep Apnea is 2.4. Epidemiologic research suggests that patients at risk for hypoglycemia-related MVAs may have some characteristics in common, including a history of severe hypoglycemia or of hypoglycemia-related driving mishaps. Experimental studies also have shown that people with a history of hypoglycemia-related driving mishaps have abnormal counter-regulatory responses to hypoglycemia and greater cognitive impairments during moderate hypoglycemia. There are medical, ethical and legal issues for health care professionals who care for people with diabetes regarding their patients’ risk of hypoglycemia-related driving mishaps. This includes identifying those at increased risk and counseling them on preventive measures, including more frequent blood glucose testing, delaying driving with low or low normal blood glucose, and carrying readily available emergency supplies in the vehicle for the treatment of hypoglycemia. PMID:23531955

Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

PubMed

Golden, Joseph W; Josleyn, Matthew; Mucker, Eric M; Hung, Chien-Fu; Loudon, Peter T; Wu, T C; Hooper, Jay W

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

Sleep apnea-related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish Traffic Accident Registry data.

PubMed

Karimi, Mahssa; Hedner, Jan; Häbel, Henrike; Nerman, Olle; Grote, Ludger

2015-03-01

Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated. MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group. Clinical sleep laboratory and population based control (n = 635,786). There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y. CPAP. The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P < 0.001). Estimated excess accident risk was most prominent in the elderly patients (65-80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score ≥ 16), short habitual sleep time (≤5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P ≤ 0.03). CPAP use ≥ 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y). The MVA risk in this large cohort of unselected patients with OSA suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk. © 2015 Associated Professional Sleep Societies, LLC.

Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice.

PubMed

Magnusson, Sofia E; Altenburg, Arwen F; Bengtsson, Karin Lövgren; Bosman, Fons; de Vries, Rory D; Rimmelzwaan, Guus F; Stertman, Linda

2018-04-01

Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines.

Side-by-Side Comparison of Gene-Based Smallpox Vaccine with MVA in Nonhuman Primates

PubMed Central

Golden, Joseph W.; Josleyn, Matthew; Mucker, Eric M.; Hung, Chien-Fu; Loudon, Peter T.; Wu, T. C.; Hooper, Jay W.

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA. PMID:22860117

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.

PubMed

Yeganeh, Behzad; Wiechec, Emilia; Ande, Sudharsana R; Sharma, Pawan; Moghadam, Adel Rezaei; Post, Martin; Freed, Darren H; Hashemi, Mohammad; Shojaei, Shahla; Zeki, Amir A; Ghavami, Saeid

2014-07-01

The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes in the use of manual vacuum aspiration for postabortion care within the public healthcare service network in Honduras.

PubMed

Chinchilla, Ana Ligia; Flores, Ivo Flores; Morales, Alma Fabiola; de Gil, Marina Padilla

2014-07-01

Honduras is one of the 17 priority countries included in the International Federation of Gynecology and Obstetrics (FIGO) Initiative for the Prevention of Unsafe Abortion and its Consequences. The priority category enables the country to request emergency funding to acquire services or commodities that could contribute toward achieving the objectives laid out in its plan of action. These objectives include improving postabortion care by increasing the use of manual vacuum aspiration (MVA) as an outpatient procedure with minimal human and material resources. Since the Ministry of Health lacked funding, use of the emergency fund was approved for the purchase and distribution of MVA kits nationwide to ensure continuity and the hope of increasing MVA use. Eleven hospitals participating in this initiative provided data for analysis of the outcome. These data show no increase in MVA use; however, as discussed in the article, further investigation provided valuable information on the reasons behind these results. Copyright © 2014. Published by Elsevier Ireland Ltd.

Cost-effectiveness analysis of unsafe abortion and alternative first-trimester pregnancy termination strategies in Nigeria and Ghana.

PubMed

Hu, Delphine; Grossman, Daniel; Levin, Carol; Blanchard, Kelly; Adanu, Richard; Goldie, Sue J

2010-06-01

To explore the policy implications of increasing access to safe abortion in Nigeria and Ghana, we developed a computer-based decision analytic model which simulates induced abortion and its potential complications in a cohort of women, and comparatively assessed the cost-effectiveness of unsafe abortion and three first-trimester abortion modalities: hospital-based dilatation and curettage, hospital- and clinic-based manual vacuum aspiration (MVA), and medical abortion using misoprostol (MA). Assuming all modalities are equally available, clinic-based MVA is the most cost-effective option in Nigeria. If clinic-based MVA is not available, MA is the next best strategy. Conversely, in Ghana, MA is the most cost-effective strategy, followed by clinic-based MVA if MA is not available. From a real world policy perspective, increasing access to safe abortion in favor over unsafe abortion is the single most important factor in saving lives and societal costs, and is more influential than the actual choice of safe abortion modality.

PTSD symptom severity and psychiatric comorbidity in recent motor vehicle accident victims: a latent class analysis.

PubMed

Hruska, Bryce; Irish, Leah A; Pacella, Maria L; Sledjeski, Eve M; Delahanty, Douglas L

2014-10-01

We conducted a latent class analysis (LCA) on 249 recent motor vehicle accident (MVA) victims to examine subgroups that differed in posttraumatic stress disorder (PTSD) symptom severity, current major depressive disorder and alcohol/other drug use disorders (MDD/AoDs), gender, and interpersonal trauma history 6-weeks post-MVA. A 4-class model best fit the data with a resilient class displaying asymptomatic PTSD symptom levels/low levels of comorbid disorders; a mild psychopathology class displaying mild PTSD symptom severity and current MDD; a moderate psychopathology class displaying severe PTSD symptom severity and current MDD/AoDs; and a severe psychopathology class displaying extreme PTSD symptom severity and current MDD. Classes also differed with respect to gender composition and history of interpersonal trauma experience. These findings may aid in the development of targeted interventions for recent MVA victims through the identification of subgroups distinguished by different patterns of psychiatric problems experienced 6-weeks post-MVA. Copyright © 2014 Elsevier Ltd. All rights reserved.

PTSD Symptom Severity and Psychiatric Comorbidity in Recent Motor Vehicle Accident Victims: A Latent Class Analysis

PubMed Central

Hruska, Bryce; Irish, Leah A.; Pacella, Maria L.; Sledjeski, Eve M.; Delahanty, Douglas L.

2014-01-01

We conducted a latent class analysis (LCA) on 249 recent motor vehicle accident (MVA) victims to examine subgroups that differed in posttraumatic stress disorder (PTSD) symptom severity, current major depressive disorder and alcohol/other drug use disorders (MDD/AoDs), gender, and interpersonal trauma history 6-weeks post-MVA. A 4-class model best fit the data with a resilient class displaying asymptomatic PTSD symptom levels/low levels of comorbid disorders; a mild psychopathology class displaying mild PTSD symptom severity and current MDD; a moderate psychopathology class displaying severe PTSD symptom severity and current MDD/AoDs; and a severe psychopathology class displaying extreme PTSD symptom severity and current MDD. Classes also differed with respect to gender composition and history of interpersonal trauma experience. These findings may aid in the development of targeted interventions for recent MVA victims through the identification of subgroups distinguished by different patterns of psychiatric problems experienced 6-weeks post-MVA. PMID:25124501

p53 regulates the mevalonate pathway in human glioblastoma multiforme

PubMed Central

Laezza, C; D'Alessandro, A; Di Croce, L; Picardi, P; Ciaglia, E; Pisanti, S; Malfitano, A M; Comegna, M; Faraonio, R; Gazzerro, P; Bifulco, M

2015-01-01

The mevalonate (MVA) pathway is an important metabolic pathway implicated in multiple aspects of tumorigenesis. In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3′-hydroxy-3′-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. Genetic and pharmacologic perturbation of p53 directly influences the expression of these genes. Furthermore, p53 is recruited to the gene promoters in designated p53-responsive elements, thereby increasing their transcription. Such effect was abolished by site-directed mutagenesis in the p53-responsive element of promoter of the genes. These findings highlight another aspect of p53 functions unrelated to tumor suppression and suggest p53 as a novel regulator of the MVA pathway providing insight into the role of this pathway in cancer progression. PMID:26469958

Modified Vaccinia Virus Ankara-Infected Dendritic Cells Present CD4+ T-Cell Epitopes by Endogenous Major Histocompatibility Complex Class II Presentation Pathways

PubMed Central

Thiele, Frank; Tao, Sha; Zhang, Yi; Muschaweckh, Andreas; Zollmann, Tina; Protzer, Ulrike; Abele, Rubert

2014-01-01

ABSTRACT CD4+ T lymphocytes play a central role in the immune system and mediate their function after recognition of their respective antigens presented on major histocompatibility complex II (MHCII) molecules on antigen-presenting cells (APCs). Conventionally, phagocytosed antigens are loaded on MHCII for stimulation of CD4+ T cells. Certain epitopes, however, can be processed directly from intracellular antigens and are presented on MHCII (endogenous MHCII presentation). Here we characterized the MHCII antigen presentation pathways that are possibly involved in the immune response upon vaccination with modified vaccinia virus Ankara (MVA), a promising live viral vaccine vector. We established CD4+ T-cell lines specific for MVA-derived epitopes as tools for in vitro analysis of MHCII antigen processing and presentation in MVA-infected APCs. We provide evidence that infected APCs are able to directly transfer endogenous viral proteins into the MHCII pathway to efficiently activate CD4+ T cells. By using knockout mice and chemical inhibitory compounds, we further elucidated the molecular basis, showing that among the various subcellular pathways investigated, proteasomes and autophagy are key players in the endogenous MHCII presentation during MVA infection. Interestingly, although proteasomal processing plays an important role, neither TAP nor LAMP-2 was found to be involved in the peptide transport. Defining the molecular mechanism of MHCII presentation during MVA infection provides a basis for improving MVA-based vaccination strategies by aiming for enhanced CD4+ T-cell activation by directing antigens into the responsible pathways. IMPORTANCE This work contributes significantly to our understanding of the immunogenic properties of pathogens by deciphering antigen processing pathways contributing to efficient activation of antigen-specific CD4+ T cells. We identified autophagosome formation, proteasomal activity, and lysosomal integrity as being crucial for endogenous CD4+ T-cell activation. Since poxvirus vectors such as MVA are already used in clinical trials as recombinant vaccines, the data provide important information for the future design of optimized poxviral vaccines for the study of advanced immunotherapy options. PMID:25520512

Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection

PubMed Central

Knitlova, Jarmila; Hajkova, Vera; Voska, Ludek; Elsterova, Jana; Obrova, Barbora; Melkova, Zora

2014-01-01

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40–50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism. PMID:25486419

Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania☆,☆☆

PubMed Central

Bakari, Muhammad; Aboud, Said; Nilsson, Charlotta; Francis, Joel; Buma, Deus; Moshiro, Candida; Aris, Eric A.; Lyamuya, Eligius F.; Janabi, Mohamed; Godoy-Ramirez, Karina; Joachim, Agricola; Polonis, Victoria R.; Bråve, Andreas; Earl, Patricia; Robb, Merlin; Marovich, Mary; Wahren, Britta; Pallangyo, Kisali; Biberfeld, Gunnel; Mhalu, Fred; Sandström, Eric

2016-01-01

Background We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Methods Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1 mg intradermally (id), n = 20, or 3.8 mg intramuscularly (im), n = 20, or placebo, n = 20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (108 pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. Results The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8+ and CD4+ T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01 AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses. PMID:21864626

Induction of long-lasting multi-specific CD8+ T cells by a four-component DNA-MVA/HIVA-RENTA candidate HIV-1 vaccine in rhesus macaques.

PubMed

Im, Eung-Jun; Nkolola, Joseph P; di Gleria, Kati; McMichael, Andrew J; Hanke, Tomás

2006-10-01

As a part of a long-term effort to develop vaccine against HIV-1 clade A inducing protective T cell responses in humans, we run mutually complementing studies in humans and non-human primates (NHP) with the aim to maximize vaccine immunogenicity. The candidate vaccine under development has four components, pTHr.HIVA and pTH.RENTA DNA, and modified vaccinia virus Ankara (MVA).HIVA and MVA.RENTA, delivered in a heterologous DNA prime-MVA boost regimen. While the HIVA (Gag/epitopes) components have been tested in NHP and over 300 human subjects, we plan to test in humans the RENTA (reverse transcriptase, gp41, Nef, Tat) vaccines designed to broaden HIVA-induced responses in year 2007. Here, we investigated the four-component vaccine long-term immunogenicity in Mamu-A*01-positive rhesus macaques and demonstrated that the vaccine-induced T cells were multi-specific, multi-functional, readily proliferated to recall peptides and were circulating in the peripheral blood of vaccine recipients over 1 year after vaccine administration. The consensus clade A-elicited T cells recognized 50% of tested epitope variants from other HIV-1 clades. Thus, the DNA-MVA/HIVA-RENTA vaccine induced memory T cells of desirable characteristics and similarities to those induced in humans by HIVA vaccines alone; however, single-clade vaccines may not elicit sufficiently cross-reactive responses.

Search for heavy sterile neutrinos in trileptons at the LHC

NASA Astrophysics Data System (ADS)

Dib, Claudio O.; Kim, C. S.; Wang, Kechen

2017-10-01

We present a search strategy for both Dirac and Majorana sterile neutrinos from the purely leptonic decays of W± → e± e± μ∓ ν and μ± μ± e∓ ν at the 14 TeV LHC. The discovery and exclusion limits for sterile neutrinos are shown using both the Cut-and-Count (CC) and Multi-Variate Analysis (MVA) methods. We also discriminate between Dirac and Majorana sterile neutrinos by exploiting a set of kinematic observables which differ between the Dirac and Majorana cases. We find that the MVA method, compared to the more common CC method, can greatly enhance the discovery and discrimination limits. Two benchmark points with sterile neutrino mass m N = 20 GeV and 50 GeV are tested. For an integrated luminosity of 3000 fb-1, sterile neutrinos can be found with 5σ significance if heavy-to-light neutrino mixings |U Ne |2 ˜ |U Nμ |2˜ 10-6, while Majorana vs. Dirac discrimination can be reached if at least one of the mixings is of order 10-5. K. W. was Supported by the International Postdoctoral Exchange Fellowship Program (No.90 Document of OCPC, 2015); C. S. K. by the NRF grant funded by the Korean government of the MEST (No. 2016R1D1A1A02936965); and C. D. by Chile grants Fondecyt No. 1130617, Conicyt ACT 1406 and PIA/Basal FB0821

Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial.

PubMed

Scurr, Martin; Pembroke, Tom; Bloom, Anja; Roberts, David; Thomson, Amanda; Smart, Kathryn; Bridgeman, Hayley; Adams, Richard; Brewster, Alison; Jones, Robert; Gwynne, Sarah; Blount, Daniel; Harrop, Richard; Wright, Melissa; Hills, Robert; Gallimore, Awen; Godkin, Andrew

2017-10-12

The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data. isrctn.org Identifier: ISRCTN54669986.

Homeless Liaisons' Awareness about the Implementation of the McKinney-Vento Act

ERIC Educational Resources Information Center

Wilkins, Brittany Taylor; Mullins, Mary H.; Mahan, Amber; Canfield, James P.

2016-01-01

The federal government enacted the McKinney--Vento Homeless Assistance Act (MVA) to equip schools with services to help alleviate the many barriers students experiencing homelessness face in pursuit of educational opportunities. Educational agencies use federally mandated liaisons to uphold the provisions of the MVA. Despite the homeless liaisons'…

[Evaluating psychological injury in motor vehicle accidents (MVA): development and validation of a protocol for detecting pretense].

PubMed

Arce, Ramón; Fariña, Francisca; Carballal, Alicia; Novo, Mercedes

2006-05-01

In order to assess the feigning ability of the psychological injury in a motor vehicle accident (MVA), a total of 105 subjects, which never had suffered a serious MVA and lay in psychopathology, responded to the MMPI-2 in line with the standard instructions. Thereafter, subjects were instructed to feign moral damage generated by a MVA prior to being evaluated using a clinical-forensic interview a week later, and responding to the MMPI-2 another week later. The results show that 60.9% of the subjects were able to effectively feign moral damage on the MMPI-2, and 3.8% in the forensic clinical interview. The analysis of the instruments and procedures for the validation of subject responses i.e., the original validity control scales of the MMPI-2 and the analysis of feigning strategies in the forensic clinical interview, revealed no efficacy in feigning detection. Nevertheless, collectively, all the control measures and procedures were effective for the detection of feigning. Therefore, a protocol for the detection of feigning of moral damage has been proposed.

Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro.

PubMed

Cartocci, Veronica; Segatto, Marco; Di Tunno, Ilenia; Leone, Stefano; Pfrieger, Frank W; Pallottini, Valentina

2016-09-01

During differentiation, neurons acquire their typical shape and functional properties. At present, it is unclear, whether this important developmental step involves metabolic changes. Here, we studied the contribution of the mevalonate (MVA) pathway to neuronal differentiation using the mouse neuroblastoma cell line N1E-115 as experimental model. Our results show that during differentiation, the activity of 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR), a key enzyme of MVA pathway, and the level of Low Density Lipoprotein receptor (LDLr) decrease, whereas the level of LDLr-related protein-1 (LRP1) and the dimerization of Scavanger Receptor B1 (SRB-1) rise. Pharmacologic inhibition of HMGR by simvastatin accelerated neuronal differentiation by modulating geranylated proteins. Collectively, our data suggest that during neuronal differentiation, the activity of the MVA pathway decreases and we postulate that any interference with this process impacts neuronal morphology and function. Therefore, the MVA pathway appears as an attractive pharmacological target to modulate neurological and metabolic symptoms of developmental neuropathologies. J. Cell. Biochem. 117: 2036-2044, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A single vaccination with non-replicating MVA at birth induces both immediate and long-term protective immune responses.

PubMed

Cheminay, Cédric; Körner, Jana; Bernig, Constanze; Brückel, Michael; Feigl, Markus; Schletz, Martin; Suter, Mark; Chaplin, Paul; Volkmann, Ariane

2018-04-25

Newborns are considered difficult to protect against infections shortly after birth, due to their ineffective immune system that shows quantitative and qualitative differences compared to adults. However, here we show that a single vaccination of mice at birth with a replication-deficient live vaccine Modified Vaccinia Ankara [MVA] efficiently induces antigen-specific B- and T-cells that fully protect against a lethal Ectromelia virus challenge. Protection was induced within 2 weeks and using genetically modified mice we show that this protection was mainly T-cell dependent. Persisting immunological T-cell memory and neutralizing antibodies were obtained with the single vaccination. Thus, MVA administered as early as at birth induced immediate and long-term protection against an otherwise fatal disease and appears attractive as a new generation smallpox vaccine that is effective also in children. Moreover, it may have the potential to serve as platform for childhood vaccines as indicated by measles specific T- and B-cell responses induced in newborn mice vaccinated with recombinant MVA expressing measles antigens. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vaccination directed against the human endogenous retrovirus-K (HERV-K) gag protein slows HERV-K gag expressing cell growth in a murine model system.

PubMed

Kraus, Benjamin; Fischer, Katrin; Sliva, Katja; Schnierle, Barbara S

2014-03-26

Human endogenous retroviruses (HERVs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. However enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed inter-alia in HIV-infected individuals and tumor patients. Therefore HERV-K might serve as a tumor-specific antigen or even as a constant target for the development of an HIV vaccine. To verify our hypothesis, we tested the immunogenicity of HERV-K Gag by using a recombinant vaccinia virus (MVA-HKcon) expressing the HERV-K Gag protein and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) and the HERV-K Gag protein (RLZ-HKGag cells). Subcutaneous application of RLZ-HKGag cells into syngenic BALB/c mice resulted in the formation of local tumors in MVA vaccinated mice. MVA-HKcon vaccination reduced the tumor growth. Furthermore, intravenous injection of RLZ-HKGag cells led to the formation of pulmonary metastases. Vaccination of tumor-bearing mice with MVA-HKcon drastically reduced the number of pulmonary RLZ-HKGag tumor nodules compared to vaccination with wild-type MVA. The data demonstrate that HERV-K Gag is a useful target for vaccine development and might offer new treatment opportunities for cancer patients.

1 MVA HTS-2G Generator for Wind Turbines

NASA Astrophysics Data System (ADS)

Kovalev, K. L.; Poltavets, V. N.; Ilyasov, R. I.; Verzhbitsky, L. G.; Kozub, S. S.

2017-10-01

The calculation, design simulations and design performance of 1 MVA HTS-2G (second-generation high-temperature superconductor) Generator for Wind Turbines were done in 2013-2014 [1]. The results of manufacturing and testing of 1 MVA generator are presented in the article. HTS-2G field coils for the rotor were redesigned, fabricated and tested. The tests have shown critical current of the coils, 41-45 A (self field within the ferromagnetic core, T = 77 K), which corresponds to the current of short samples at self field. Application of the copper inner frame on the pole has improved internal cooling conditions of HTS coil windings and reduced the magnetic field in the area, thereby increased the critical current value. The original construction of the rotor with a rotating cryostat was developed, which decreases the thermal in-flow to the rotor. The stator of 1 MW HTS-2G generator has been manufactured. In order to improve the specific weight of the generator, the wave (harmonic drive) multiplier was used, which provides increasing RPM from 15 RPM up to 600 RPM. The total mass of the multiplier and generator is significantly smaller compared to traditional direct-drive wind turbines generators [2-7]. Parameters of the multiplier and generator were chosen based on the actual parameters of wind turbines, namely: 15 RPM, power is 1 MVA. The final test of the assembled synchronous generator with HTS-2G field coils for Wind Turbines with output power 1 MVA was completed during 2015.

TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome

PubMed Central

Ochiai, Hiroshi; Miyamoto, Tatsuo; Kanai, Akinori; Hosoba, Kosuke; Sakuma, Tetsushi; Kudo, Yoshiki; Asami, Keiko; Ogawa, Atsushi; Watanabe, Akihiro; Kajii, Tadashi; Yamamoto, Takashi; Matsuura, Shinya

2014-01-01

Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy [PCS (MVA) syndrome] is a rare autosomal recessive disorder characterized by constitutional aneuploidy and a high risk of childhood cancer. We previously reported monoallelic mutations in the BUB1B gene (encoding BUBR1) in seven Japanese families with the syndrome. No second mutation was found in the opposite allele of any of the families studied, although a conserved BUB1B haplotype and a decreased transcript were identified. To clarify the molecular pathology of the second allele, we extended our mutational search to a candidate region surrounding BUB1B. A unique single nucleotide substitution, G > A at ss802470619, was identified in an intergenic region 44 kb upstream of a BUB1B transcription start site, which cosegregated with the disorder. To examine whether this is the causal mutation, we designed a transcription activator-like effector nuclease–mediated two-step single-base pair editing strategy and biallelically introduced this substitution into cultured human cells. The cell clones showed reduced BUB1B transcripts, increased PCS frequency, and MVA, which are the hallmarks of the syndrome. We also encountered a case of a Japanese infant with PCS (MVA) syndrome carrying a homozygous single nucleotide substitution at ss802470619. These results suggested that the nucleotide substitution identified was the causal mutation of PCS (MVA) syndrome. PMID:24344301

Low pathogenic avian influenza (H9N2) in chicken: Evaluation of an ancestral H9-MVA vaccine.

PubMed

Ducatez, Mariette F; Becker, Jens; Freudenstein, Astrid; Delverdier, Maxence; Delpont, Mattias; Sutter, Gerd; Guérin, Jean-Luc; Volz, Asisa

2016-06-30

Modified Vaccinia Ankara (MVA) has proven its efficacy as a recombinant vector vaccine for numerous pathogens including influenza virus. The present study aimed at evaluating a recombinant MVA candidate vaccine against low pathogenic avian influenza virus subtype H9N2 in the chicken model. As the high genetic and antigenic diversity of H9N2 viruses increases vaccine design complexity, one strategy to widen the range of vaccine coverage is to use an ancestor sequence. We therefore generated a recombinant MVA encoding for the gene sequence of an ancestral hemagglutinin H9 protein (a computationally derived amino acid sequence of the node of the H9N2 G1 lineage strains was obtained using the ANCESCON program). We analyzed the genetics and the growth properties of the MVA vector virus confirming suitability for use under biosafety level 1 and tested its efficacy when applied either as an intra-muscular (IM) or an oral vaccine in specific pathogen free chickens challenged with A/chicken/Tunisia/12/2010(H9N2). Two control groups were studied in parallel (unvaccinated and inoculated birds; unvaccinated and non-inoculated birds). IM vaccinated birds seroconverted as early as four days post vaccination and neutralizing antibodies were detected against A/chicken/Tunisia/12/2010(H9N2) in all the birds before challenge. The role of local mucosal immunity is unclear here as no antibodies were detected in eye drop or aerosol vaccinated birds. Clinical signs were not detected in any of the infected birds even in absence of vaccination. Virus replication was observed in both vaccinated and unvaccinated chickens, suggesting the MVA-ancestral H9 vaccine may not stop virus spread in the field. However vaccinated birds showed less histological damage, fewer influenza-positive cells and shorter virus shedding than their unvaccinated counterparts. Copyright © 2016 Elsevier B.V. All rights reserved.

The costs and cost effectiveness of providing first-trimester, medical and surgical safe abortion services in KwaZulu-Natal Province, South Africa.

PubMed

Lince-Deroche, Naomi; Fetters, Tamara; Sinanovic, Edina; Devjee, Jaymala; Moodley, Jack; Blanchard, Kelly

2017-01-01

Despite a liberal abortion law, access to safe abortion services in South Africa is challenging for many women. Medication abortion was introduced in 2013, but its reach remains limited. We aimed to estimate the costs and cost effectiveness of providing first-trimester medication abortion and manual vacuum aspiration (MVA) services to inform planning for first-trimester service provision in South Africa and similar settings. We obtained data on service provision and outcomes from an operations research study where medication abortion was introduced alongside existing MVA services in public hospitals in KwaZulu-Natal province. Clinical data were collected through interviews with first-trimester abortion clients and summaries completed by nurses performing the procedures. In parallel, we performed micro-costing at three of the study hospitals. Using a model built in Excel, we estimated the average cost per medical and surgical procedure and determined the cost per complete abortion performed. Results are presented in 2015 US dollars. A total of 1,129 women were eligible for a first trimester abortion at the three study sites. The majority (886, 78.5%) were eligible to choose their abortion procedure; 94.1% (n = 834) chose medication abortion. The total average cost per medication abortion was $63.91 (52.32-75.51). The total average cost per MVA was higher at $69.60 (52.62-86.57); though the cost ranges for the two procedures overlapped. Given average costs, the cost per complete medication abortion was lower than the cost per complete MVA despite three (0.4%) medication abortion women being hospitalized and two (0.3%) having ongoing pregnancies at study exit. Personnel costs were the largest component of the total average cost of both abortion methods. This analysis supports the scale-up of medication abortion alongside existing MVA services in South Africa. Women can be offered a choice of methods, including medication abortion with MVA as a back-up, without increasing costs.

A modified vaccinia Ankara vaccine vector expressing a mosaic H5 hemagglutinin reduces viral shedding in rhesus macaques

PubMed Central

Mutschler, James P.; Kingstad-Bakke, Brock; Schultz-Darken, Nancy; Broman, Karl W.; Osorio, Jorge E.

2017-01-01

The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a “mosaic” hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus. To assess its potential as a human vaccine we evaluated the ability of MVA-H5M to provide heterosubtypic immunity to influenza viruses in a non-human primate model. Rhesus macaques received an initial dose of either MVA-H5M or plasmid DNA encoding H5M, followed by a boost of MVA-H5M, and then were challenged, together with naïve controls, with the heterosubtypic virus A/California/04/2009 (H1N1pdm). Macaques receiving either vaccine regimen cleared H1N1pdm challenge faster than naïve controls. Vaccination with H5M elicited antibodies that bound H1N1pdm HA, but did not neutralize the H1N1pdm challenge virus. Plasma from vaccinated macaques activated NK cells in the presence of H1N1pdm HA, suggesting that vaccination elicited cross-reactive antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Although HA-specific T cell responses to the MVA-H5M vaccine were weak, responses after challenge were stronger in vaccinated macaques than in control animals. Together these data suggest that mosaic HA antigens may provide a means for inducing broadly cross-reactive immunity to influenza viruses. PMID:28771513

Deletion of Specific Immune-Modulatory Genes from Modified Vaccinia Virus Ankara-Based HIV Vaccines Engenders Improved Immunogenicity in Rhesus Macaques

PubMed Central

O'Mara, Leigh A.; Gangadhara, Sailaja; McQuoid, Monica; Zhang, Xiugen; Zheng, Rui; Gill, Kiran; Verma, Meena; Yu, Tianwei; Johnson, Brent; Li, Bing; Derdeyn, Cynthia A.; Ibegbu, Chris; Altman, John D.; Hunter, Eric; Feinberg, Mark B.

2012-01-01

Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 108 PFU) or low-dose (1 × 107 PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates. PMID:22973033

A modified vaccinia Ankara vaccine vector expressing a mosaic H5 hemagglutinin reduces viral shedding in rhesus macaques.

PubMed

Florek, Nicholas W; Kamlangdee, Attapon; Mutschler, James P; Kingstad-Bakke, Brock; Schultz-Darken, Nancy; Broman, Karl W; Osorio, Jorge E; Friedrich, Thomas C

2017-01-01

The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a "mosaic" hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus. To assess its potential as a human vaccine we evaluated the ability of MVA-H5M to provide heterosubtypic immunity to influenza viruses in a non-human primate model. Rhesus macaques received an initial dose of either MVA-H5M or plasmid DNA encoding H5M, followed by a boost of MVA-H5M, and then were challenged, together with naïve controls, with the heterosubtypic virus A/California/04/2009 (H1N1pdm). Macaques receiving either vaccine regimen cleared H1N1pdm challenge faster than naïve controls. Vaccination with H5M elicited antibodies that bound H1N1pdm HA, but did not neutralize the H1N1pdm challenge virus. Plasma from vaccinated macaques activated NK cells in the presence of H1N1pdm HA, suggesting that vaccination elicited cross-reactive antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Although HA-specific T cell responses to the MVA-H5M vaccine were weak, responses after challenge were stronger in vaccinated macaques than in control animals. Together these data suggest that mosaic HA antigens may provide a means for inducing broadly cross-reactive immunity to influenza viruses.

Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems.

PubMed

Tapia, Felipe; Jordan, Ingo; Genzel, Yvonne; Reichl, Udo

2017-01-01

One important aim in cell culture-based viral vaccine and vector production is the implementation of continuous processes. Such a development has the potential to reduce costs of vaccine manufacturing as volumetric productivity is increased and the manufacturing footprint is reduced. In this work, continuous production of Modified Vaccinia Ankara (MVA) virus was investigated. First, a semi-continuous two-stage cultivation system consisting of two shaker flasks in series was established as a small-scale approach. Cultures of the avian AGE1.CR.pIX cell line were expanded in the first shaker, and MVA virus was propagated and harvested in the second shaker over a period of 8-15 days. A total of nine small-scale cultivations were performed to investigate the impact of process parameters on virus yields. Harvest volumes of 0.7-1 L with maximum TCID50 titers of up to 1.0×109 virions/mL were obtained. Genetic analysis of control experiments using a recombinant MVA virus containing green-fluorescent-protein suggested that the virus was stable over at least 16 d of cultivation. In addition, a decrease or fluctuation of infectious units that may indicate an excessive accumulation of defective interfering particles was not observed. The process was automated in a two-stage continuous system comprising two connected 1 L stirred tank bioreactors. Stable MVA virus titers, and a total production volume of 7.1 L with an average TCID50 titer of 9×107 virions/mL was achieved. Because titers were at the lower range of the shake flask cultivations potential for further process optimization at large scale will be discussed. Overall, MVA virus was efficiently produced in continuous and semi-continuous cultivations making two-stage stirred tank bioreactor systems a promising platform for industrial production of MVA-derived recombinant vaccines and viral vectors.

Rapid and Effective Virucidal Activity of Povidone-Iodine Products Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Modified Vaccinia Virus Ankara (MVA).

PubMed

Eggers, Maren; Eickmann, Markus; Zorn, Juergen

2015-12-01

Since the first case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection was reported in 2012, the virus has infected more than 1300 individuals in 26 countries, and caused more than 480 deaths. Human-to-human transmission requires close contact, and has typically occurred in the healthcare setting. Improved global awareness, together with improved hygiene practices in healthcare facilities, has been highlighted as key strategies in controlling the spread of MERS-CoV. This study tested the in vitro efficacy of three formulations of povidone iodine (PVP-I: 4% PVP-I skin cleanser, 7.5% PVP-I surgical scrub, and 1% PVP-I gargle/mouthwash) against a reference virus (Modified vaccinia virus Ankara, MVA) and MERS-CoV. According to EN14476, a standard suspension test was used to assess virucidal activity against MVA and large volume plating was used for MERS-CoV. All products were tested under clean (0.3 g/L bovine serum albumin, BSA) and dirty conditions (3.0 g/L BSA + 3.0 mL/L erythrocytes), with application times of 15, 30, and 60 s for MVA, and 15 s for MERS-CoV. The products were tested undiluted, 1:10 and 1:100 diluted against MVA, and undiluted against MERS-CoV. A reduction in virus titer of ≥4 log10 (corresponding to an inactivation of ≥99.99%) was regarded as evidence of virucidal activity. This was achieved versus MVA and MERS-CoV, under both clean and dirty conditions, within 15 s of application of each undiluted PVP-I product. These data indicate that PVP-I-based hand wash products for potentially contaminated skin, and PVP-I gargle/mouthwash for reduction of viral load in the oral cavity and the oropharynx, may help to support hygiene measures to prevent transmission of MERS-CoV. Mundipharma Research GmbH & Co.

Lateral parapatellar and subvastus approaches are superior to the medial parapatellar approach in terms of soft tissue perfusion.

PubMed

Koçak, Aykut; Özmeriç, Ahmet; Koca, Gökhan; Senes, Mehmet; Yumuşak, Nihat; Iltar, Serkan; Korkmaz, Meliha; Alemdaroğlu, Kadir Bahadır

2017-08-23

The arthrotomy techniques of knee surgery may cause varying degrees of disruption to the tissue blood supply. The aim of this study was to investigate the effects of the medial parapatellar (MPPa), midvastus (MVa), subvastus (SVa) and lateral parapatellar (LPPa) approaches on regional tissue perfusion of the knee. In this experimental study, a total of 28 female rabbits were applied with four different arthrotomy techniques as Group MPPa, Group MVa, Group SVa and Group LPPa. The blood supply of the tissue around the knee was examined by scintigraphic imaging including the perfusion reserve and T max , and biochemical alteration of the oxidative stress parameters including malondialdehyde (MDA), fluorescent oxidation products (FlOPs), and histopathological findings were evaluated on tissue samples after 3 weeks. The perfusion reserve was increased in all four groups compared to the healthy, contralateral knees. In the Group LPPa, the vascularity was significantly increased compared to the Group MPPa (p = 0.006). In the examination of biochemical parameters, the increase in MDA levels was statistically significant in the Group MPPa compared with the Group LPPa (p = 0.004), and in the Group MVa compared with the Group LPPa (p = 0.006). The increase in the value of MDA levels was striking in the Group MPPa and Group MVa compared with the control group (p = 0.004, p = 0.004, respectively). The increase in another oxidative stress parameter, the tissue FlOPs levels, was statistically significant in the Group MPPa compared with the control group (p = 0.035). The LPPa and SVa caused less oxidative stress and less disruption of the muscle blood supply, in biochemical and scintigraphic parameters, compared to the MPPa and MVa. Therefore, in clinical practice, the SVa is preferable to the MPPa and MVa in total knee arthroplasty and the LPPa should be preferred more frequently in selected cases with critical soft tissue viability.

Mitral valve resistance determines hemodynamic consequences of severe rheumatic mitral stenosis and immediate outcomes of percutaneous valvuloplasty.

PubMed

Sanati, Hamidreza; Zolfaghari, Reza; Samiei, Niloufar; Rezaei, Yousef; Chitsazan, Mitra; Zahedmehr, Ali; Shakerian, Farshad; Kiani, Reza; Firouzi, Ata; Rezaei Tabrizi, Reza

2017-02-01

The mitral valve area (MVA) poorly reflects the hemodynamic status of (MS). In this study, we compared the MVA with mitral valve resistance (MVR) with regard to the determination of hemodynamic consequences of MS and the immediate outcomes of percutaneous balloon mitral valvuloplasty (PBMV). In a prospective study, 36 patients with severe rheumatic MS with left ventricular ejection fraction (LVEF) >50% were evaluated. They underwent transthoracic echocardiography (TTE) and catheterization. The MVA was measured by two-dimensional planimetry and pressure half-time (PHT), and the MVR was calculated using the equation: 1333 × transmitral pressure gradient mean transmitral diastolic flow rate. The patients' mean age was 47.8±10.5 years. MVR ≥140.6 dynes·s/cm 5 detected systolic pulmonary arterial pressure (sPAP) >55 mm Hg with a sensitivity of 100% and a specificity of 74%. The sensitivity and specificity of MVA<0.75 cm 2 to discriminate elevated sPAP were 81% and 89%, respectively. PHT ≥323.5 mseconds had a sensitivity of 78% and a specificity of 96% to detect an elevated sPAP. To predict a successful PBMV, preprocedural MVR ≥106.1 dynes·s/cm 5 had a sensitivity of 100% and a specificity of 67% (area under the curve [AUC]=0.763; 95% confidence interval [CI]=0.520-1.006; P=.034); preprocedural MVA <0.95 cm 2 had a sensitivity of 78% and a specificity of 73% (AUC=0.730; 95% CI=0.503-0.956; P=.065); and preprocedural PHT ≥210.5 mseconds had a sensitivity of 73% and a specificity of 78% (AUC=0.707; 95% CI=0.474-0.941; P=.095). MVR seems to be more accurate than MVA in determining the hemodynamic consequences of severe MS as determined by sPAP. In addition, preprocedural MVR detected successful PBMVs. © 2017, Wiley Periodicals, Inc.

Mosaic H5 Hemagglutinin Provides Broad Humoral and Cellular Immune Responses against Influenza Viruses

PubMed Central

Kamlangdee, Attapon; Kingstad-Bakke, Brock

2016-01-01

ABSTRACT The most effective way to prevent influenza virus infection is via vaccination. However, the constant mutation of influenza viruses due to antigenic drift and shift compromises vaccine efficacy. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. Using the modified vaccinia Ankara (MVA) virus, we had previously generated a recombinant vaccine against highly pathogenic avian influenza virus (H5N1) based on an in silico mosaic approach. This MVA-H5M construct protected mice against multiple clades of H5N1 and H1N1 viruses. We have now further characterized the immune responses using immunodepletion of T cells and passive serum transfer, and these studies indicate that antibodies are the main contributors in homosubtypic protection (H5N1 clades). Compared to a MVA construct expressing hemagglutinin (HA) from influenza virus A/VN/1203/04 (MVA-HA), the MVA-H5M vaccine markedly increased and broadened B cell and T cell responses against H5N1 virus. The MVA-H5M also provided effective protection with no morbidity against H5N1 challenge, whereas MVA-HA-vaccinated mice showed clinical signs and experienced significant weight loss. In addition, MVA-H5M induced CD8+ T cell responses that play a major role in heterosubtypic protection (H1N1). Finally, expression of the H5M gene as either a DNA vaccine or a subunit protein protected mice against H5N1 challenge, indicating the effectiveness of the mosaic sequence without viral vectors for the development of a universal influenza vaccine. IMPORTANCE Influenza viruses infect up to one billion people around the globe each year and are responsible for 300,000 to 500,000 deaths annually. Vaccines are still the main intervention to prevent infection, but they fail to provide effective protection against heterologous strains of viruses. We developed broadly reactive H5N1 vaccine based on an in silico mosaic approach and previously demonstrated that modified vaccinia Ankara expressing an H5 mosaic hemagglutinin prevented infection with multiple clades of H5N1 and limited severe disease after H1N1 infection. Further characterization revealed that antibody responses and T cells are main contributors to protection against H5N1 and H1N1 viruses, respectively. The vaccine also broadens both T cell and B cell responses compared to native H5 vaccine from influenza virus A/Vietnam/1203/04. Finally, delivering the H5 mosaic as a DNA vaccine or as a purified protein demonstrated effective protection similar to the viral vector approach. PMID:27194759

Modified vaccinia virus Ankara encoding influenza virus hemagglutinin induces heterosubtypic immunity in macaques.

PubMed

Florek, Nicholas W; Weinfurter, Jason T; Jegaskanda, Sinthujan; Brewoo, Joseph N; Powell, Tim D; Young, Ginger R; Das, Subash C; Hatta, Masato; Broman, Karl W; Hungnes, Olav; Dudman, Susanne G; Kawaoka, Yoshihiro; Kent, Stephen J; Stinchcomb, Dan T; Osorio, Jorge E; Friedrich, Thomas C

2014-11-01

Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA-based vaccines 4 weeks apart and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza virus HA and/or NP had high frequencies of virus-specific CD4(+) and CD8(+) T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC plays a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective. Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. Therefore, we evaluated a vaccine strategy designed to induce both antibody and T cell responses, which may provide more broadly cross-protective immunity against influenza. Here, we show in a translational primate model that vaccination with a modified vaccinia virus Ankara encoding hemagglutinin from a heterosubtypic H5N1 virus was associated with reduced shedding of a pandemic H1N1 virus challenge, while vaccination with MVA encoding nucleoprotein, an internal viral protein, was not. Unexpectedly, this reduced shedding was associated with nonneutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Therefore, antibody-dependent cellular cytotoxicity (ADCC) may play a role in cross-protective immunity to influenza virus. Vaccines that stimulate ADCC antibodies may enhance protection against pandemic influenza virus. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Modified Vaccinia Virus Ankara Encoding Influenza Virus Hemagglutinin Induces Heterosubtypic Immunity in Macaques

PubMed Central

Florek, Nicholas W.; Weinfurter, Jason T.; Jegaskanda, Sinthujan; Brewoo, Joseph N.; Powell, Tim D.; Young, Ginger R.; Das, Subash C.; Hatta, Masato; Broman, Karl W.; Hungnes, Olav; Dudman, Susanne G.; Kawaoka, Yoshihiro; Kent, Stephen J.; Stinchcomb, Dan T.

2014-01-01

ABSTRACT Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA-based vaccines 4 weeks apart and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza virus HA and/or NP had high frequencies of virus-specific CD4+ and CD8+ T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC plays a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective. IMPORTANCE Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. Therefore, we evaluated a vaccine strategy designed to induce both antibody and T cell responses, which may provide more broadly cross-protective immunity against influenza. Here, we show in a translational primate model that vaccination with a modified vaccinia virus Ankara encoding hemagglutinin from a heterosubtypic H5N1 virus was associated with reduced shedding of a pandemic H1N1 virus challenge, while vaccination with MVA encoding nucleoprotein, an internal viral protein, was not. Unexpectedly, this reduced shedding was associated with nonneutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Therefore, antibody-dependent cellular cytotoxicity (ADCC) may play a role in cross-protective immunity to influenza virus. Vaccines that stimulate ADCC antibodies may enhance protection against pandemic influenza virus. PMID:25210172

76 FR 52945 - Notice of Supplemental Filing; International Transmission Company, d/b/a ITC Transmission.

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-24

... replace a failed 675-MVA transformer with two 700-MVA phase-shifting transformers connected in series at... facilities with the installation of the new transformers, also known as phase angle regulators (PARs). On... further notice so that the transformers can be placed into service and benefits from controlling the Lake...

Analysis of variola and vaccinia virus neutralization assays for smallpox vaccines.

PubMed

Hughes, Christine M; Newman, Frances K; Davidson, Whitni B; Olson, Victoria A; Smith, Scott K; Holman, Robert C; Yan, Lihan; Frey, Sharon E; Belshe, Robert B; Karem, Kevin L; Damon, Inger K

2012-07-01

Possible smallpox reemergence drives research for third-generation vaccines that effectively neutralize variola virus. A comparison of neutralization assays using different substrates, variola and vaccinia (Dryvax and modified vaccinia Ankara [MVA]), showed significantly different 90% neutralization titers; Dryvax underestimated while MVA overestimated variola neutralization. Third-generation vaccines may rely upon neutralization as a correlate of protection.

High-resolution AM LCD development for avionic applications

NASA Astrophysics Data System (ADS)

Lamberth, Larry S.; Laddu, Ravindra R.; Harris, Doug; Sarma, Kalluri R.; Li, Wang-Yang; Chien, C. C.; Chu, C. Y.; Lee, C. S.; Kuo, Chen-Lung

2003-09-01

For the first time, an avionic grade MVA AM LCD with wide viewing angle has been developed for use in either landscape or portrait mode. The development of a high resolution Multi-domain Vertical Alignment (MVA) Active Matrix Liquid Crystal Display (AM LCD) is described. Challenges met in this development include achieving the required performance with high luminance and sunlight readability while meeting stringent optical (image quality) and environmental performance requirements of avionics displays. In this paper the optical and environmental performance of this high resolution 14.1" MVA-AM-LCD are discussed and some performance comparisons to conventional AM-LCDs are documented. This AM LCD has found multiple Business Aviation and Military display applications and cockpit pictures are presented.

Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy.

PubMed

Davuluri, Rajayogesh; Jiang, Wen; Fang, Penny; Xu, Cai; Komaki, Ritsuko; Gomez, Daniel R; Welsh, James; Cox, James D; Crane, Christopher H; Hsu, Charles C; Lin, Steven H

2017-09-01

Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival. 504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis. The median follow-up time was 36 months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton-based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001). G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

Bioterrorism Preparedness for Infectious Disease (BTPID) Proposal

DTIC Science & Technology

2007-01-01

approximately $210,000/ year x 5 years. (Pending) Safety, Tolerability and Immunogenicity of ACAM3000 Modified Vaccinia Ankara (MVA) Small Pox ...Hospital. • (Pending) Safety, Tolerability and Immunogenicity of ACAM3000 Modified Vaccinia Ankara (MVA) Small Pox Vaccine in HIV-Seropositive...choosing optimal pox virus derived vectors as vaccines in terms of reducing clinical reactogenicity and inducing dendritic cell (DC) aturation. 2006 Elsevier

Progress of gas-insulated transformers

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

Togawa, Y.; Ikeda, M.; Toda, K.

The world`s first transformer was manufactured at Ganz in Hungary in 1885. Two years later in 1887 patents applications were made for about oil immersed transformers in the US. Since then, oil immersed types have predominated for medium- and large-capacity transformers, which are now giving way to gas insulated transformers in some areas. Behind such trends are plans to construct substations inside buildings or underground, because of the difficulty in acquiring land for substations in large cities where power demand is concentrated. Requirements are protection against accidents, compactness and overall economy. Total gas insulated substations combining GIS units and gasmore » insulated transformers these needs. Demand for gas insulated transformers has been increasing rapidly, particularly in Japan and Hong Kong. First, relatively small-capacity models below 20--30 MVA were put into practical use and today 275 kV, 300 MVa models are in use and 500kV, 1,500 MVA models are coming into use. Engineering is progressing very rapidly in these areas. This paper describes the design techniques and important maintenance techniques for the latest gas insulated transformers from 5,000 kVA to 300 MVA.« less

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa.

PubMed

Nkolola, J P; Wee, E G-T; Im, E-J; Jewell, C P; Chen, N; Xu, X-N; McMichael, A J; Hanke, T

2004-07-01

For the development of human immunodeficiency virus type 1 (HIV-1) vaccines, traditional approaches inducing virus-neutralizing antibodies have so far failed. Thus the effort is now focused on elicitation of cellular immunity. We are currently testing in clinical trials in the United Kingdom and East Africa a T-cell vaccine consisting of HIV-1 clade A Gag-derived immunogen HIVA delivered in a prime-boost regimen by a DNA plasmid and modified vaccinia virus Ankara (MVA). Here, we describe engineering and preclinical development of a second immunogen RENTA, which will be used in combination with the present vaccine in a four-component DNA/HIVA-RENTA prime-MVA/HIVA-RENTA boost formulation. RENTA is a fusion protein derived from consensus HIV clade A sequences of Tat, reverse transcriptase, Nef and gp41. We inactivated the natural biological activities of the HIV components and confirmed immunogenicities of the pTHr.RENTA and MVA.RENTA vaccines in mice. Furthermore, we demonstrated in mice and rhesus monkeys broadening of HIVA-elicited T-cell responses by a parallel induction of HIVA- and RENTA-specific responses recognizing multiple HIV epitopes.

Anatomic, histologic, and two-dimensional-echocardiographic evaluation of mitral valve anatomy in dogs.

PubMed

Borgarelli, Michele; Tursi, Massimiliano; La Rosa, Giuseppe; Savarino, Paolo; Galloni, Marco

2011-09-01

To compare echocardiographic variables of dogs with postmortem anatomic measurements and histologic characteristics of the mitral valve (MV). 21 cardiologically normal dogs. The MV was measured echocardiographically by use of the right parasternal 5-chamber long-axis view. Dogs were euthanized, and anatomic measurements of the MV annulus (MVa) were performed at the level of the left circumflex coronary artery. Mitral valve leaflets (MVLs) and chordae tendineae were measured. Structure of the MVLs was histologically evaluated in 3 segments (proximal, middle, and distal). Echocardiographic measurements of MVL length did not differ significantly from anatomic measurements. A positive correlation was detected between body weight and MVa area. There was a negative correlation between MVa area and the percentage by which the MVL area exceeded the MVa area. Anterior MVLs had a significantly higher number of chordae tendineae than did posterior MVLs. Histologically, layering of MVLs was less preserved in the distal segment, whereas the muscular component and adipose tissue were significantly more diffuse in the proximal and middle segments. The MV in cardiologically normal dogs had wide anatomic variability. Anatomic measurements of MVL length were correlated with echocardiographic measurements.

Identification of vaccinia virus epitope-specific HLA-A*0201-restricted T cells and comparative analysis of smallpox vaccines

PubMed Central

Drexler, Ingo; Staib, Caroline; Kastenmüller, Wolfgang; Stevanović, Stefan; Schmidt, Burkhard; Lemonnier, François A.; Rammensee, Hans-Georg; Busch, Dirk H.; Bernhard, Helga; Erfle, Volker; Sutter, Gerd

2003-01-01

Despite worldwide eradication of naturally occurring variola virus, smallpox remains a potential threat to both civilian and military populations. New, safe smallpox vaccines are being developed, and there is an urgent need for methods to evaluate vaccine efficacy after immunization. Here we report the identification of an immunodominant HLA-A*0201-restricted epitope that is recognized by cytotoxic CD8+ T cells and conserved among Orthopoxvirus species including variola virus. This finding has permitted analysis and monitoring of epitope-specific T cell responses after immunization and demonstration of the identified T cell specificity in an A*0201-positive human donor. Vaccination of transgenic mice allowed us to compare the immunogenicity of several vaccinia viruses including highly attenuated, replication-deficient modified vaccinia virus Ankara (MVA). MVA vaccines elicited levels of CD8+ T cell responses that were comparable to those induced by the replication-competent vaccinia virus strains. Finally, we demonstrate that MVA vaccination is fully protective against a lethal respiratory challenge with virulent vaccinia virus strain Western Reserve. Our data provide a basis to rationally estimate immunogenicity of safe, second-generation poxvirus vaccines and suggest that MVA may be a suitable candidate. PMID:12518065

Do Cognitive Models Help in Predicting the Severity of Posttraumatic Stress Disorder, Phobia, and Depression After Motor Vehicle Accidents? A Prospective Longitudinal Study

PubMed Central

Ehring, Thomas; Ehlers, Anke; Glucksman, Edward

2008-01-01

The study investigated the power of theoretically derived cognitive variables to predict posttraumatic stress disorder (PTSD), travel phobia, and depression following injury in a motor vehicle accident (MVA). MVA survivors (N = 147) were assessed at the emergency department on the day of their accident and 2 weeks, 1 month, 3 months, and 6 months later. Diagnoses were established with the Structured Clinical Interview for DSM–IV. Predictors included initial symptom severities; variables established as predictors of PTSD in E. J. Ozer, S. R. Best, T. L. Lipsey, and D. S. Weiss's (2003) meta-analysis; and variables derived from cognitive models of PTSD, phobia, and depression. Results of nonparametric multiple regression analyses showed that the cognitive variables predicted subsequent PTSD and depression severities over and above what could be predicted from initial symptom levels. They also showed greater predictive power than the established predictors, although the latter showed similar effect sizes as in the meta-analysis. In addition, the predictors derived from cognitive models of PTSD and depression were disorder-specific. The results support the role of cognitive factors in the maintenance of emotional disorders following trauma. PMID:18377119

Molecular cloning of mevalonate pathway genes from Taraxacum brevicorniculatum and functional characterisation of the key enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

PubMed

van Deenen, Nicole; Bachmann, Anne-Lena; Schmidt, Thomas; Schaller, Hubert; Sand, Jennifer; Prüfer, Dirk; Schulze Gronover, Christian

2012-04-01

Taraxacum brevicorniculatum is known to produce high quality rubber. The biosynthesis of rubber is dependent on isopentenyl pyrophosphate (IPP) precursors derived from the mevalonate (MVA) pathway. The cDNA sequences of seven MVA pathway genes from latex of T. brevicorniculatum were isolated, including three cDNA sequences encoding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductases (TbHMGR1-3). Expression analyses indicate an important role of TbHMGR1 as well as for the HMG-CoA synthase (TbHMGS), the diphosphomevalonate decarboxylase and the mevalonate kinase in the provision of precursors for rubber biosynthesis. The amino acid sequences of the TbHMGRs show the typical motifs described for plant HMGRs such as two transmembrane domains and a catalytic domain containing two HMG-CoA and two NADP(H) binding sites. The functionality of the HMGRs was demonstrated by complementation assay using an IPP auxotroph mutant of Escherichia coli. Furthermore, the transient expression of the catalytic domains of TbHMGR1 and TbHMGR2 in Nicotiana benthamiana resulted in a strong accumulation of sterol precursors, one of the major groups of pathway end-products.

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

PubMed Central

Joseph, Sarah; Quinn, Killian; Greenwood, Aldona; Cope, Alethea V.; McKay, Paul F.; Hayes, Peter J.; Kopycinski, Jakub T.; Gilmour, Jill; Miller, Aleisha N.; Geldmacher, Christof; Nadai, Yuka; Ahmed, Mohamed I. M.; Montefiori, David C.; Dally, Len; Bouliotis, George; Lewis, David J. M.; Tatoud, Roger; Wagner, Ralf; Esteban, Mariano; Shattock, Robin J.; McCormack, Sheena; Weber, Jonathan

2017-01-01

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen. PMID:28275375

A Chimeric HIV-1 gp120 Fused with Vaccinia Virus 14K (A27) Protein as an HIV Immunogen

PubMed Central

Vijayan, Aneesh; García-Arriaza, Juan; C. Raman, Suresh; Conesa, José Javier; Chichón, Francisco Javier; Santiago, César; Sorzano, Carlos Óscar S.; Carrascosa, José L.; Esteban, Mariano

2015-01-01

In the HIV vaccine field, there is a need to produce highly immunogenic forms of the Env protein with the capacity to trigger broad B and T-cell responses. Here, we report the generation and characterization of a chimeric HIV-1 gp120 protein (termed gp120-14K) by fusing gp120 from clade B with the vaccinia virus (VACV) 14K oligomeric protein (derived from A27L gene). Stable CHO cell lines expressing HIV-1 gp120-14K protein were generated and the protein purified was characterized by size exclusion chromatography, electron microscopy and binding to anti-Env antibodies. These approaches indicate that gp120-14K protein is oligomeric and reacts with a wide spectrum of HIV-1 neutralizing antibodies. Furthermore, in human monocyte-derived dendritic cells (moDCs), gp120-14K protein upregulates the levels of several proinflammatory cytokines and chemokines associated with Th1 innate immune responses (IL-1β, IFN-γ, IL-6, IL-8, IL-12, RANTES). Moreover, we showed in a murine model, that a heterologous prime/boost immunization protocol consisting of a DNA prime with a plasmid expressing gp120-14K protein followed by a boost with MVA-B [a recombinant modified vaccinia virus Ankara (MVA) expressing HIV-1 gp120, Gag, Pol and Nef antigens from clade B], generates stronger, more polyfunctional, and greater effector memory HIV-1-specific CD4+ and CD8+ T-cell immune responses, than immunization with DNA-gp120/MVA-B. The DNA/MVA protocol was superior to immunization with the combination of protein/MVA and the latter was superior to a prime/boost of MVA/MVA or protein/protein. In addition, these immunization protocols enhanced antibody responses against gp120 of the class IgG2a and IgG3, together favoring a Th1 humoral immune response. These results demonstrate that fusing HIV-1 gp120 with VACV 14K forms an oligomeric protein which is highly antigenic as it activates a Th1 innate immune response in human moDCs, and in vaccinated mice triggers polyfunctional HIV-1-specific adaptive and memory T-cell immune responses, as well as humoral responses. This novel HIV-1 gp120-14K immunogen might be considered as an HIV vaccine candidate for broad T and B-cell immune responses. PMID:26208356

Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults

PubMed Central

Green, C A; Scarselli, E; Voysey, M; Capone, S; Vitelli, A; Nicosia, A; Cortese, R; Thompson, A J; Sande, C S; de Lara, Catherine; Klenerman, P; Pollard, A J

2015-01-01

Introduction Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults. Methods and analysis Heterologous and homologous ‘prime’/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18–50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60–75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK. Ethics and dissemination RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums. Trial registration number NCT01805921. PMID:26510727

The costs and cost effectiveness of providing first-trimester, medical and surgical safe abortion services in KwaZulu-Natal Province, South Africa

PubMed Central

Devjee, Jaymala; Moodley, Jack

2017-01-01

Background Despite a liberal abortion law, access to safe abortion services in South Africa is challenging for many women. Medication abortion was introduced in 2013, but its reach remains limited. We aimed to estimate the costs and cost effectiveness of providing first-trimester medication abortion and manual vacuum aspiration (MVA) services to inform planning for first-trimester service provision in South Africa and similar settings. Methods We obtained data on service provision and outcomes from an operations research study where medication abortion was introduced alongside existing MVA services in public hospitals in KwaZulu-Natal province. Clinical data were collected through interviews with first-trimester abortion clients and summaries completed by nurses performing the procedures. In parallel, we performed micro-costing at three of the study hospitals. Using a model built in Excel, we estimated the average cost per medical and surgical procedure and determined the cost per complete abortion performed. Results are presented in 2015 US dollars. Results A total of 1,129 women were eligible for a first trimester abortion at the three study sites. The majority (886, 78.5%) were eligible to choose their abortion procedure; 94.1% (n = 834) chose medication abortion. The total average cost per medication abortion was $63.91 (52.32–75.51). The total average cost per MVA was higher at $69.60 (52.62–86.57); though the cost ranges for the two procedures overlapped. Given average costs, the cost per complete medication abortion was lower than the cost per complete MVA despite three (0.4%) medication abortion women being hospitalized and two (0.3%) having ongoing pregnancies at study exit. Personnel costs were the largest component of the total average cost of both abortion methods. Conclusion This analysis supports the scale-up of medication abortion alongside existing MVA services in South Africa. Women can be offered a choice of methods, including medication abortion with MVA as a back-up, without increasing costs. PMID:28369061

In vitro toxicology of respirable Montserrat volcanic ash.

PubMed

Wilson, M R; Stone, V; Cullen, R T; Searl, A; Maynard, R L; Donaldson, K

2000-11-01

In July 1995 the Soufriere Hills volcano on the island of Montserrat began to erupt. Preliminary reports showed that the ash contained a substantial respirable component and a large percentage of the toxic silica polymorph, cristobalite. In this study the cytotoxicity of three respirable Montserrat volcanic ash (MVA) samples was investigated: M1 from a single explosive event, M2 accumulated ash predominantly derived from pyroclastic flows, and M3 from a single pyroclastic flow. These were compared with the relatively inert dust TiO(2) and the known toxic quartz dust, DQ12. Surface area of the particles was measured with the Brunauer, Emmet, and Teller (BET) adsorption method and cristobalite content of MVA was determined by x ray diffraction (XRD). After exposure to particles, the metabolic competence of the epithelial cell line A549 was assessed to determine cytotoxic effects. The ability of the particles to induce sheep blood erythrocyte haemolysis was used to assess surface reactivity. Treatment with either MVA, quartz, or titanium dioxide decreased A549 epithelial cell metabolic competence as measured by ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On addition of mannitol, the cytotoxic effect was significantly less with M1, quartz, and TiO(2). All MVA samples induced a dose dependent increase in haemolysis, which, although less than the haemolysis induced by quartz, was significantly greater than that induced by TiO(2). Addition of mannitol and superoxide dismutase (SOD) significantly reduced the haemolytic activity only of M1, but not M2 or M3, the samples derived from predominantly pyroclastic flow events. Neither the cristobalite content nor the surface area of the MVA samples correlated with observed in vitro reactivity. A role for reactive oxygen species could only be shown in the cytotoxicity of M1, which was the only sample derived from a purely explosive event. These results suggest that in general the bioreactivity of MVA samples in vitro is low compared with pure quartz, but that the bioreactivity and mechanisms of biological interaction may vary according to the ash source.

Survival Outcomes of Whole-Pelvic Versus Prostate-Only Radiation Therapy for High-Risk Prostate Cancer Patients With Use of the National Cancer Data Base

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

Amini, Arya; Jones, Bernard L.; Yeh, Norman

Purpose/Objectives: The addition of whole pelvic (WP) compared with prostate-only (PO) radiation therapy (RT) for clinically node-negative prostate cancer remains controversial. The purpose of our study was to evaluate the survival benefit of adding WPRT versus PO-RT for high-risk, node-negative prostate cancer, using the National Cancer Data Base (NCDB). Methods and Materials: Patients with high-risk prostate cancer treated from 2004 to 2006, with available data for RT volume, coded as prostate and pelvis (WPRT) or prostate alone (PO-RT) were included. Multivariate analysis (MVA) and propensity-score matched analysis (PSM) were performed. Recursive partitioning analysis (RPA) based on overall survival (OS) usingmore » Gleason score (GS), T stage, and pretreatment prostate-specific antigen (PSA) was also conducted. Results: A total of 14,817 patients were included: 7606 (51.3%) received WPRT, and 7211 (48.7%) received PO-RT. The median follow-up time was 81 months (range, 2-122 months). Under MVA, the addition of WPRT for high-risk patients had no OS benefit compared with PO-RT (HR 1.05; P=.100). On subset analysis, patients receiving dose-escalated RT also did not benefit from WPRT (HR 1.01; P=.908). PSM confirmed no survival benefit with the addition of WPRT for high-risk patients (HR 1.05; P=.141). In addition, RPA was unable to demonstrate a survival benefit of WPRT for any subset. Other prognostic factors for inferior OS under MVA included older age (HR 1.25; P<.001), increasing comorbidity scores (HR 1.46; P<.001), higher T stage (HR 1.17; P<.001), PSA (HR 1.81; P<.001), and GS (HR 1.29; P<.001), and decreasing median county household income (HR 1.15; P=.011). Factors improving OS included the addition of androgen deprivation therapy (HR 0.92; P=.033), combination external beam RT plus brachytherapy boost (HR 0.71; P<.001), and treatment at an academic/research institution (HR 0.84; P=.002). Conclusion: In the largest reported analysis of WPRT for patients with high-risk prostate cancer treated in the dose-escalated era, the addition of WPRT demonstrated no survival advantage compared with PO-RT.« less

S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation1[C][W

PubMed Central

Huchelmann, Alexandre; Gastaldo, Clément; Veinante, Mickaël; Zeng, Ying; Heintz, Dimitri; Tritsch, Denis; Schaller, Hubert; Rohmer, Michel; Bach, Thomas J.; Hemmerlin, Andréa

2014-01-01

S-Carvone has been described as a negative regulator of mevalonic acid (MVA) production by interfering with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) activity, a key player in isoprenoid biosynthesis. The impact of this monoterpene on the production of capsidiol in Nicotiana tabacum, an assumed MVA-derived sesquiterpenoid phytoalexin produced in response to elicitation by cellulase, was investigated. As expected, capsidiol production, as well as early stages of elicitation such as hydrogen peroxide production or stimulation of 5-epi-aristolochene synthase activity, were repressed. Despite the lack of capsidiol synthesis, apparent HMGR activity was boosted. Feeding experiments using (1-13C)Glc followed by analysis of labeling patterns by 13C-NMR, confirmed an MVA-dependent biosynthesis; however, treatments with fosmidomycin, an inhibitor of the MVA-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) isoprenoid pathway, unexpectedly down-regulated the biosynthesis of this sesquiterpene as well. We postulated that S-carvone does not directly inhibit the production of MVA by inactivating HMGR, but possibly targets an MEP-derived isoprenoid involved in the early steps of the elicitation process. A new model is proposed in which the monoterpene blocks an MEP pathway–dependent protein geranylgeranylation necessary for the signaling cascade. The production of capsidiol was inhibited when plants were treated with some inhibitors of protein prenylation or by further monoterpenes. Moreover, S-carvone hindered isoprenylation of a prenylable GFP indicator protein expressed in N. tabacum cell lines, which can be chemically complemented with geranylgeraniol. The model was further validated using N. tabacum cell extracts or recombinant N. tabacum protein prenyltransferases expressed in Escherichia coli. Our study endorsed a reevaluation of the effect of S-carvone on plant isoprenoid metabolism. PMID:24367019

A Whole-Cell Phenotypic Screening Platform for Identifying Methylerythritol Phosphate Pathway-Selective Inhibitors as Novel Antibacterial Agents

PubMed Central

Johnson, L. Jeffrey

2012-01-01

Isoprenoid biosynthesis is essential for survival of all living organisms. More than 50,000 unique isoprenoids occur naturally, with each constructed from two simple five-carbon precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Two pathways for the biosynthesis of IPP and DMAPP are found in nature. Humans exclusively use the mevalonate (MVA) pathway, while most bacteria, including all Gram-negative and many Gram-positive species, use the unrelated methylerythritol phosphate (MEP) pathway. Here we report the development of a novel, whole-cell phenotypic screening platform to identify compounds that selectively inhibit the MEP pathway. Strains of Salmonella enterica serovar Typhimurium were engineered to have separately inducible MEP (native) and MVA (nonnative) pathways. These strains, RMC26 and CT31-7d, were then used to differentiate MVA pathway- and MEP pathway-specific perturbation. Compounds that inhibit MEP pathway-dependent bacterial growth but leave MVA-dependent growth unaffected represent MEP pathway-selective antibacterials. This screening platform offers three significant results. First, the compound is antibacterial and is therefore cell permeant, enabling access to the intracellular target. Second, the compound inhibits one or more MEP pathway enzymes. Third, the MVA pathway is unaffected, suggesting selectivity for targeting the bacterial versus host pathway. The cell lines also display increased sensitivity to two reported MEP pathway-specific inhibitors, further biasing the platform toward inhibitors selective for the MEP pathway. We demonstrate development of a robust, high-throughput screening platform that combines phenotypic and target-based screening that can identify MEP pathway-selective antibacterials simply by monitoring optical density as the readout for cell growth/inhibition. PMID:22777049

Safety and immunogenicity of heterologous prime-boost immunization with viral-vectored malaria vaccines adjuvanted with Matrix-M™.

PubMed

Venkatraman, Navin; Anagnostou, Nicholas; Bliss, Carly; Bowyer, Georgina; Wright, Danny; Lövgren-Bengtsson, Karin; Roberts, Rachel; Poulton, Ian; Lawrie, Alison; Ewer, Katie; V S Hill, Adrian

2017-10-27

The use of viral vectors in heterologous prime-boost regimens to induce potent T cell responses in addition to humoral immunity is a promising vaccination strategy in the fight against malaria. We conducted an open-label, first-in-human, controlled Phase I study evaluating the safety and immunogenicity of Matrix-M adjuvanted vaccination with a chimpanzee adenovirus serotype 63 (ChAd63) prime followed by a modified vaccinia Ankara (MVA) boost eight weeks later, both encoding the malaria ME-TRAP antigenic sequence (a multiple epitope string fused to thrombospondin-related adhesion protein). Twenty-two healthy adults were vaccinated intramuscularly with either ChAd63-MVA ME-TRAP alone (n=6) or adjuvanted with 25μg (n=8) or 50μg (n=8) Matrix-M. Vaccinations appeared to be safe and generally well tolerated, with the majority of local and systemic adverse events being mild in nature. The addition of Matrix-M to the vaccine did not increase local reactogenicity; however, systemic adverse events were reported more frequently by volunteers who received adjuvanted vaccine in comparison to the control group. T cell ELISpot responses peaked at 7-days post boost vaccination with MVA ME-TRAP in all three groups. TRAP-specific IgG responses were highest at 28-days post boost with MVA ME-TRAP in all three groups. There were no differences in cellular and humoral immunogenicity at any of the time points between the control group and the adjuvanted groups. We demonstrate that Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity. Clinical Trials Registration NCT01669512. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of mammalian cell derived and Modified Vaccinia Ankara vectored African swine fever subunit antigens in swine.

PubMed

Lopera-Madrid, Jaime; Osorio, Jorge E; He, Yongqun; Xiang, Zuoshuang; Adams, L Garry; Laughlin, Richard C; Mwangi, Waithaka; Subramanya, Sandesh; Neilan, John; Brake, David; Burrage, Thomas G; Brown, William Clay; Clavijo, Alfonso; Bounpheng, Mangkey A

2017-03-01

A reverse vaccinology system, Vaxign, was used to identify and select a subset of five African Swine Fever (ASF) antigens that were successfully purified from human embryonic kidney 293 (HEK) cells and produced in Modified vaccinia virus Ankara (MVA) viral vectors. Three HEK-purified antigens [B646L (p72), E183L (p54), and O61R (p12)], and three MVA-vectored antigens [B646L, EP153R, and EP402R (CD2v)] were evaluated using a prime-boost immunization regimen swine safety and immunogenicity study. Antibody responses were detected in pigs following prime-boost immunization four weeks apart with the HEK-293-purified p72, p54, and p12 antigens. Notably, sera from the vaccinees were positive by immunofluorescence on ASFV (Georgia 2007/1)-infected primary macrophages. Although MVA-vectored p72, CD2v, and EP153R failed to induce antibody responses, interferon-gamma (IFN-γ + ) spot forming cell responses against all three antigens were detected one week post-boost. The highest IFN-γ + spot forming cell responses were detected against p72 in pigs primed with MVA-p72 and boosted with the recombinant p72. Antigen-specific (p12, p72, CD2v, and EP153R) T-cell proliferative responses were also detected post-boost. Collectively, these results are the first demonstration that ASFV subunit antigens purified from mammalian cells or expressed in MVA vectors are safe and can induce ASFV-specific antibody and T-cell responses following a prime-boost immunization regimen in swine. Copyright © 2017 Elsevier B.V. All rights reserved.

CD70 encoded by modified vaccinia virus Ankara enhances CD8 T-cell-dependent protective immunity in MHC class II-deficient mice.

PubMed

Bathke, Barbara; Pätzold, Juliane; Kassub, Ronny; Giessel, Raphael; Lämmermann, Kerstin; Hinterberger, Maria; Brinkmann, Kay; Chaplin, Paul; Suter, Mark; Hochrein, Hubertus; Lauterbach, Henning

2017-12-27

The immunological outcome of infections and vaccinations is largely determined during the initial first days in which antigen-presenting cells instruct T cells to expand and differentiate into effector and memory cells. Besides the essential stimulation of the T-cell receptor complex a plethora of co-stimulatory signals not only ensures a proper T-cell activation but also instils phenotypic and functional characteristics in the T cells appropriate to fight off the invading pathogen. The tumour necrosis factor receptor/ligand pair CD27/CD70 gained a lot of attention because of its key role in regulating T-cell activation, survival, differentiation and maintenance, especially in the course of viral infections and cancer. We sought to investigate the role of CD70 co-stimulation for immune responses induced by the vaccine vector modified vaccinia virus Ankara-Bavarian Nordic ® (MVA-BN ® ). Short-term blockade of CD70 diminished systemic CD8 T-cell effector and memory responses in mice. The dependence on CD70 became even more apparent in the lungs of MHC class II-deficient mice. Importantly, genetically encoded CD70 in MVA-BN ® not only increased CD8 T-cell responses in wild-type mice but also substituted for CD4 T-cell help. MHC class II-deficient mice that were immunized with recombinant MVA-CD70 were fully protected against a lethal virus infection, whereas MVA-BN ® -immunized mice failed to control the virus. These data are in line with CD70 playing an important role for vaccine-induced CD8 T-cell responses and prove the potency of integrating co-stimulatory molecules into the MVA-BN ® backbone. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

A role for the mevalonate pathway in early plant symbiotic signaling

PubMed Central

Venkateshwaran, Muthusubramanian; Jayaraman, Dhileepkumar; Chabaud, Mireille; Genre, Andrea; Balloon, Allison J.; Maeda, Junko; Forshey, Kari; den Os, Désirée; Kwiecien, Nicholas W.; Coon, Joshua J.; Barker, David G.; Ané, Jean-Michel

2015-01-01

Rhizobia and arbuscular mycorrhizal fungi produce signals that are perceived by host legume receptors at the plasma membrane and trigger sustained oscillations of the nuclear and perinuclear Ca2+ concentration (Ca2+ spiking), which in turn leads to gene expression and downstream symbiotic responses. The activation of Ca2+ spiking requires the plasma membrane-localized receptor-like kinase Does not Make Infections 2 (DMI2) as well as the nuclear cation channel DMI1. A key enzyme regulating the mevalonate (MVA) pathway, 3-Hydroxy-3-Methylglutaryl CoA Reductase 1 (HMGR1), interacts with DMI2 and is required for the legume–rhizobium symbiosis. Here, we show that HMGR1 is required to initiate Ca2+ spiking and symbiotic gene expression in Medicago truncatula roots in response to rhizobial and arbuscular mycorrhizal fungal signals. Furthermore, MVA, the direct product of HMGR1 activity, is sufficient to induce nuclear-associated Ca2+ spiking and symbiotic gene expression in both wild-type plants and dmi2 mutants, but interestingly not in dmi1 mutants. Finally, MVA induced Ca2+ spiking in Human Embryonic Kidney 293 cells expressing DMI1. This demonstrates that the nuclear cation channel DMI1 is sufficient to support MVA-induced Ca2+ spiking in this heterologous system. PMID:26199419

A role for the mevalonate pathway in early plant symbiotic signaling.

PubMed

Venkateshwaran, Muthusubramanian; Jayaraman, Dhileepkumar; Chabaud, Mireille; Genre, Andrea; Balloon, Allison J; Maeda, Junko; Forshey, Kari; den Os, Désirée; Kwiecien, Nicholas W; Coon, Joshua J; Barker, David G; Ané, Jean-Michel

2015-08-04

Rhizobia and arbuscular mycorrhizal fungi produce signals that are perceived by host legume receptors at the plasma membrane and trigger sustained oscillations of the nuclear and perinuclear Ca(2+) concentration (Ca(2+) spiking), which in turn leads to gene expression and downstream symbiotic responses. The activation of Ca(2+) spiking requires the plasma membrane-localized receptor-like kinase Does not Make Infections 2 (DMI2) as well as the nuclear cation channel DMI1. A key enzyme regulating the mevalonate (MVA) pathway, 3-Hydroxy-3-Methylglutaryl CoA Reductase 1 (HMGR1), interacts with DMI2 and is required for the legume-rhizobium symbiosis. Here, we show that HMGR1 is required to initiate Ca(2+) spiking and symbiotic gene expression in Medicago truncatula roots in response to rhizobial and arbuscular mycorrhizal fungal signals. Furthermore, MVA, the direct product of HMGR1 activity, is sufficient to induce nuclear-associated Ca(2+) spiking and symbiotic gene expression in both wild-type plants and dmi2 mutants, but interestingly not in dmi1 mutants. Finally, MVA induced Ca(2+) spiking in Human Embryonic Kidney 293 cells expressing DMI1. This demonstrates that the nuclear cation channel DMI1 is sufficient to support MVA-induced Ca(2+) spiking in this heterologous system.

Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese.

PubMed

Mashiba, Junko; Koike, George; Kamiunten, Hitoshi; Ikeda, Manami; Sunagawa, Kenji

2005-12-01

Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.

Predicting functional mitral stenosis after restrictive annuloplasty for ischemic mitral regurgitation.

PubMed

Li, Baotong; Wu, Hengchao; Sun, Hansong; Xu, Jianping; Song, Yunhu; Wang, Wei; Wang, Shuiyun

2018-03-07

Although it has been realized that restrictive mitral valve annuloplasty (MVA) may result in clinically significant functional mitral stenosis (MS), it still cannot be predicted. The purpose of this study was to identify risk factors for clinically significant functional MS following restrictive MVA surgery for chronic ischemic mitral regurgitation (CIMR). 114 patients who underwent restrictive MVA with coronary artery bypass grafting (CABG) for treatment of CIMR were retrospectively reviewed. Clinically significant functional MS was defined as resting transmitral peak pressure gradient (PPG) ≥ 13 mmHg. During the follow-up period (range 6-12 months), 28 (24.56%) patients developed clinically significant functional MS. The PPG at follow-up was significantly higher than that measured in the early postoperative stage (3-5 days after surgery). Moreover, there was a linear correlation between the two measurements (r = 0.398, p < 0.001). Annuloplasty size ≤ 27 mm and early postoperative PPG ≥ 7.4 mmHg could predict clinically significant functional MS at 6-12 months postoperatively. Chronic ischemic mitral regurgitation patients treated with restrictive MVA and CABG have significant increases in PPG postoperatively. Annuloplasty size ≤ 27 mm and early postoperative PPG ≥ 7.4 mmHg can predict clinically significant functional MS at 6-12 months after surgery.

Trends in pediatric liver transplant donors and deceased donor circumstance of death in the United States, 2002-2015.

PubMed

Yoeli, Dor; Goss, Matthew; Galván, Nhu Thao N; Desai, Moreshwar S; Miloh, Tamir A; Rana, Abbas

2018-05-01

While much of the discussion regarding expanding the donor pool for pediatric liver transplantation has surrounded the use of technical variant grafts, little attention has been directed toward changes in the deceased donor population. The aim of this study was to investigate trends in the circumstance of the death of deceased donors used for pediatric liver transplantation. All pediatric liver transplant recipients transplanted between 2002 and 2015 were identified in the UNOS database and were categorized based on the donor circumstance of death. There was no significant correlation between year of transplantation and number of pediatric liver transplants performed, pediatric donors, split livers, or living donors. There was a significant downward trend in donors from motor vehicle fatalities and an upward trend in suicide, non-MVA, and death due to natural causes. There was also an upward trend in drowning, one of the most common mechanisms of death among non-MVA in 2015. While the number of donors who died in MVA has fallen, the number of deceased donors who died from suicide, natural causes, and non-MVA, especially drowning, has increased, maintaining the overall number of pediatric deceased donor livers transplanted. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ultrasound based mitral valve annulus tracking for off-pump beating heart mitral valve repair

NASA Astrophysics Data System (ADS)

Li, Feng P.; Rajchl, Martin; Moore, John; Peters, Terry M.

2014-03-01

Mitral regurgitation (MR) occurs when the mitral valve cannot close properly during systole. The NeoChordtool aims to repair MR by implanting artificial chordae tendineae on flail leaflets inside the beating heart, without a cardiopulmonary bypass. Image guidance is crucial for such a procedure due to the lack of direct vision of the targets or instruments. While this procedure is currently guided solely by transesophageal echocardiography (TEE), our previous work has demonstrated that guidance safety and efficiency can be significantly improved by employing augmented virtuality to provide virtual presentation of mitral valve annulus (MVA) and tools integrated with real time ultrasound image data. However, real-time mitral annulus tracking remains a challenge. In this paper, we describe an image-based approach to rapidly track MVA points on 2D/biplane TEE images. This approach is composed of two components: an image-based phasing component identifying images at optimal cardiac phases for tracking, and a registration component updating the coordinates of MVA points. Preliminary validation has been performed on porcine data with an average difference between manually and automatically identified MVA points of 2.5mm. Using a parallelized implementation, this approach is able to track the mitral valve at up to 10 images per second.

A phase I trial of preventive HIV vaccination with heterologous poxviral-vectors containing matching HIV-1 inserts in healthy HIV-uninfected subjects

PubMed Central

Keefer, Michael C.; Frey, Sharon E.; Elizaga, Marnie; Metch, Barbara; De Rosa, Stephen C.; Barroso, Paulo F.; Tomaras, Georgia; Cardinali, Massimo; Goepfert, Paul; Kalichman, Artur; Philippon, Valérie; McElrath, M. Juliana; Jin, Xia; Ferrari, Guido; Defawe, Olivier D.; Mazzara, Gail P.; Montefiori, David; Pensiero, Michael; Panicali, Dennis L.; Corey, Lawrence

2011-01-01

We evaluated replication-defective poxvirus vectors (modified vaccinia Ankara [MVA] and fowlpox [FPV]) in a homologous and heterologous vector prime-boost vaccination regimen containing matching HIV inserts (MVA-HIV and FPV-HIV) given at months 0, 1, 3, 5 and 7 in 150 healthy HIV-negative vaccinia-naïve participants. FPV-HIV alone was poorly immunogenic, while the high dose (109 pfu/2ml) of MVA-HIV alone elicited maximal responses after two injections: CD4+ and CD8+ T-cell responses in 26/55 (47.3%) and 5/60 (8.3%) of participants, respectively and IFN-γ ELISpot responses in 28/62 (45.2%). The infrequent CD8+ T-cell responses following MVA-HIV priming were boosted only by the heterologous (FPV-HIV) construct in 14/27 [51.9%] of participants post-4th vaccination. Alternatively, HIV envelope-specific binding antibodies were demonstrated in approximately two-thirds of recipients of the homologous boosting regimen, but in less than 20% of subjects after the heterologous vector boost. Thus, a heterologous poxvirus vector prime-boost regimen can induce an HIV-specific CD8+ T-cell and CD4+ T-cell responses, which may be an important feature of an optimal regimen for preventive HIV vaccination. PMID:21216311

Newborn Mice Vaccination with BCG.HIVA222 + MVA.HIVA Enhances HIV-1-Specific Immune Responses: Influence of Age and Immunization Routes

PubMed Central

Saubi, Narcís; Im, Eung-Jun; Fernández-Lloris, Raquel; Gil, Olga; Cardona, Pere-Joan; Gatell, Josep Maria; Hanke, Tomáš; Joseph, Joan

2011-01-01

We have evaluated the influence of age and immunization routes for induction of HIV-1- and M. tuberculosis-specific immune responses after neonatal (7 days old) and adult (7 weeks old) BALB/c mice immunization with BCG.HIVA222 prime and MVA.HIVA boost. The specific HIV-1 cellular immune responses were analyzed in spleen cells. The body weight of the newborn mice was weekly recorded. The frequencies of HIV-specific CD8+ T cells producing IFN-γ were higher in adult mice vaccinated intradermally and lower in adult and newborn mice vaccinated subcutaneously. In all cases the IFN-γ production was significantly higher when mice were primed with BCG.HIVA222 compared with BCGwt. When the HIV-specific CTL activity was assessed, the frequencies of specific killing were higher in newborn mice than in adults. The prime-boost vaccination regimen which includes BCG.HIVA222 and MVA.HIVA was safe when inoculated to newborn mice. The administration of BCG.HIVA222 to newborn mice is safe and immunogenic and increased the HIV-specific responses induced by MVA.HIVA vaccine. It might be a good model for infant HIV and Tuberculosis bivalent vaccine. PMID:21603216

Managing moral hazard in motor vehicle accident insurance claims.

PubMed

Ebrahim, Shanil; Busse, Jason W; Guyatt, Gordon H; Birch, Stephen

2013-05-01

Motor vehicle accident (MVA) insurance in Canada is based primarily on two different compensation systems: (i) no-fault, in which policyholders are unable to seek recovery for losses caused by other parties (unless they have specified dollar or verbal thresholds) and (ii) tort, in which policyholders may seek general damages. As insurance companies pay for MVA-related health care costs, excess use of health care services may occur as a result of consumers' (accident victims) and/or producers' (health care providers) behavior - often referred to as the moral hazard of insurance. In the United States, moral hazard is greater for low dollar threshold no-fault insurance compared with tort systems. In Canada, high dollar threshold or pure no-fault versus tort systems are associated with faster patient recovery and reduced MVA claims. These findings suggest that high threshold no-fault or pure no-fault compensation systems may be associated with improved outcomes for patients and reduced moral hazard.

Two studies of psychiatric morbidity among motor vehicle accident survivors 1 year after the crash.

PubMed

Blanchard, Edward B; Hickling, Edward J; Freidenberg, Brian M; Malta, Loretta S; Kuhn, Eric; Sykes, Mark A

2004-05-01

We assessed the psychiatric co-morbidity associated with chronic posttraumatic stress disorder (PTSD) (1-2 years) secondary to personal injury motor vehicle accidents (MVAs) in two studies. In Study 1, we compared the results of SCID assessments for 75 treatment-seeking MVA survivors (51 with PTSD and 24 with symptoms but no PTSD). In Study 2, we compared similar results among 132 MVA survivors who had been followed prospectively for 12+ months after their accidents (19 with PTSD, 32 who had PTSD but who had remitted, and 81 who never met criteria for PTSD). We found comparable levels of current co-morbid major depression (53%), any mood disorder (62-68%), generalized anxiety disorder (26%) and any anxiety disorder (42%) for both groups of participants with chronic PTSD. These rates of co-morbidity were higher than those found in non-PTSD comparison groups with similar MVA histories.

Dynamics of Monoterpene Formation in Spike Lavender Plants.

PubMed

Mendoza-Poudereux, Isabel; Kutzner, Erika; Huber, Claudia; Segura, Juan; Arrillaga, Isabel; Eisenreich, Wolfgang

2017-12-19

The metabolic cross-talk between the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways was analyzed in spike lavender ( Lavandula latifolia Med) on the basis of 13 CO₂-labelling experiments using wildtype and transgenic plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the first and key enzyme of the MVA pathway. The plants were labelled in the presence of 13 CO₂ in a gas chamber for controlled pulse and chase periods of time. GC/MS and NMR analysis of 1,8-cineole and camphor, the major monoterpenes present in their essential oil, indicated that the C5-precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) of both monoterpenes are predominantly biosynthesized via the MEP pathway. Surprisingly, overexpression of HMGR did not have significant impact upon the crosstalk between the MVA and MEP pathways indicating that the MEP route is the preferred pathway for the synthesis of C5 monoterpene precursors in spike lavender.

Severe mitral regurgitation due to mitral leaflet aneurysm diagnosed by three-dimensional transesophageal echocardiography: a case report.

PubMed

Konishi, Takao; Funayama, Naohiro; Yamamoto, Tadashi; Hotta, Daisuke; Kikuchi, Kenjiro; Ohori, Katsumi; Nishihara, Hiroshi; Tanaka, Shinya

2016-11-22

A small mitral valve aneurysm (MVA) presenting as severe mitral regurgitation (MR) is uncommon. A 47-year-old man with a history of hypertension complained of exertional chest discomfort. A transthoracic echocardiogram (TTE) revealed the presence of MR and prolapse of the posterior leaflet. A 6-mm in diameter MVA, not clearly visualized by TTE, was detected on the posterior leaflet on a three-dimensional (3D) transesophageal echocardiography (TEE). The patient underwent uncomplicated triangular resection of P2 and mitral valve annuloplasty, and was discharged from postoperative rehabilitation, 2 weeks after the operation. Histopathology of the excised leaflet showed myxomatous changes without infective vegetation or signs of rheumatic heart disease. A small, isolated MVA is a cause of severe MR, which might be overlooked and, therefore, managed belatedly. 3D TEE was helpful in imaging its morphologic details.

The relationship between HPV status and chemoradiotherapy in the locoregional control of penile cancer.

PubMed

Yuan, Zhigang; Naghavi, Arash O; Tang, Dominic; Kim, Youngchul; Ahmed, Kamran A; Dhillon, Jasreman; Giuliano, Anna R; Spiess, Philippe E; Johnstone, Peter A

2018-03-27

Penile cancer (PeCa) is a rare, aggressive malignancy often associated with the human papillomavirus (HPV). The practice of a personalized risk-adapted approach is not yet established. This study is to assess the relationship between HPV tumor status and chemoradiotherapy (CRT) in PeCa locoregional control (LRC). We retrospectively identified patients with HPV status who were diagnosed with squamous cell carcinoma of the penis and treated with surgical resection between 1999 and 2016. The relationship between tumor/treatment characteristics and LRC were analyzed with univariate and multivariate Cox proportional hazard regression analysis (UVA and MVA, respectively). Time-to-event outcomes were estimated with Kaplan-Meier curves and compared via log-rank tests. Fifty-one patients were identified. The median follow-up was 36.6 months. Patients were primarily HPV-negative (HPV-) (n = 28, 55%), and pathologic node positive (pN+) (55%). The 2 year LRC rate was 54%. pN+ patients had a significantly lower 2 year LRC (37 vs. 81%, p = 0.002). In the subgroup analysis of pN+ patients (n = 28), there was a LRC benefit associated with the addition of CRT (HR 0.19; 95% CI 0.05-0.70, p = 0.012) and HPV-positive (HPV+) disease (HR 0.18; 95% CI 0.039-0.80, p = 0.024) using MVA. HPV+ patients treated with CRT had improved 2 year LRC compared to HPV- patients (83 vs. 38%, p = 0.038). Adjuvant CRT and HPV+ disease independently predicted for improved LRC in pN+ PeCa. In HPV+ PeCa, the LRC benefit was primarily observed in patients treated with adjuvant CRT. Prospective investigation of HPV+ and CRT is required to further delineate their roles in optimizing PeCa treatment.

Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study.

PubMed

Faught, E; Duh, M S; Weiner, J R; Guérin, A; Cunnington, M C

2008-11-11

The primary objective was to investigate whether nonadherence to antiepileptic drugs (AEDs) is associated with increased mortality and the secondary objective to examine whether nonadherence increases the risk of serious clinical events, including emergency department (ED) visits, hospitalizations, motor vehicle accident (MVA) injuries, fractures, and head injuries. A retrospective open-cohort design was employed using Medicaid claims data from Florida, Iowa, and New Jersey from January 1997 through June 2006. Patients aged > or =18 years with > or =1 diagnosis of epilepsy by a neurologist and > or =2 AED pharmacy dispensings were selected. Medication possession ratio (MPR) was used to evaluate AED adherence on a quarterly basis with MPR > or =0.80 considered adherent and <0.80 nonadherent. The association of nonadherence with mortality was assessed using a time-varying Cox regression model adjusting for demographic and clinical confounders. Incidence rates for serious clinical events were compared between adherent and nonadherent quarters using incidence rate ratios (IRRs) with 95% CIs calculated based on the Poisson distribution. The 33,658 study patients contributed 388,564 AED-treated quarters (26% nonadherent). Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11-3.54) after multivariate adjustments. Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49-1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84-1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81-2.39), and fractures (IRR = 1.21, 95% CI = 1.18-1.23) than periods of adherence. These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.

PubMed

Tapia, Milagritos D; Sow, Samba O; Lyke, Kirsten E; Haidara, Fadima Cheick; Diallo, Fatoumata; Doumbia, Moussa; Traore, Awa; Coulibaly, Flanon; Kodio, Mamoudou; Onwuchekwa, Uma; Sztein, Marcelo B; Wahid, Rezwanul; Campbell, James D; Kieny, Marie-Paule; Moorthy, Vasee; Imoukhuede, Egeruan B; Rampling, Tommy; Roman, Francois; De Ryck, Iris; Bellamy, Abbie R; Dally, Len; Mbaya, Olivier Tshiani; Ploquin, Aurélie; Zhou, Yan; Stanley, Daphne A; Bailer, Robert; Koup, Richard A; Roederer, Mario; Ledgerwood, Julie; Hill, Adrian V S; Ballou, W Ripley; Sullivan, Nancy; Graham, Barney; Levine, Myron M

2016-01-01

The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo). In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian). Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 10(10) pu, 35 [38%] to 2·5 × 10(10) pu, 35 [38%] to 5 × 10(10) pu, and 11 [12%] to 1 × 10(11) pu) and 20 in the USA (ten [50%] to 1 × 10(10) pu and ten [50%] to 1 × 10(11) pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 10(10) and two [2%] received 1 × 10(11) pu) and four (20%) of 20 in the USA (all received 1 × 10(11) pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness. 1 × 10(11) pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers). Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases. Copyright © 2016 Tapia et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Advantage of wavelet technique to highlight the observed geomagnetic perturbations linked to the Chilean tsunami (2010)

NASA Astrophysics Data System (ADS)

Klausner, V.; Mendes, Odim; Domingues, Margarete O.; Papa, Andres R. R.; Tyler, Robert H.; Frick, Peter; Kherani, Esfhan A.

2014-04-01

The vertical component (Z) of the geomagnetic field observed by ground-based observatories of the International Real-Time Magnetic Observatory Network has been used to analyze the induced magnetic fields produced by the movement of a tsunami, electrically conducting sea water through the geomagnetic field. We focus on the survey of minutely sampled geomagnetic variations induced by the tsunami of 27 February 2010 at Easter Island (IPM) and Papeete (PPT) observatories. In order to detect the tsunami disturbances in the geomagnetic data, we used wavelet techniques. We have observed an 85% correlation between the Z component variation and the tide gauge measurements in period range of 10 to 30 min which may be due to two physical mechanisms: gravity waves and the electric currents in the sea. As an auxiliary tool to verify the disturbed magnetic fields, we used the maximum variance analysis (MVA). At PPT, the analyses show local magnetic variations associated with the tsunami arriving in advance of sea surface fluctuations by about 2 h. The first interpretation of the results suggests that wavelet techniques and MVA can be effectively used to characterize the tsunami contributions to the geomagnetic field and further used to calibrate tsunami models and implemented to real-time analysis for forecast tsunami scenarios.

[Pediatric facial fractures. Characteristics of Portuguese population].

PubMed

Ferreira, Pedro; Silva, Natividade; Silva, Alvaro; Cardoso, Augusta; Rodrigues, Jorge; Reis, Jorge; Amarante, José

2004-01-01

Fractures of the facial skeleton are relatively uncommon in children and adolescents, and there are only few reports that review a significative number of patients. We performed a retrospective study to analyse the different characteristics of such fractures in the pediatric population in the north of Portugal. We reviewed the clinical and the surgical records of a series of 247 patients younger than 19 years, that were submitted to operation due to facial fractures by the Plastic, Reconstructive and Aesthetic Service of São João Hospital, Oporto (Portugal) between 1993 and 2002. The following parameters were evaluated: age, sex, cause of the accident, time and month of hospital admission, location and type of fractures, presence and location of associated injuries, treatment methods, length of in-hospital stay, and complications. Surgical treatment of 325 fractures was performed. The ratio of boys to girls was 3.3:1. The majority of injuries occurred in patients with 16 to 18 years old. Motor-vehicle accident (MVA) was the most common cause of injuries (57.1%). Mandibular fractures were the most common (62.5%). Associated injuries occurred in 63.2% of patients. Pediatric facial fractures are usually associated with severe trauma. Although MVA was the most frequent cause of fractures, this has decreased. The incidence of these type of fractures is high in Portugal.

In vitro toxicology of respirable Montserrat volcanic ash

PubMed Central

Wilson, M.; Stone, V.; Cullen, R.; Searl, A.; Maynard, R.; Donaldson, K.

2000-01-01

OBJECTIVES—In July 1995 the Soufriere Hills volcano on the island of Montserrat began to erupt. Preliminary reports showed that the ash contained a substantial respirable component and a large percentage of the toxic silica polymorph, cristobalite. In this study the cytotoxicity of three respirable Montserrat volcanic ash (MVA) samples was investigated: M1 from a single explosive event, M2 accumulated ash predominantly derived from pyroclastic flows, and M3 from a single pyroclastic flow. These were compared with the relatively inert dust TiO2 and the known toxic quartz dust, DQ12.
METHODS—Surface area of the particles was measured with the Brunauer, Emmet, and Teller (BET) adsorption method and cristobalite content of MVA was determined by x ray diffraction (XRD). After exposure to particles, the metabolic competence of the epithelial cell line A549 was assessed to determine cytotoxic effects. The ability of the particles to induce sheep blood erythrocyte haemolysis was used to assess surface reactivity.
RESULTS—Treatment with either MVA, quartz, or titanium dioxide decreased A549 epithelial cell metabolic competence as measured by ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On addition of mannitol, the cytotoxic effect was significantly less with M1, quartz, and TiO2. All MVA samples induced a dose dependent increase in haemolysis, which, although less than the haemolysis induced by quartz, was significantly greater than that induced by TiO2. Addition of mannitol and superoxide dismutase (SOD) significantly reduced the haemolytic activity only of M1, but not M2 or M3, the samples derived from predominantly pyroclastic flow events.
CONCLUSIONS—Neither the cristobalite content nor the surface area of the MVA samples correlated with observed in vitro reactivity. A role for reactive oxygen species could only be shown in the cytotoxicity of M1, which was the only sample derived from a purely explosive event. These results suggest that in general the bioreactivity of MVA samples in vitro is low compared with pure quartz, but that the bioreactivity and mechanisms of biological interaction may vary according to the ash source.


Keywords: volcanic ash; cristobalite; surface reactivity PMID:11024195

PedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi.

PubMed

Njuguna, Irene N; Ambler, Gwen; Reilly, Marie; Ondondo, Beatrice; Kanyugo, Mercy; Lohman-Payne, Barbara; Gichuhi, Christine; Borthwick, Nicola; Black, Antony; Mehedi, Shams-Rony; Sun, Jiyu; Maleche-Obimbo, Elizabeth; Chohan, Bhavna; John-Stewart, Grace C; Jaoko, Walter; Hanke, Tomáš

2014-10-07

A safe, effective vaccine for breastfeeding infants born to HIV-1-positive mothers could complement antiretroviral therapy (ART) for prevention of mother-to-child transmission of HIV-1. To date, only a few HIV-1 vaccine candidates have been tested in infants. A phase I/II randomized controlled trial PedVacc 002 was conducted to determine the safety and immunogenicity of a single, low dose of MVA.HIVA vaccine delivered intramuscularly to healthy 20-week-old infants born to HIV-1-positive mothers in Nairobi, Kenya. Pregnant HIV-1-positive women in the 2nd/3rd trimester of gestation were enrolled, provided with ART and self-selected their infant-feeding modality. Infants received nevirapine and cotrimoxazole prophylaxis. At 20 weeks of age, eligible HIV-1-negative infants were randomized to vaccine versus no-treatment arms and followed to 48 weeks of age for assessments of vaccine safety, HIV-1-specific T-cell responses and antibodies to routine childhood vaccines. Between February and November 2010, 182 mothers were screened, 104 were eligible and followed on ART during pregnancy/postpartum, of whom 73 had eligible infants at 20 weeks postpartum. Thirty-six infants were randomized to vaccine and 37 to no treatment. Eighty-four percent of infants breastfed, and retention at 48 weeks was 99%. Adverse events were rare and similar between the two arms. HIV-1-specific T-cell frequencies in interferon-γ ELISPOT assay were transiently higher in the MVA.HIVA arm (p=0.002), but not above the threshold for a positive assay. Protective antibody levels were adequate and similar between arms for all routine childhood vaccines except HBV, where 71% of MVA.HIVA subjects compared to 92% of control subjects were protected (p=0.05). This trial tested for the first time an MVA-vectored candidate HIV-1 vaccine in HIV-1-exposed infants in Africa, demonstrating trial feasibility and vaccine safety, low immunogenicity, and compatibility with routine childhood vaccinations. These results are reassuring for use of the MVA vector in more potent prime-boost regimens. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Review of Quantitative Monitoring Methodologies for Emissions Verification and Accounting for Carbon Dioxide Capture and Storage for California’s Greenhouse Gas Cap-and-Trade and Low-Carbon Fuel Standard Programs

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

Oldenburg, Curtis M.; Birkholzer, Jens T.

The Cap-and-Trade and Low Carbon Fuel Standard (LCFS) programs being administered by the California Air Resources Board (CARB) include Carbon Dioxide Capture and Storage (CCS) as a potential means to reduce greenhouse gas (GHG) emissions. However, there is currently no universal standard approach that quantifies GHG emissions reductions for CCS and that is suitable for the quantitative needs of the Cap-and-Trade and LCFS programs. CCS involves emissions related to the capture (e.g., arising from increased energy needed to separate carbon dioxide (CO 2) from a flue gas and compress it for transport), transport (e.g., by pipeline), and storage of COmore » 2 (e.g., due to leakage to the atmosphere from geologic CO 2 storage sites). In this project, we reviewed and compared monitoring, verification, and accounting (MVA) protocols for CCS from around the world by focusing on protocols specific to the geologic storage part of CCS. In addition to presenting the review of these protocols, we highlight in this report those storage-related MVA protocols that we believe are particularly appropriate for CCS in California. We find that none of the existing protocols is completely appropriate for California, but various elements of all of them could be adopted and/or augmented to develop a rigorous, defensible, and practical surface leakage MVA protocol for California. The key features of a suitable surface leakage MVA plan for California are that it: (1) informs and validates the leakage risk assessment, (2) specifies use of the most effective monitoring strategies while still being flexible enough to accommodate special or site-specific conditions, (3) quantifies stored CO 2, and (4) offers defensible estimates of uncertainty in monitored properties. California’s surface leakage MVA protocol needs to be applicable to the main CO 2 storage opportunities (in California and in other states with entities participating in California’s Cap-and-Trade or LCFS programs), specifically CO 2-enhanced oil recovery (CO 2-EOR), CO 2 injection into depleted gas reservoirs (with or without CO 2-enhanced gas recovery (CO 2-EGR)), as well as deep saline storage. Regarding the elements of an effective surface leakage MVA protocol, our recommendations for California are that: (1) both CO 2 and methane (CH 4) surface leakage should be monitored, especially for enhanced recovery scenarios, (2) emissions from all sources not directly related to injection and geologic storage (e.g., from capture, or pipeline transport) should be monitored and reported under a plan separate from the surface leakage MVA plan that is included as another component of the quantification methodology (QM), (3) the primary objective of the surface leakage MVA plan should be to quantify surface leakage of CO 2 and CH 4 and its uncertainty, with consideration of best-practices and state-of-the-art approaches to monitoring including attribution assessment, (4) effort should be made to monitor CO 2 storage and migration in the subsurface to anticipate future surface leakage monitoring needs, (5) detailed descriptions of specific monitoring technologies and approaches should be provided in the MVA plan, (6) the main purpose of the CO 2 injection project (CO 2-EOR, CO 2-EGR, or pure geologic carbon sequestration (GCS)) needs to be stated up front, (7) approaches to dealing with missing data and quantifying uncertainty need to be described, and (8) post-injection monitoring should go on for a period consistent with or longer than that prescribed by the U.S. EPA.« less

Metabolic plasticity for isoprenoid biosynthesis in bacteria.

PubMed

Pérez-Gil, Jordi; Rodríguez-Concepción, Manuel

2013-05-15

Isoprenoids are a large family of compounds synthesized by all free-living organisms. In most bacteria, the common precursors of all isoprenoids are produced by the MEP (methylerythritol 4-phosphate) pathway. The MEP pathway is absent from archaea, fungi and animals (including humans), which synthesize their isoprenoid precursors using the completely unrelated MVA (mevalonate) pathway. Because the MEP pathway is essential in most bacterial pathogens (as well as in the malaria parasites), it has been proposed as a promising new target for the development of novel anti-infective agents. However, bacteria show a remarkable plasticity for isoprenoid biosynthesis that should be taken into account when targeting this metabolic pathway for the development of new antibiotics. For example, a few bacteria use the MVA pathway instead of the MEP pathway, whereas others possess the two full pathways, and some parasitic strains lack both the MVA and the MEP pathways (probably because they obtain their isoprenoids from host cells). Moreover, alternative enzymes and metabolic intermediates to those of the canonical MVA or MEP pathways exist in some organisms. Recent work has also shown that resistance to a block of the first steps of the MEP pathway can easily be developed because several enzymes unrelated to isoprenoid biosynthesis can produce pathway intermediates upon spontaneous mutations. In the present review, we discuss the major advances in our knowledge of the biochemical toolbox exploited by bacteria to synthesize the universal precursors for their essential isoprenoids.

Maritime Analytics Prototype: Phase 3 Validation

DTIC Science & Technology

2014-01-01

maritim arehouse (GP ported on th sability Sca the training sks, errors m estionnaire, as assessed u the trial was t ” in the scien icant improv...which ed that MVA tools, and th ated the mo e, and becaus lot of prais essels. t - s, e s) n r e e e - e n s, e is P e st e e ii...rapport a environne en raison permet de une bonne navires d’ é ….... t documente n banc d’ess l’analyse de intérêt. Les c iel Widget A DDC) sur l ISTIP

Older Patients With Early-stage Breast Cancer: Adjuvant Radiation Therapy and Predictive Factors for Cancer-related Death.

PubMed

Nagar, Himanshu; Yan, Weisi; Christos, Paul; Chao, K S Clifford; Nori, Dattatreyudu; Ravi, Akkamma

2017-06-01

Studies have shown that older women are undertreated for breast cancer. Few data are available on cancer-related death in elderly women aged 70 years and older with pathologic stage T1a-b N0 breast cancer and the impact of prognostic factors on cancer-related death. The Surveillance, Epidemiology, and End Results (SEER) database was queried for women aged 70 years or above diagnosed with pT1a or pT1b, N0 breast cancer who underwent breast conservation surgery from 1999 to 2003. The Kaplan-Meier survival analysis was performed to evaluate breast cause-specific survival (CSS) and overall survival (OS), and the log-rank test was employed to compare CSS/OS between different groups of interest. Multivariable analysis (MVA), using Cox proportional hazards regression analysis, was performed to evaluate the independent effect of age, race, stage, grade, ER status, and radiation treatment on CSS. Adjusted hazard ratios were calculated from the MVA and reflect the increased risk of breast cancer death. Competing-risks survival regression was also performed to adjust the univariate and multivariable CSS hazard ratios for the competing event of death due to causes other than breast cancer. Patients aged 85 and above had a greater risk of breast cancer death compared with patients aged 70 to 74 years (referent category) (adjusted hazard ratio [HRs]=1.98). Race had no effect on CSS. Patients with stage T1bN0 breast cancer had a greater risk of breast cancer death compared with stage T1aN0 patients (adjusted HR=1.35; P=0.09). ER negative patients had a greater risk of breast cancer death compared with ER positive patients (adjusted HR=1.59; P<0.017). Patients with higher grade tumors had a greater risk of breast cancer death compared with patients with grade 1 tumors (referent category) (adjusted HRs=1.69 and 2.96 for grade 2 and 3, respectively). Patients who underwent radiation therapy had a lower risk of breast cancer death compared with patients who did not (adjusted HR=0.55; P<0.0001). Older patients with higher grade, pT1b, ER-negative breast cancer had increased risk of breast cancer-related death. Adjuvant radiation therapy may provide a CSS benefit in this elderly patient population.

Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap

PubMed Central

Mayer, Kenneth H.; Elizaga, Marnie L.; Bekker, Linda-Gail; Allen, Mary; Morris, Lynn; Montefiori, David; De Rosa, Stephen C.; Sato, Alicia; Gu, Niya; Tomaras, Georgia D.; Tucker, Timothy; Barnett, Susan W.; Mkhize, Nonhlanhla N.; Shen, Xiaoying; Downing, Katrina; Williamson, Carolyn; Pensiero, Michael; Corey, Lawrence; Williamson, Anna-Lise

2016-01-01

A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 109 PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4+ T-cell and CD8+ T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4+ T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4+ T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.) PMID:27098021

Modified vaccinia virus Ankara expressing the hemagglutinin of pandemic (H1N1) 2009 virus induces cross-protective immunity against Eurasian 'avian-like' H1N1 swine viruses in mice.

PubMed

Castrucci, Maria R; Facchini, Marzia; Di Mario, Giuseppina; Garulli, Bruno; Sciaraffia, Ester; Meola, Monica; Fabiani, Concetta; De Marco, Maria A; Cordioli, Paolo; Siccardi, Antonio; Kawaoka, Yoshihiro; Donatelli, Isabella

2014-05-01

To examine cross-reactivity between hemagglutinin (HA) derived from A/California/7/09 (CA/09) virus and that derived from representative Eurasian "avian-like" (EA) H1N1 swine viruses isolated in Italy between 1999 and 2008 during virological surveillance in pigs. Modified vaccinia virus Ankara (MVA) expressing the HA gene of CA/09 virus (MVA-HA-CA/09) was used as a vaccine to investigate cross-protective immunity against H1N1 swine viruses in mice. Two classical swine H1N1 (CS) viruses and four representative EA-like H1N1 swine viruses previously isolated during outbreaks of respiratory disease in pigs on farms in Northern Italy were used in this study. Female C57BL/6 mice were vaccinated with MVA/HA/CA/09 and then challenged intranasally with H1N1 swine viruses. Cross-reactive antibody responses were determined by hemagglutination- inhibition (HI) and virus microneutralizing (MN) assays of sera from MVA-vaccinated mice. The extent of protective immunity against infection with H1N1 swine viruses was determined by measuring lung viral load on days 2 and 4 post-challenge. Systemic immunization of mice with CA/09-derived HA, vectored by MVA, elicited cross-protective immunity against recent EA-like swine viruses. This immune protection was related to the levels of cross-reactive HI antibodies in the sera of the immunized mice and was dependent on the similarity of the antigenic site Sa of H1 HAs. Our findings suggest that the herd immunity elicited in humans by the pandemic (H1N1) 2009 virus could limit the transmission of recent EA-like swine HA genes into the influenza A virus gene pool in humans. © 2013 The Authors Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine.

PubMed

Longley, Rhea J; Halbroth, Benedict R; Salman, Ahmed M; Ewer, Katie J; Hodgson, Susanne H; Janse, Chris J; Khan, Shahid M; Hill, Adrian V S; Spencer, Alexandra J

2017-03-01

Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei - P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei ; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced. Copyright © 2017 Longley et al.

MVA ROP2 vaccinia virus recombinant as a vaccine candidate for toxoplasmosis.

PubMed

Roque-Reséndiz, J L; Rosales, R; Herion, P

2004-04-01

Toxoplasma gondii is the aetiological agent of toxoplasmosis and is the most frequent and best known of the parasitic diseases. In the United States, a serological survey from the Third National Health and Nutrition Examination Survey found that an estimated 23% of adolescents and adults have laboratory evidence of infection with T. gondii. Although toxoplasmosis is asymptomatic or shows self-limited symptoms in adults, in pregnant women infections can cause severe health problems to the fetus if the parasites are transmitted. Also, in immunodeficient patients, chronic infection with T. gondii can reactivate and produce encephalitis, which is frequently lethal. In addition, in veterinary medicine, T. gondii infection is of economic importance due to abortion and neonatal loss in sheep and goats. Recently, the development of vaccines against toxoplasmosis has progressed considerably. The live attenuated S48 strain of Toxoplasma has been broadly used for veterinary purposes. DNA vaccines containing the full-length of SAG1/P30, ROP2 or ROP1 genes have proved to be a promising candidate to induce protection against toxoplasmosis. Viral vectors have proved to be the best candidates for vaccination in different diseases. A recombinant Herpes virus carrying the ROP2 gene is able to induce protective immunity in cats. In the present work we describe the potential of the MVA ROP2 recombinant vaccinia virus as a vaccine against toxoplasmosis. MVA ROP2 induces antibodies against the ROP2 protein in similar amount and types as the thermo-sensible strain ts-4 of T. gondii, which is able to fully protect mice against challenge with the virulent RH strain of T. gondii. Also, the life-span of mice is increased in MVA ROP2 vaccinated animals. We conclude that MVA ROP2 vaccine can possibly generate an immune response, which could be useful in protection against toxoplasmosis.

Radiological-Pathological Correlations Following Blast-Related Traumatic Brain Injury in the Whole Human Brain Using ex Vivo Diffusion Tensor Imaging

DTIC Science & Technology

2014-01-01

were as follows: Blast TBI: Suicide drug overdose – blast years prior Ruptured aneurysm – blast years prior intraventricular hemorrhage...drug overdose Suicide blunt trauma - fall Cancer Cardiac Arrest Tissue fixation was highly variable because cases were obtained from 4 different...blast years prior Civilian Blast DOA Non-blast TBI: MVA – DOA MVA – DOS Suicide – NFL – GSW to chest Cardiac Arrest – NFL Controls: Suicide

Reconstruction and Evaluation of the Synthetic Bacterial MEP Pathway in Saccharomyces cerevisiae

PubMed Central

Partow, Siavash; Siewers, Verena; Daviet, Laurent; Schalk, Michel; Nielsen, Jens

2012-01-01

Isoprenoids, which are a large group of natural and chemical compounds with a variety of applications as e.g. fragrances, pharmaceuticals and potential biofuels, are produced via two different metabolic pathways, the mevalonate (MVA) pathway and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. Here, we attempted to replace the endogenous MVA pathway in Saccharomyces cerevisiae by a synthetic bacterial MEP pathway integrated into the genome to benefit from its superior properties in terms of energy consumption and productivity at defined growth conditions. It was shown that the growth of a MVA pathway deficient S. cerevisiae strain could not be restored by the heterologous MEP pathway even when accompanied by the co-expression of genes erpA, hISCA1 and CpIscA involved in the Fe-S trafficking routes leading to maturation of IspG and IspH and E. coli genes fldA and fpr encoding flavodoxin and flavodoxin reductase believed to be responsible for electron transfer to IspG and IspH. PMID:23285068

Recombinant modified vaccinia virus Ankara–simian immunodeficiency virus gag pol elicits cytotoxic T lymphocytes in rhesus monkeys detected by a major histocompatibility complex class I/peptide tetramer

PubMed Central

Seth, Aruna; Ourmanov, Ilnour; Kuroda, Marcelo J.; Schmitz, Jörn E.; Carroll, Miles W.; Wyatt, Linda S.; Moss, Bernard; Forman, Meryl A.; Hirsch, Vanessa M.; Letvin, Norman L.

1998-01-01

The utility of modified vaccinia virus Ankara (MVA) as a vector for eliciting AIDS virus-specific cytotoxic T lymphocytes (CTL) was explored in the simian immunodeficiency virus (SIV)/rhesus monkey model. After two intramuscular immunizations with recombinant MVA-SIVSM gag pol, the monkeys developed a Gag epitope-specific CTL response readily detected in peripheral blood lymphocytes by using a functional killing assay. Moreover, those immunizations also elicited a population of CD8+ T lymphocytes in the peripheral blood that bound a specific major histocompatibility complex class I/peptide tetramer. These Gag epitope-specific CD8+ T lymphocytes also were demonstrated by using both functional and tetramer-binding assays in lymph nodes of the immunized monkeys. These observations suggest that MVA may prove a useful vector for an HIV-1 vaccine. They also suggest that tetramer staining may be a useful technology for monitoring CTL generation in vaccine trials in nonhuman primates and in humans. PMID:9707609

Self-evaluative appraisals of coping capability and posttraumatic distress following motor vehicle accidents.

PubMed

Benight, Charles C; Cieslak, Roman; Molton, Ivan R; Johnson, Lesley E

2008-08-01

This study tested the importance of coping self-efficacy (CSE) perceptions and change in perceptions of CSE for recovery from motor vehicle accident (MVA) trauma. Data were collected 7 days following the accident (Time 1; n = 163), 1 month after the accident (Time 2; n = 91), and 3 months after the accident (Time 3; n = 70). Early changes in CSE (i.e., from Time 1 to Time 2) predicted posttraumatic distress at 3 months after MVA trauma, even after controlling for Time 1 or Time 2 posttraumatic distress and other trauma-related variables (i.e., accident responsibility, litigation involvement, and peritraumatic dissociation). Early changes in CSE perceptions, however, neither moderated nor mediated the effects of early posttraumatic distress (Time 1) on 3-month posttraumatic distress. Time 2 CSE levels, however, did mediate the relationship between acute posttraumatic distress (Time 1) and 3-month posttraumatic distress (Time 3). These findings highlight the importance of early interventions aimed at strengthening self-efficacy after MVA trauma. Copyright 2008 APA, all rights reserved.

A Case of Severe Airbag Related Ocular Alkali Injury

PubMed Central

Wong, William; Affeldt, John C

2012-01-01

While airbags have saved many lives and are clearly beneficial overall, sodium hydroxide (NaOH) powder produced by the inflation reaction can cause significant alkali ocular injury if not irrigated promptly. Here we report a case of severe airbag related ocular alkali injury as a way to bring attention to the need for prompt ocular irrigation following motor vehicle accidents (MVA) with airbag deployment. A 47-year-old man was involved in a MVA with airbag deployment in a rural setting. Attention was paid to several other life-threatening traumatic injuries, however, ocular irrigation was not performed until some 6–7 hours after the MVA. Over the course of 6 months, airbag related alkali injury caused severe limbal ischemia, conjunctivalization of the cornea, corneal epithelial defects, cicatricial scarring, haze, and corneal/limbal vascularization despite amniotic membrane graft. Awareness of the importance of ocular irrigation following airbag deployment must be raised both in the ophthalmology and emergency medicine communities. PMID:22900239

EMDR therapy for PTSD after motor vehicle accidents: meta-analytic evidence for specific treatment

PubMed Central

Boccia, Maddalena; Piccardi, Laura; Cordellieri, Pierluigi; Guariglia, Cecilia; Giannini, Anna Maria

2015-01-01

Motor vehicle accident (MVA) victims may suffer both acute and post-traumatic stress disorders (PTSD). With PTSD affecting social, interpersonal and occupational functioning, clinicians as well as the National Institute of Health are very interested in identifying the most effective psychological treatment to reduce PTSD. From research findings, eye movement desensitization and reprocessing (EMDR) therapy is considered as one of the effective treatment of PTSD. In this paper, we present the results of a meta-analysis of fMRI studies on PTSD after MVA through activation likelihood estimation. We found that PTSD following MVA is characterized by neural modifications in the anterior cingulate cortex (ACC), a cerebral structure involved in fear-conditioning mechanisms. Basing on previous findings in both humans and animals, which demonstrate that desensitization techniques and extinction protocols act on the limbic system, the effectiveness of EMDR and of cognitive behavioral therapies (CBT) may be related to the fact that during these therapies the ACC is stimulated by desensitization. PMID:25954183

Improvement of BCG protective efficacy with a novel chimpanzee adenovirus and a modified vaccinia Ankara virus both expressing Ag85A.

PubMed

Stylianou, E; Griffiths, K L; Poyntz, H C; Harrington-Kandt, R; Dicks, M D; Stockdale, L; Betts, G; McShane, H

2015-11-27

A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also expressing Ag85A (MVA85A), for its immunogenicity and protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge in mice. Naïve and BCG-primed mice were vaccinated or boosted with ChAdOx1.85A and MVA85A in different combinations. Although intranasally administered ChAdOx1.85A induced strong immune responses in the lungs, it failed to consistently protect against aerosol M.tb challenge. In contrast, ChAdOx1.85A followed by MVA85A administered either mucosally or systemically, induced strong immune responses and was able to improve the protective efficacy of BCG. This vaccination regime has consistently shown superior protection over BCG alone and should be evaluated further. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dynamics of Monoterpene Formation in Spike Lavender Plants

PubMed Central

Kutzner, Erika; Huber, Claudia; Segura, Juan; Arrillaga, Isabel

2017-01-01

The metabolic cross-talk between the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways was analyzed in spike lavender (Lavandula latifolia Med) on the basis of 13CO2-labelling experiments using wildtype and transgenic plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the first and key enzyme of the MVA pathway. The plants were labelled in the presence of 13CO2 in a gas chamber for controlled pulse and chase periods of time. GC/MS and NMR analysis of 1,8-cineole and camphor, the major monoterpenes present in their essential oil, indicated that the C5-precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) of both monoterpenes are predominantly biosynthesized via the MEP pathway. Surprisingly, overexpression of HMGR did not have significant impact upon the crosstalk between the MVA and MEP pathways indicating that the MEP route is the preferred pathway for the synthesis of C5 monoterpene precursors in spike lavender. PMID:29257083

Short- and long-term immunogenicity and protection induced by non-replicating smallpox vaccine candidates in mice and comparison with the traditional 1st generation vaccine.

PubMed

Ferrier-Rembert, Audrey; Drillien, Robert; Tournier, Jean-Nicolas; Garin, Daniel; Crance, Jean-Marc

2008-03-25

This study assessed three non-replicating smallpox vaccine candidates (modified vaccinia Ankara (MVA), NYVAC and HR) for their immunogenicity and ability to protect mice against an intranasal cowpox virus challenge and compared them with the traditional replicating vaccine. A single immunisation with the non-replicating vaccines induced a complete protection from death at short-term, but was not fully protective when mice were challenged 150 days post-vaccination with protection correlated with the specific neutralizing antibodies and CD4(+) T-cells responses. Prime-boost vaccination enabled effective long-term protection from death for mice vaccinated with MVA, but protection from disease and CD4(+) T-cell level were lower than the ones induced by the traditional vaccine over the long-term period. Further investigations are necessary with MVA to determine the optimal conditions of immunisation to induce at long-term immunogenicity and protection observed with the 1st generation smallpox vaccine.

Sterol partitioning by HMGR and DXR for routing intermediates toward withanolide biosynthesis.

PubMed

Singh, Shefali; Pal, Shaifali; Shanker, Karuna; Chanotiya, Chandan Singh; Gupta, Madan Mohan; Dwivedi, Upendra Nath; Shasany, Ajit Kumar

2014-12-01

Withanolides biosynthesis in the plant Withania somnifera (L.) Dunal is hypothesized to be diverged from sterol pathway at the level of 24-methylene cholesterol. The conversion and translocation of intermediates for sterols and withanolides are yet to be characterized in this plant. To understand the influence of mevalonate (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways on sterols and withanolides biosynthesis in planta, we overexpressed the WsHMGR2 and WsDXR2 in tobacco, analyzed the effect of transient suppression through RNAi, inhibited MVA and MEP pathways and fed the leaf tissue with different sterols. Overexpression of WsHMGR2 increased cycloartenol, sitosterol, stigmasterol and campesterol compared to WsDXR2 transgene lines. Increase in cholesterol was, however, marginally higher in WsDXR2 transgenic lines. This was further validated through transient suppression analysis, and pathway inhibition where cholesterol reduction was found higher due to WsDXR2 suppression and all other sterols were affected predominantly by WsHMGR2 suppression in leaf. The transcript abundance and enzyme analysis data also correlate with sterol accumulation. Cholesterol feeding did not increase the withanolide content compared to cycloartenol, sitosterol, stigmasterol and campesterol. Hence, a preferential translocation of carbon from MVA and MEP pathways was found differentiating the sterols types. Overall results suggested that MVA pathway was predominant in contributing intermediates for withanolides synthesis mainly through the campesterol/stigmasterol route in planta. © 2014 Scandinavian Plant Physiology Society.

The Putative Mevalonate Diphosphate Decarboxylase from Picrophilus torridus Is in Reality a Mevalonate-3-Kinase with High Potential for Bioproduction of Isobutene

PubMed Central

Hall, Stephen J.; Eastham, Graham; Licence, Peter; Stephens, Gill

2015-01-01

Mevalonate diphosphate decarboxylase (MVD) is an ATP-dependent enzyme that catalyzes the phosphorylation/decarboxylation of (R)-mevalonate-5-diphosphate to isopentenyl pyrophosphate in the mevalonate (MVA) pathway. MVD is a key enzyme in engineered metabolic pathways for bioproduction of isobutene, since it catalyzes the conversion of 3-hydroxyisovalerate (3-HIV) to isobutene, an important platform chemical. The putative homologue from Picrophilus torridus has been identified as a highly efficient variant in a number of patents, but its detailed characterization has not been reported. In this study, we have successfully purified and characterized the putative MVD from P. torridus. We discovered that it is not a decarboxylase per se but an ATP-dependent enzyme, mevalonate-3-kinase (M3K), which catalyzes the phosphorylation of MVA to mevalonate-3-phosphate. The enzyme's potential in isobutene formation is due to the conversion of 3-HIV to an unstable 3-phosphate intermediate that undergoes consequent spontaneous decarboxylation to form isobutene. Isobutene production rates were as high as 507 pmol min−1 g cells−1 using Escherichia coli cells expressing the enzyme and 2,880 pmol min−1 mg protein−1 with the purified histidine-tagged enzyme, significantly higher than reported previously. M3K is a key enzyme of the novel MVA pathway discovered very recently in Thermoplasma acidophilum. We suggest that P. torridus metabolizes MVA by the same pathway. PMID:25636853

Motor Vehicle Trauma: An Unnecessary Disease

PubMed Central

Johnson, Douglas H.

1987-01-01

The motor vehicle accident kills and maims more of our young people than any other affliction. Yet prevention of injuries and deaths from MVA receives less emphasis in medical education, medical publications and collective political action than the problem merits. In daily practice, there are numerous opportunities for prevention counselling, alcoholic driver case finding, and critical assessment of the privilege of driving. Within their community, family physicians can have input into some preventive programs. At government level, physicians should increase their pressure for legislative action to reduce MVA injuries and deaths. PMID:21267343

Sterol Composition and Biosynthetic Genes of Vitrella brassicaformis, a Recently Discovered Chromerid: Comparison to Chromera velia and Phylogenetic Relationship with Apicomplexan Parasites.

PubMed

Khadka, Manoj; Salem, Mohamed; Leblond, Jeffrey D

2015-01-01

Vitrella brassicaformis is the second discovered species in the Chromerida, and first in the family Vitrellaceae. Chromera velia, the first discovered species, forms an independent photosynthetic lineage with V. brassicaformis, and both are closely related to peridinin-containing dinoflagellates and nonphotosynthetic apicomplexans; both also show phylogenetic closeness with red algal plastids. We have utilized gas chromatography/mass spectrometry to identify two free sterols, 24-ethylcholest-5-en-3β-ol, and a minor unknown sterol which appeared to be a C(28:4) compound. We have also used RNA Seq analysis to identify seven genes found in the nonmevalonate/methylerythritol pathway (MEP) for sterol biosynthesis. Subsequent genome analysis of V. brassicaformis showed the presence of two mevalonate (MVA) pathway genes, though the genes were not observed in the transcriptome analysis. Transcripts from four genes (dxr, ispf, ispd, and idi) were selected and translated into proteins to study the phylogenetic relationship of sterol biosynthesis in V. brassicaformis and C. velia to other groups of algae and apicomplexans. On the basis of our genomic and transcriptomic analyses, we hypothesize that the MEP pathway was the primary pathway that apicomplexans used for sterol biosynthesis before they lost their sterol biosynthesis ability, although contribution of the MVA pathway cannot be discounted. © 2015 The Author(s) Journal of Eukaryotic Microbiology © 2015 International Society of Protistologists.

Priming with a simplified intradermal HIV-1 DNA vaccine regimen followed by boosting with recombinant HIV-1 MVA vaccine is safe and immunogenic: a phase IIa randomized clinical trial.

PubMed

Munseri, Patricia J; Kroidl, Arne; Nilsson, Charlotta; Joachim, Agricola; Geldmacher, Christof; Mann, Philipp; Moshiro, Candida; Aboud, Said; Lyamuya, Eligius; Maboko, Leonard; Missanga, Marco; Kaluwa, Bahati; Mfinanga, Sayoki; Podola, Lilly; Bauer, Asli; Godoy-Ramirez, Karina; Marovich, Mary; Moss, Bernard; Hoelscher, Michael; Gotch, Frances; Stöhr, Wolfgang; Stout, Richard; McCormack, Sheena; Wahren, Britta; Mhalu, Fred; Robb, Merlin L; Biberfeld, Gunnel; Sandström, Eric; Bakari, Muhammad

2015-01-01

Intradermal priming with HIV-1 DNA plasmids followed by HIV-1MVA boosting induces strong and broad cellular and humoral immune responses. In our previous HIVIS-03 trial, we used 5 injections with 2 pools of HIV-DNA at separate sites for each priming immunization. The present study explores whether HIV-DNA priming can be simplified by reducing the number of DNA injections and administration of combined versus separated plasmid pools. In this phase IIa, randomized trial, priming was performed using 5 injections of HIV-DNA, 1000 μg total dose, (3 Env and 2 Gag encoding plasmids) compared to two "simplified" regimens of 2 injections of HIV-DNA, 600 μg total dose, of Env- and Gag-encoding plasmid pools with each pool either administered separately or combined. HIV-DNA immunizations were given intradermally at weeks 0, 4, and 12. Boosting was performed intramuscularly with 108 pfu HIV-MVA at weeks 30 and 46. 129 healthy Tanzanian participants were enrolled. There were no differences in adverse events between the groups. The proportion of IFN-γ ELISpot responders to Gag and/or Env peptides after the second HIV-MVA boost did not differ significantly between the groups primed with 2 injections of combined HIV-DNA pools, 2 injections with separated pools, and 5 injections with separated pools (90%, 97% and 97%). There were no significant differences in the magnitude of Gag and/or Env IFN-γ ELISpot responses, in CD4+ and CD8+ T cell responses measured as IFN-γ/IL-2 production by intracellular cytokine staining (ICS) or in response rates and median titers for binding antibodies to Env gp160 between study groups. A simplified intradermal vaccination regimen with 2 injections of a total of 600 μg with combined HIV-DNA plasmids primed cellular responses as efficiently as the standard regimen of 5 injections of a total of 1000 μg with separated plasmid pools after boosting twice with HIV-MVA. World Health Organization International Clinical Trials Registry Platform PACTR2010050002122368.

Sleep Apnea Related Risk of Motor Vehicle Accidents is Reduced by Continuous Positive Airway Pressure: Swedish Traffic Accident Registry Data

PubMed Central

Karimi, Mahssa; Hedner, Jan; Häbel, Henrike; Nerman, Olle; Grote, Ludger

2015-01-01

Study Objectives: Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated. Design: MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group. Setting: Clinical sleep laboratory and population based control (n = 635,786). Patients: There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y. Interventions: CPAP. Measurements and Results: The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P < 0.001). Estimated excess accident risk was most prominent in the elderly patients (65–80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score ≥ 16), short habitual sleep time (≤ 5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P ≤ 0.03). CPAP use ≥ 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y). Conclusions: The motor vehicle accident risk in this large cohort of unselected patients with obstructive sleep apnea suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk. Citation: Karimi M, Hedner J, Häbel H, Nerman O, Grote L. Sleep apnea related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish traffic accident registry data. SLEEP 2015;38(3):341–349. PMID:25325460

Longitudinal Associations Between PTSD Symptoms and Dyadic Conflict Communication Following a Severe Motor Vehicle Accident.

PubMed

Fredman, Steffany J; Beck, J Gayle; Shnaider, Philippe; Le, Yunying; Pukay-Martin, Nicole D; Pentel, Kimberly Z; Monson, Candice M; Simon, Naomi M; Marques, Luana

2017-03-01

There are well-documented associations between posttraumatic stress disorder (PTSD) symptoms and intimate relationship impairments, including dysfunctional communication at times of relationship conflict. To date, the extant research on the associations between PTSD symptom severity and conflict communication has been cross-sectional and focused on military and veteran couples. No published work has evaluated the extent to which PTSD symptom severity and communication at times of relationship conflict influence each other over time or in civilian samples. The current study examined the prospective bidirectional associations between PTSD symptom severity and dyadic conflict communication in a sample of 114 severe motor vehicle accident (MVA) survivors in a committed intimate relationship at the time of the accident. PTSD symptom severity and dyadic conflict communication were assessed at 4 and 16weeks post-MVA, and prospective associations were examined using path analysis. Total PTSD symptom severity at 4weeks prospectively predicted greater dysfunctional communication at 16weeks post-MVA but not vice versa. Examination at the level of PTSD symptom clusters revealed that effortful avoidance at 4weeks prospectively predicted greater dysfunctional communication at 16weeks, whereas dysfunctional communication 4weeks after the MVA predicted more severe emotional numbing at 16weeks. Findings highlight the role of PTSD symptoms in contributing to dysfunctional communication and the importance of considering PTSD symptom clusters separately when investigating the dynamic interplay between PTSD symptoms and relationship functioning over time, particularly during the early posttrauma period. Clinical implications for the prevention of chronic PTSD and associated relationship problems are discussed. Copyright © 2016. Published by Elsevier Ltd.

[Survival elongation of Pseudomonas aeruginosa improves power output of microbial fuel cells].

PubMed

You, Ting; Liu, Jihua; Liang, Rubing; Liu, Jianhua

2017-04-25

The secondary metabolites, phenazine products, produced by Pseudomonas aeruginosa can mediate the electrons transfer in microbial fuel cells (MFCs). How increase the total electricity production in MFCs by improving the characteristics of Pseudomonas aeruginosa is one of research hot spots and problems. In this study, P. aeruginosa strain SJTD-1 and its knockout mutant strain SJTD-1 (ΔmvaT) were used to construct MFCs, and the discharge processes of the two MFCs were analyzed to determine the key factors to electricity yields. Results indicated that not only phenazine but also the viable cells in the fermentation broth were essential for the discharge of MFCs. The mutant strain SJTD-1 (ΔmvaT) could produce more phenazine products and continue discharging over 160 hours in MFCs, more than that of the wild-type SJTD-1 strain (90 hours discharging time). The total electricity generated by SJTD-1 (ΔmvaT) strain could achieve 2.32 J in the fermentation process, much higher than the total 1.30 J electricity of the wild-type SJTD-1 strain. Further cell growth analysis showed that the mutant strain SJTD-1 (ΔmvaT) could keep a longer stationary period, survive much longer in MFCs and therefore, discharge more electron than those of the wild-type SJTD-1 strain. Therefore, the cell survival elongation of P. aeruginosa in MFCs could enhance its discharging time and improve the overall energy yield. This work could give a clue to improve the characteristics of MFCs using genetic engineering strain, and could promote related application studies on MFCs.

Cardiac Computed Tomography versus Echocardiography in the Assessment of Stenotic Rheumatic Mitral Valve.

PubMed

Unal Aksu, Hale; Gorgulu, Sevket; Diker, Mustafa; Celik, Omer; Aksu, Huseyin; Ozturk, Derya; Kırıs, Adem; Kalkan, Ali Kemal; Erturk, Mehmet; Bakır, İhsan

2016-03-01

There are different clinical cardiac applications of dual source computed tomography (DSCT). Here, we aimed to compare the DSCT with the transthoracic echocardiography (TTE) for evaluating the Wilkins score and planimetric mitral valve area (MVA) of a rheumatic stenotic mitral valve. We prospectively evaluated mitral valvular structure and function in 31 patients with known mitral stenosis undergoing electrocardiogram-gated, second-generation DSCT, in our heart center for different indications. Mitral valve was evaluated using Wilkins score, and also, the planimetric MVA was assessed. We found a significant difference between MVAs determined by DSCT (average 1.42 ± 0.44 cm2) and MVAs determined by TTE (average 1.35 ± 0.43 cm2 ; difference 0.07 ± 0.16 cm2; P = 0.018). Linear regression analysis revealed a good correlation between the two techniques (r = 0.934; P < 0.0001). The limits of agreement for DSCT and TTE in the Bland-Altman analysis were ±0.31 cm2 . DSCT using TTE as the reference enabled good discrimination between mild and moderate-to-severe stenosis and had an area under the ROC curve of 0.967 (CI 0.912-1.023; P < 0.0001). Wilkins scores obtained by DSCT (7.51 ± 1.17, range 5-10) and TTE (8.16 ± 1.27, range 6-10) had a moderate correlation (r = 0.686; P < 0.0001). We found that planimetric MVA measurements assessed by DSCT were closely correlated with MVA calculations by TTE. The moderate correlation was observed for the Wilkins score. © 2015, Wiley Periodicals, Inc.

Symptoms and beyond: Self-concept among sexually assaulted women.

PubMed

Keshet, Hadar; Gilboa-Schechtman, Eva

2017-09-01

The unique characteristics of sexual assault (SA)-a toxic mix of an interpersonal harm, a violent exploitation of one's body, and a transformation of an act of connectedness into an act of submission-are postulated to negatively affect the self-concept. We sought to deepen the understanding of self-concept impairments among sexually assaulted women with varying levels of posttraumatic distress. To this end, we compared women with a main trauma of SA to women with a main trauma of motor-vehicle accident (MVA) and to nontraumatized (NT) women on several self-concept aspects. Our main hypotheses were (a) sexually assaulted women without PTSD exhibit impaired self-concept as compared with NT women and (b) SA is related to greater self-concept impairments as compared with MVA, even when posttraumatic distress is statistically controlled. Women (N = 235: NT = 69, MVA = 87, SA = 79) completed a web-based survey including measures designed to assess the global and domain-specific contents and structure of the self-concept as well as background and clinical questionnaires. Sexually assaulted women without PTSD reported impaired self-concept as compared with NT women. Furthermore, SA was related to greater self-concept impairments as compared with MVA, even when considering participants' levels of posttraumatic distress. SA is related to unique self-concept impairments that extend beyond symptoms, emphasizing the need to assess and address self-concept impairments in sexually assaulted women. The importance of adopting a multifaceted conceptualization of the self to gain a deeper understanding of the aftermath of trauma is highlighted. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Development of Mitral Stenosis After Mitral Valve Repair: Importance of Mitral Valve Area.

PubMed

Chan, Kwan Leung; Chen, Shin-Yee; Mesana, Thierry; Lam, Buu Khanh

2017-12-01

The development of mitral stenosis (MS) is not uncommon after mitral valve (MV) repair for degenerative mitral regurgitation (MR), but the significance of MS in this setting has not been defined. We prospectively studied 110 such patients who underwent supine bicycle exercise testing to assess intracardiac hemodynamics at rest and at peak exercise. B-type natriuretic peptide (BNP) levels were measured at rest and after the exercise test. The patients also performed the 6-minute walk test and completed the 36-Item Short Form Survey (SF-36). Follow-up was performed by a review of the medical record and telephone interview. Of 110 patients, 22 had MS defined by a mitral valve area (MVA) ≤ 1.5 cm 2 . The resting and peak exercise mitral gradients and pulmonary artery systolic pressure were significantly higher in patients with MS compared with patients with an MVA > 1.5 cm 2 . BNP levels at rest and after exercise were also higher in the patients with MS, who also had lower exercise capacity and worse perception of well-being in 3 domains (physical function, vitality, and social function) on the SF-36. MVA had higher specificity and positive predictive value in predicting outcome events compared with a mean gradient of 3 or 5 mm Hg. In patients who had MV repair for degenerative MR, an MVA ≤ 1.5 cm 2 occurs in about one-fifth of patients and is associated with adverse intracardiac hemodynamics, lower exercise capacity, and adverse outcomes. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

An examination of PTSD symptoms as a mediator of the relationship between trauma history characteristics and physical health following a motor vehicle accident.

PubMed

Irish, Leah A; Gabert-Quillen, Crystal A; Ciesla, Jeffrey A; Pacella, Maria L; Sledjeski, Eve M; Delahanty, Douglas L

2013-05-01

It has been suggested that a history of trauma exposure is associated with increased vulnerability to the physical health consequences of subsequent trauma exposure, and that posttraumatic stress symptoms (PTSS) may serve as a key pathway in this vulnerability. However, few studies have modeled these relationships using mediation, and most have failed to consider whether specific characteristics of the prior trauma exposure have a differential impact on physical and mental health outcomes. The present study examined 180 victims of a serious motor vehicle accident (MVA) who reported prior exposure to traumatic events. PTSS were assessed by clinical interview 6 weeks post-MVA, and physical health was assessed 6 months post-MVA. Using structural equation modeling, the present study examined the extent to which event (age at first trauma, number, and types of trauma) and response (perceptions of life threat, physical injury, and distress) characteristics of prior trauma were related to physical health outcomes following a serious MVA, and whether these relationships were mediated by PTSS. Results revealed that both event and response characteristics of prior trauma history were associated with poorer physical health, and that PTSS served as a mechanism through which response characteristics, but not event characteristics, led to poorer physical health. These results highlight the enduring impact of trauma exposure on physical health outcomes, and underscore the importance of considering multiple mechanisms through which different aspects of prior trauma exposure may impact physical health. © 2012 Wiley Periodicals, Inc.

The mevalonate pathway in neurons: It's not just about cholesterol.

PubMed

Moutinho, Miguel; Nunes, Maria João; Rodrigues, Elsa

2017-11-01

Cholesterol homeostasis greatly impacts neuronal function due to the essential role of this sterol in the brain. The mevalonate (MVA) pathway leads to the synthesis of cholesterol, but also supplies cells with many other intermediary molecules crucial for neuronal function. Compelling evidence point to a model in which neurons shutdown cholesterol synthesis, and rely on a shuttle derived from astrocytes to meet their cholesterol needs. Nevertheless, several reports suggest that neurons maintain the MVA pathway active, even with sustained cholesterol supply by astrocytes. Hence, in this review we focus not on cholesterol production, but rather on the role of the MVA pathway in the synthesis of particular intermediaries, namely isoprenoids, and on their role on neuronal function. Isoprenoids act as anchors for membrane association, after being covalently bound to proteins, such as most of the small guanosine triphosphate-binding proteins, which are critical to neuronal cell function. Based on literature, on our own results, and on the analysis of public transcriptomics databases, we raise the idea that in neurons there is a shift of the MVA pathway towards the non-sterol branch, responsible for isoprenoid synthesis, in detriment to post-squalene branch, and that this is ultimately essential for synaptic activity. Nevertheless new tools that facilitate imaging and the biochemical characterization and quantification of the prenylome in neurons and astrocytes are needed to understand the regulation of isoprenoid production and protein prenylation in the brain, and to analyze its differences on diverse physiological or pathological conditions, such as aging and neurodegenerative states. Copyright © 2017 Elsevier Inc. All rights reserved.

A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector

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

Wang, Z.; Zhou, W.; Srivastava, T.

2008-08-01

A therapeutic CMV vaccine incorporating an antigenic repertoire capable of eliciting a cellular immune response has yet to be successfully implemented for patients who already have acquired an infection. To address this problem, we have developed a vaccine candidate derived from modified vaccinia Ankara (MVA) that expresses three immunodominant antigens (pp65, IE1, IE2) from CMV. The novelty of this vaccine is the fusion of two adjacent exons from the immediate-early region of CMV, their successful expression in MVA, and robust immunogenicity in both primary and memory response models. Evaluation of the immunogenicity of the viral vaccine in mouse models showsmore » that it can stimulate primary immunity against all three antigens in both the CD4{sup +} and CD8{sup +} T cell subsets. Evaluation of human PBMC from healthy CMV-positive donors or patients within 6 months of receiving hematopoietic cell transplant shows robust stimulation of existing CMV-specific CD4{sup +} and CD8{sup +} T cell subsets.« less

Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis.

PubMed

Jozwiak, Adam; Lipko, Agata; Kania, Magdalena; Danikiewicz, Witold; Surmacz, Liliana; Witek, Agnieszka; Wojcik, Jacek; Zdanowski, Konrad; Pączkowski, Cezary; Chojnacki, Tadeusz; Poznanski, Jaroslaw; Swiezewska, Ewa

2017-06-01

The cooperation of the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways, operating in parallel in plants to generate isoprenoid precursors, has been studied extensively. Elucidation of the isoprenoid metabolic pathways is indispensable for the rational design of plant and microbial systems for the production of industrially valuable terpenoids. Here, we describe a new method, based on numerical modeling of mass spectra of metabolically labeled dolichols (Dols), designed to quantitatively follow the cooperation of MVA and MEP reprogrammed upon osmotic stress (sorbitol treatment) in Arabidopsis ( Arabidopsis thaliana ). The contribution of the MEP pathway increased significantly (reaching 100%) exclusively for the dominating Dols, while for long-chain Dols, the relative input of the MEP and MVA pathways remained unchanged, suggesting divergent sites of synthesis for dominating and long-chain Dols. The analysis of numerically modeled Dol mass spectra is a novel method to follow modulation of the concomitant activity of isoprenoid-generating pathways in plant cells; additionally, it suggests an exchange of isoprenoid intermediates between plastids and peroxisomes. © 2017 American Society of Plant Biologists. All Rights Reserved.

Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis1[OPEN

PubMed Central

Kania, Magdalena; Witek, Agnieszka; Wojcik, Jacek; Zdanowski, Konrad; Pączkowski, Cezary; Chojnacki, Tadeusz; Poznanski, Jaroslaw

2017-01-01

The cooperation of the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways, operating in parallel in plants to generate isoprenoid precursors, has been studied extensively. Elucidation of the isoprenoid metabolic pathways is indispensable for the rational design of plant and microbial systems for the production of industrially valuable terpenoids. Here, we describe a new method, based on numerical modeling of mass spectra of metabolically labeled dolichols (Dols), designed to quantitatively follow the cooperation of MVA and MEP reprogrammed upon osmotic stress (sorbitol treatment) in Arabidopsis (Arabidopsis thaliana). The contribution of the MEP pathway increased significantly (reaching 100%) exclusively for the dominating Dols, while for long-chain Dols, the relative input of the MEP and MVA pathways remained unchanged, suggesting divergent sites of synthesis for dominating and long-chain Dols. The analysis of numerically modeled Dol mass spectra is a novel method to follow modulation of the concomitant activity of isoprenoid-generating pathways in plant cells; additionally, it suggests an exchange of isoprenoid intermediates between plastids and peroxisomes. PMID:28385729

(1)H NMR metabolomic profiling of the blue crab (Callinectes sapidus) from the Adriatic Sea (SE Italy): A comparison with warty crab (Eriphia verrucosa), and edible crab (Cancer pagurus).

PubMed

Zotti, Maurizio; De Pascali, Sandra Angelica; Del Coco, Laura; Migoni, Danilo; Carrozzo, Leonardo; Mancinelli, Giorgio; Fanizzi, Francesco Paolo

2016-04-01

The metabolomic profile of blue crab (Callinectes sapidus) captured in the Acquatina lagoon (SE Italy) was compared to an autochthonous (Eriphia verrucosa) and to a commercial crab species (Cancer pagurus). Both lipid and aqueous extracts of raw claw muscle were analyzed by (1)H NMR spectroscopy and MVA (multivariate data analysis). Aqueous extracts were characterized by a higher inter-specific discriminating power compared to lipid fractions. Specifically, higher levels of glutamate, alanine and glycine characterized the aqueous extract of C. sapidus, while homarine, lactate, betaine and taurine characterized E. verrucosa and C. pagurus. On the other hand, only the signals of monounsaturated fatty acids distinguished the lipid profiles of the three crab species. These results support the commercial exploitation and the integration of the blue crab in human diet of European countries as an healthy and valuable seafood. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simulation of π 0-γ separation study for proposed CMS forward electromagnetic calorimeter

DOE PAGES

Roy, Ashim; Jain, Shilpi; Banerjee, Sunanda; ...

2016-11-11

The Forward Electromagnetic Calorimeter of the CMS detector is going to be upgraded in the high luminosity running as the energy of the present Electromagnetic Calorimeter (PbWO4) will degrade in the high luminosity (luminosity 10 34 cm -2 s -1) running due to extensive radiation (hadron flux 10 13 neutrons cm, -2). Shashlik Electromagnetic Calorimeter which consists of alternate layers of 1.5 mm LYSO(Ce) crystal plates and 2.5 mm Tungsten absorbers, was a proposal for high luminosity running. One of the performance points for any electromagnetic calorimeter is the ability to separate π 0 s from true photons, since finalmore » states with photons are a clean and one of the most important final states in proton-proton collisions at the LHC. As a result, the objective of this project is to study the possibility of π 0 and γ separation in the Shashlik detector using Multivariate Analysis (MVA) technique.« less

Simulation of π 0-γ separation study for proposed CMS forward electromagnetic calorimeter

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

Roy, Ashim; Jain, Shilpi; Banerjee, Sunanda

The Forward Electromagnetic Calorimeter of the CMS detector is going to be upgraded in the high luminosity running as the energy of the present Electromagnetic Calorimeter (PbWO4) will degrade in the high luminosity (luminosity 10 34 cm -2 s -1) running due to extensive radiation (hadron flux 10 13 neutrons cm, -2). Shashlik Electromagnetic Calorimeter which consists of alternate layers of 1.5 mm LYSO(Ce) crystal plates and 2.5 mm Tungsten absorbers, was a proposal for high luminosity running. One of the performance points for any electromagnetic calorimeter is the ability to separate π 0 s from true photons, since finalmore » states with photons are a clean and one of the most important final states in proton-proton collisions at the LHC. As a result, the objective of this project is to study the possibility of π 0 and γ separation in the Shashlik detector using Multivariate Analysis (MVA) technique.« less

Effect of Enzyme Inhibitors on Terpene Trilactones Biosynthesis and Gene Expression Profiling in Ginkgo biloba Cultured Cells.

PubMed

Chen, Lijia; Tong, Hui; Wang, Mingxuan; Zhu, Jianhua; Zi, Jiachen; Song, Liyan; Yu, Rongmin

2015-12-01

The biosynthetic pathway of terpene trilactones of Ginkgo biloba is unclear. In this present study, suspension cultured cells of G. biloba were used to explore the regulation of the mevalonic acid (MVA) and methylerythritol 4-phosphate (MEP) pathways in response to specific enzyme inhibitors (lovastatin and clomazone). The results showed that the biosynthesis of bilobalide was more highly correlated with the MVA pathway, and the biosynthesis of ginkgolides was more highly correlated with the MEP pathway. Meanwhile, according to the results, it could be speculated that bilobalide might be a product of ginkgolide metabolism.

Recombinant modified vaccinia virus Ankara generating excess early double-stranded RNA transiently activates protein kinase R and triggers enhanced innate immune responses.

PubMed

Wolferstätter, Michael; Schweneker, Marc; Späth, Michaela; Lukassen, Susanne; Klingenberg, Marieken; Brinkmann, Kay; Wielert, Ursula; Lauterbach, Henning; Hochrein, Hubertus; Chaplin, Paul; Suter, Mark; Hausmann, Jürgen

2014-12-01

Double-stranded RNA (dsRNA) is an important molecular pattern associated with viral infection and is detected by various extra- and intracellular recognition molecules. Poxviruses have evolved to avoid producing dsRNA early in infection but generate significant amounts of dsRNA late in infection due to convergent transcription of late genes. Protein kinase R (PKR) is activated by dsRNA and triggers major cellular defenses against viral infection, including protein synthesis shutdown, apoptosis, and type I interferon (IFN-I) production. The poxviral E3 protein binds and sequesters viral dsRNA and is a major antagonist of the PKR pathway. We found that the highly replication-restricted modified vaccinia virus Ankara (MVA) engineered to produce excess amounts of dsRNA early in infection showed enhanced induction of IFN-β in murine and human cells in the presence of an intact E3L gene. IFN-β induction required a minimum overlap length of 300 bp between early complementary transcripts and was strongly PKR dependent. Excess early dsRNA produced by MVA activated PKR early but transiently in murine cells and induced enhanced systemic levels of IFN-α, IFN-γ, and other cytokines and chemokines in mice in a largely PKR-dependent manner. Replication-competent chorioallantois vaccinia virus Ankara (CVA) generating excess early dsRNA also enhanced IFN-I production and was apathogenic in mice even at very high doses but showed no in vitro host range defect. Thus, genetically adjuvanting MVA and CVA to generate excess early dsRNA is an effective method to enhance innate immune stimulation by orthopoxvirus vectors and to attenuate replicating vaccinia virus in vivo. Efficient cellular sensing of pathogen-specific components, including double-stranded RNA (dsRNA), is an important prerequisite of an effective antiviral immune response. The prototype poxvirus vaccinia virus (VACV) and its derivative modified vaccinia virus Ankara (MVA) produce dsRNA as a by-product of viral transcription. We found that inhibition of cellular dsRNA recognition established by the virus-encoded proteins E3 and K3 can be overcome by directing viral overexpression of dsRNA early in infection without compromising replication of MVA in permissive cells. Early dsRNA induced transient activation of the cellular dsRNA sensor protein kinase R (PKR), resulting in enhanced production of interferons and cytokines in cells and mice. Enhancing the capacity of MVA to activate the innate immune system is an important approach to further improve the immunogenicity of this promising vaccine vector. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis.

PubMed

Patel, Kirtesh R; Burri, Stuart H; Boselli, Danielle; Symanowski, James T; Asher, Anthony L; Sumrall, Ashley; Fraser, Robert W; Press, Robert H; Zhong, Jim; Cassidy, Richard J; Olson, Jeffrey J; Curran, Walter J; Shu, Hui-Kuo G; Crocker, Ian R; Prabhu, Roshan S

2017-02-01

Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan-Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, p = 0.001) and smaller median lesion volume (8.3 cc vs. 15.3 cc, p = 0.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (p = 0.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (p = 0.81), distant brain failure (DBF): 53.2% vs. 45% (p = 0.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (p = 0.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post-WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed.

Long-term outcomes in patients with early stage nodular lymphocyte-predominant Hodgkin's lymphoma treated with radiotherapy.

PubMed

Solanki, Abhishek A; LeMieux, Melissa Horoschak; Chiu, Brian C-H; Mahmood, Usama; Hasan, Yasmin; Koshy, Matthew

2013-01-01

Radiation therapy (RT) is commonly used as definitive treatment for early-stage nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL). We evaluated the cause-specific survival (CSS), overall survival (OS), and second malignancy (SM) rates in patients with early-stage NLPHL treated with RT. Patients with stage I-II NLPHL between 1988 and 2009 who underwent RT were selected from the Surveillance, Epidemiology and End Results database. Univariate analysis (UVA) for CSS and Os was performed using the Kaplan-Meier method and included age, gender, involved site, year of diagnosis, presence of B-symptoms, and extranodal involvement (ENI). Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling and included the above clinical variables. SM were classified as RT-related or non-RT-related. Freedom from SM and freedom from RT-related SM were determined using the Kaplan-Meier method. The study cohort included 469 patients. Median age was 37 years. The most common involved sites were the head and neck (36%), axilla/arm (26%), and multiple lymph node regions (18%). Sixty-eight percent had stage I disease, 70% were male, 4% had ENI, and 7% had B-symptoms. Median follow-up was 6 years. Ten-year CSS and Os were 98% and 88%, respectively. On UVA, none of the covariates was associated with CSS. Increasing age (p<0.01) and female gender (p<0.01) were associated with worse Os. On MVA, older age (p<0.01), female gender (p=0.04), multiple regions of involvement (p=0.03), stage I disease (p=0.02), and presence of B-symptoms (p=0.02) were associated with worse Os. Ten-year freedom from SM and freedom from RT-related SM were 89% and 99%, respectively. This is the largest series to evaluate the outcomes of stage I-II NLPHL patients treated with RT and found that this patient population has an excellent long-term prognosis and a low rate of RT-related second malignancies.

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury.

PubMed

Heery, Christopher R; Palena, Claudia; McMahon, Sheri; Donahue, Renee N; Lepone, Lauren M; Grenga, Italia; Dirmeier, Ulrike; Cordes, Lisa; Marté, Jenn; Dahut, William; Singh, Harpreet; Madan, Ravi A; Fernando, Romaine I; Hamilton, Duane H; Schlom, Jeffrey; Gulley, James L

2017-11-15

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine. Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients ( n = 38) to define safety and to identify brachyury-specific T-cell responses. Results: MVA-brachyury-TRICOM-infected human DCs activated CD8 + and CD4 + T cells specific against the self-antigen brachyury in vitro No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients. Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833-45. ©2017 AACR . ©2017 American Association for Cancer Research.

Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen

PubMed Central

Hanke, Tomas; Samuel, Rachel V.; Blanchard, Tom J.; Neumann, Veronica C.; Allen, Todd M.; Boyson, Jon E.; Sharpe, Sally A.; Cook, Nicola; Smith, Geoffrey L.; Watkins, David I.; Cranage, Martin P.; McMichael, Andrew J.

1999-01-01

DNA and modified vaccinia virus Ankara (MVA) are vaccine vehicles suitable and safe for use in humans. Here, by using a multicytotoxic T-lymphocyte (CTL) epitope gene and a DNA prime-MVA boost vaccination regimen, high levels of CTLs specific for a single simian immunodeficiency virus (SIV) gag-derived epitope were elicited in rhesus macaques. These vaccine-induced CTLs were capable of killing SIV-infected cells in vitro. Fluorescence-activated cell sorter analysis using soluble tetrameric major histocompatibility complex-peptide complexes showed that the vaccinated animals had 1 to 5% circulating CD8+ lymphocytes specific for the vaccine epitope, frequencies comparable to those in SIV-infected monkeys. Upon intrarectal challenge with pathogenic SIVmac251, no evidence for protection was observed in at least two of the three vaccinated animals. This study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques. It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus infections are now available: epitope-based vaccines, a protocol for an effective induction of CTLs in primates, and a simple and sensitive method for quantitation of epitope-specific T cells. The advantages of the DNA prime-MVA boost regimen as well as the correlations of tetramer staining of peripheral blood lymphocytes with CTL killing in vitro and postchallenge control of viremia are discussed. PMID:10438842

A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer.

PubMed

Taylor, Graham S; Jia, Hui; Harrington, Kevin; Lee, Lip Wai; Turner, James; Ladell, Kristin; Price, David A; Tanday, Manjit; Matthews, Jen; Roberts, Claudia; Edwards, Ceri; McGuigan, Lesley; Hartley, Andrew; Wilson, Steve; Hui, Edwin P; Chan, Anthony T C; Rickinson, Alan B; Steven, Neil M

2014-10-01

Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively. MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials. ©2014 American Association for Cancer Research.

Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.

PubMed

García-Castillo, Herbert; Vásquez-Velásquez, Ana Isabel; Rivera, Horacio; Barros-Núñez, Patricio

2008-07-01

Mosaic variegated aneuploidy (MVA) is a rare autosomal recessive syndrome related to BUB1B gene mutations and characterized by multiple mosaic aneuploidies, cancer predisposition, and a distinct phenotype. We report on two mildly affected sibs with MVA syndrome but without BUB1B mutation. Both patients exhibited growth retardation, frontal bossing, triangular face and micrognathia but not microcephaly or cancer. Aneuploidies were assessed both in G-banded metaphases from lymphocyte cultures and in interphase nuclei from buccal cells by FISH. Screening of 23 exons and intron-exon boundaries of BUB1B was also carried out. These patients were then compared with other 19 MVA patients screened for BUB1B mutations. Around one half of the cultured lymphocytes from our patients had aneuploidies ranging from nullisomies to heptasomies; the most frequent abnormalities were trisomies (42%) and monosomies (28%). FISH results demonstrated more chromosomal losses than gains. Screening of BUB1B in our two patients failed to identify any mutation. A review of the 21/35 patients screened for BUB1B demonstrated three clinical pictures. Patients with monoallelic BUB1B mutations were severely affected with Dandy-Walker complex (7/8), cataracts (6/6), and Wilms' tumor (7/8); premature chromatid separation (PCS) was observed in 8/8 propositi and 7/7 carrier parents. Patients without BUB1B mutations were mildly affected with no evidence of cancer, Dandy-Walker malformation or cataract, and rarely (1/7) showed PCS. Finally, patients with biallelic BUB1B mutations showed a moderate phenotype. The distinct MVA clinical groups delineated here point to involvement of at least another mitotic spindle checkpoint gene in addition to the BUB1B gene. (c) 2008 Wiley-Liss, Inc.

Multiple genes of mevalonate and non-mevalonate pathways contribute to high aconites content in an endangered medicinal herb, Aconitum heterophyllum Wall.

PubMed

Malhotra, Nikhil; Kumar, Varun; Sood, Hemant; Singh, Tiratha Raj; Chauhan, Rajinder Singh

2014-12-01

Aconitum heterophyllum Wall, popularly known as Atis or Patis, is an important medicinal herb of North-Western and Eastern Himalayas. No information exists on molecular aspects of aconites biosynthesis, including atisine- the major chemical constituent of A. heterophyllum. Atisine content ranged from 0.14% to 0.37% and total alkaloids (aconites) from 0.20% to 2.49% among 14 accessions of A. heterophyllum. Two accessions contained the highest atisine content with 0.30% and 0.37% as well as the highest alkaloids content with 2.22% and 2.49%, respectively. No atisine was detected in leaves and shoots of A. heterophyllum, thereby, suggesting that the biosynthesis and accumulation of aconite alkaloids occur mainly in roots. Quantitative expression analysis of 15 genes of MVA/MEP pathways in roots versus shoots, differing for atisine content (0-2.2 folds) showed 11-100 folds increase in transcript amounts of 4 genes of MVA pathway; HMGS, HMGR, PMK, IPPI, and 4 genes of MEP pathway; DXPS, ISPD, HDS, GDPS, respectively. The overall expression of 8 genes decreased to 5-12 folds after comparative expression analysis between roots of high (0.37%) versus low (0.14%) atisine content accessions, but their relative transcript amounts remained higher in high content accessions, thereby implying their role in atisine biosynthesis and accumulation. PCA analysis revealed a positive correlation between MVA/MEP pathways genes and alkaloids content. The current study provides first report wherein partial sequences of 15 genes of MVA/MEP pathways have been cloned and studied for their possible role in aconites biosynthesis. The outcome of study has potential applications in the genetic improvement of A. heterophyllum. Copyright © 2014 Elsevier Ltd. All rights reserved.

Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis.

PubMed

Vordermeier, H Martin; Villarreal-Ramos, Bernardo; Cockle, Paul J; McAulay, Martin; Rhodes, Shelley G; Thacker, Tyler; Gilbert, Sarah C; McShane, Helen; Hill, Adrian V S; Xing, Zhou; Hewinson, R Glyn

2009-08-01

Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.

Liquid chromatography-tandem mass spectrometry method for the measurement of serum mevalonic acid: a novel marker of hydroxymethylglutaryl coenzyme A reductase inhibition by statins.

PubMed

Waldron, Jenna; Webster, Craig

2011-05-01

Mevalonic acid (MVA) is synthesized at an early and rate-limiting step in the biosynthesis of cholesterol by the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, and is a useful measure of statin efficacy or treatment. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum MVA has been developed. Following the in vitro conversion of MVA to mevalonic acid lactone (MVAL) in the serum, MVAL and a deuterated internal standard were extracted using an online solid-phase extraction procedure. Chromatographic separation was achieved using a Luna PFP column (Phenomenex), with enhanced selectivity and improved resolution for polar compounds. A gradient system was used, with mobile phase comprising methanol and water (5 mmol/L ammonium formate buffer, pH 2.5). Analysis was performed using an API 5000 tandem mass spectrometer (Applied Biosystems) in positive electrospray ionization mode. The method showed excellent recoveries (98 ± 8%) and imprecision (intra-assay coefficient of variation of 2.2% [6.5 ng/mL] and 2.6% [10.5 ng/mL], and inter-assay coefficient of variation of 9% [10.5 ng/mL]). The assay provides a calibration range up to 50 ng/mL with a limit of detection at 0.1 ng/mL. A simple, rapid and analytically specific method has been developed for the measurement of serum MVA, in the form of MVAL. The high analytical sensitivity of the method allows for accurate quantitation of MVAL in serum samples, both at the endogenous levels found in healthy individuals and in statin-treated patients where normal levels are expected to be greatly reduced through the inhibition of HMG-CoA reductase.

Novel mucosal DNA-MVA HIV vaccination in which DNA-IL-12 plus cholera toxin B subunit (CTB) cooperates to enhance cellular systemic and mucosal genital tract immunity.

PubMed

Maeto, Cynthia; Rodríguez, Ana María; Holgado, María Pía; Falivene, Juliana; Gherardi, María Magdalena

2014-01-01

Induction of local antiviral immune responses at the mucosal portal surfaces where HIV-1 and other viral pathogens are usually first encountered remains a primary goal for most vaccines against mucosally acquired viral infections. Exploring mucosal immunization regimes in order to find optimal vector combinations and also appropriate mucosal adjuvants in the HIV vaccine development is decisive. In this study we analyzed the interaction of DNA-IL-12 and cholera toxin B subunit (CTB) after their mucosal administration in DNA prime/MVA boost intranasal regimes, defining the cooperation of both adjuvants to enhance immune responses against the HIV-1 Env antigen. Our results demonstrated that nasal mucosal DNA/MVA immunization schemes can be effectively improved by the co-delivery of DNA-IL-12 plus CTB inducing elevated HIV-specific CD8 responses in spleen and more importantly in genital tract and genito-rectal draining lymph nodes. Remarkably, these CTL responses were of superior quality showing higher avidity, polyfunctionality and a broader cytokine profile. After IL-12+CTB co-delivery, the cellular responses induced showed an enhanced breadth recognizing with higher efficiency Env peptides from different subtypes. Even more, an in vivo CTL cytolytic assay demonstrated the higher specific CD8 T-cell performance after the IL-12+CTB immunization showing in an indirect manner its potential protective capacity. Improvements observed were maintained during the memory phase where we found higher proportions of specific central memory and T memory stem-like cells T-cell subpopulations. Together, our data show that DNA-IL-12 plus CTB can be effectively employed acting as mucosal adjuvants during DNA prime/MVA boost intranasal vaccinations, enhancing magnitude and quality of HIV-specific systemic and mucosal immune responses.

Determinants of splenectomy in splenic injuries following blunt abdominal trauma.

PubMed

Akinkuolie, A A; Lawal, O O; Arowolo, O A; Agbakwuru, E A; Adesunkanmi, A R K

2010-02-01

The management of splenic injuries has shifted from splenectomy to splenic preservation owing to the risk of overwhelming post-splenectomy infection (OPSI). This study aimed to identify the factors that determine splenectomy in patients with isolated splenic injuries, with a view to increasing the rate of splenic preservation. Files of 55 patients managed for isolated splenic injuries from blunt abdominal trauma between 1998 and 2007 were retrospectively analysed using a pro forma. Management options were classified into nonoperative, operative salvage and splenectomy. The majority of patients suffered splenic injury as a result of motor vehicle accident (MVA) trauma or falls. Splenectomy was undertaken in 33 (60%) patients, 12 (22%) had non-operative management, and operative salvage was achieved in 10 (18%) patients. Significant determinants of splenectomy were grade of splenic injury, hierarchy of the surgeon, and hierarchy of the assistant. MVA injury and falls accounted for the vast majority of blunt abdominal trauma in this study. The rate and magnitude of energy transferred versus splenic protective mechanisms at the time of blunt abdominal trauma seems to determine the grade of splenic injury. Interest in splenic salvage surgery, availability of technology that enables splenic salvage surgery, and the experience of the surgeon and assistant appear to determine the surgical management. Legislation on vehicle safety and good parental control may reduce the severity of splenic injury in blunt abdominal trauma. When surgery is indicated, salvage surgery should be considered in intermediate isolated splenic injury to reduce the incidence of OPSI.

Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia.

PubMed

Muñoz-Bertomeu, Jesús; Sales, Ester; Ros, Roc; Arrillaga, Isabel; Segura, Juan

2007-11-01

Spike lavender (Lavandula latifolia) essential oil is widely used in the perfume, cosmetic, flavouring and pharmaceutical industries. Thus, modifications of yield and composition of this essential oil by genetic engineering should have important scientific and commercial applications. We generated transgenic spike lavender plants expressing the Arabidopsis thaliana HMG1 cDNA, encoding the catalytic domain of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR1S), a key enzyme of the mevalonic acid (MVA) pathway. Transgenic T0 plants accumulated significantly more essential oil constituents as compared to controls (up to 2.1- and 1.8-fold in leaves and flowers, respectively). Enhanced expression of HMGR1S also increased the amount of the end-product sterols, beta-sitosterol and stigmasterol (average differences of 1.8- and 1.9-fold, respectively), but did not affect the accumulation of carotenoids or chlorophylls. We also analysed T1 plants derived from self-pollinated seeds of T0 lines that flowered after growing for 2 years in the greenhouse. The increased levels of essential oil and sterols observed in the transgenic T0 plants were maintained in the progeny that inherited the HMG1 transgene. Our results demonstrate that genetic manipulation of the MVA pathway increases essential oil yield in spike lavender, suggesting a contribution for this cytosolic pathway to monoterpene and sesquiterpene biosynthesis in leaves and flowers of the species.

A single immunization with modified vaccinia virus Ankara-based influenza virus H7 vaccine affords protection in the influenza A(H7N9) pneumonia ferret model.

PubMed

Kreijtz, Joost H C M; Wiersma, Lidewij C M; De Gruyter, Heidi L M; Vogelzang-van Trierum, Stella E; van Amerongen, Geert; Stittelaar, Koert J; Fouchier, Ron A M; Osterhaus, Albert D M E; Sutter, Gerd; Rimmelzwaan, Guus F

2015-03-01

Since the first reports in early 2013, >440 human cases of infection with avian influenza A(H7N9) have been reported including 122 fatalities. After the isolation of the first A(H7N9) viruses, the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 hemagglutinin gene, a codon-optimized gene was synthesized and cloned into a recombinant modified vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock vaccinated or received empty vector developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss, and heavy breathing. In contrast, animals vaccinated with MVA-H7-Sh2 were protected from severe disease. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine Regimen.

PubMed

Bauer, Asli; Podola, Lilli; Mann, Philipp; Missanga, Marco; Haule, Antelmo; Sudi, Lwitiho; Nilsson, Charlotta; Kaluwa, Bahati; Lueer, Cornelia; Mwakatima, Maria; Munseri, Patricia J; Maboko, Leonard; Robb, Merlin L; Tovanabutra, Sodsai; Kijak, Gustavo; Marovich, Mary; McCormack, Sheena; Joseph, Sarah; Lyamuya, Eligius; Wahren, Britta; Sandström, Eric; Biberfeld, Gunnel; Hoelscher, Michael; Bakari, Muhammad; Kroidl, Arne; Geldmacher, Christof

2017-09-15

Prime-boost vaccination strategies against HIV-1 often include multiple variants for a given immunogen for better coverage of the extensive viral diversity. To study the immunologic effects of this approach, we characterized breadth, phenotype, function, and specificity of Gag-specific T cells induced by a DNA-prime modified vaccinia virus Ankara (MVA)-boost vaccination strategy, which uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding a subtype B and AB-recombinant Gag p37 and two vaccinations with MVA-CMDR encoding subtype A Gag p55 Gag-specific T-cell responses were studied in 42 vaccinees using fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost, vaccine-induced gamma interferon-positive (IFN-γ + ) Gag-specific T-cell responses were dominated by CD4 + T cells ( P < 0.001 compared to CD8 + T cells) that coexpressed interleukin-2 (IL-2) (66.4%) and/or tumor necrosis factor alpha (TNF-α) (63.7%). A median of 3 antigenic regions were targeted with a higher-magnitude median response to Gag p24 regions, more conserved between prime and boost, compared to those of regions within Gag p15 (not primed) and Gag p17 (less conserved; P < 0.0001 for both). Four regions within Gag p24 each were targeted by 45% to 74% of vaccinees upon restimulation with DNA-SMI-Gag matched peptides. The response rate to individual antigenic regions correlated with the sequence homology between the MVA- and DNA Gag-encoded immunogens ( P = 0.04, r 2 = 0.47). In summary, after the first MVA-CMDR boost, the sequence-mismatched DNA-prime MVA-boost vaccine strategy induced a Gag-specific T-cell response that was dominated by polyfunctional CD4 + T cells and that targeted multiple antigenic regions within the conserved Gag p24 protein. IMPORTANCE Genetic diversity is a major challenge for the design of vaccines against variable viruses. While including multiple variants for a given immunogen in prime-boost vaccination strategies is one approach that aims to improve coverage for global virus variants, the immunologic consequences of this strategy have been poorly defined so far. It is unclear whether inclusion of multiple variants in prime-boost vaccination strategies improves recognition of variant viruses by T cells and by which mechanisms this would be achieved, either by improved cross-recognition of multiple variants for a given antigenic region or through preferential targeting of antigenic regions more conserved between prime and boost. Engineering vaccines to induce adaptive immune responses that preferentially target conserved antigenic regions of viral vulnerability might facilitate better immune control after preventive and therapeutic vaccination for HIV and for other variable viruses. Copyright © 2017 American Society for Microbiology.

Traumatic rupture of the tricuspid valve and multi-modality imaging

PubMed Central

Corneli, Mariana; Conde, Diego; Ronderos, Ricardo

2014-01-01

Introduction Motor vehicle accident (MVA) account for most cases of traumatic rupture of the tricuspid valve. Valve rupture during an MVA is generated by an abrupt deceleration coupled with an increase in right-side cardiac pressures (Valsalva maneuver and thorax compression). Case A 39-year-old asymptomatic man was referred for an echocardiogram due to the presence of a systolic murmur. He had no prior significant medical history, except for a remote MVA 3 years ago. Real-time 3D echocardiography (RT3DE) showed a tear in the body of the anterior leaflet and not at the cord, as was suggested by two-dimensional transthoracic echocardiography (2D-TTE). Based on these findings, the mechanism was considered anterior leaflet rupture of the tricuspid valve, secondary to chest blunt trauma. The anterior leaflet was repaired using two polytetrafluoroethylene sutures, and tricuspid annuloplasty with an Edwards ring was performed. Conclusions Multimodality imaging helps to determine timing of surgery in asymptomatic traumatic tricuspid rupture. The combination of echocardiography and magnetic resonance imaging provide information of volumetric data and contractility of the right ventricle (RV) during follow-up. RT3DE gives information relevant to the morphological and functional characterization of the valve, allowing the planning of appropriate surgical procedure. PMID:25414827

Illicit drug detection using energy dispersive x-ray diffraction

NASA Astrophysics Data System (ADS)

Cook, E. J.; Griffiths, J. A.; Koutalonis, M.; Gent, C.; Pani, S.; Horrocks, J. A.; George, L.; Hardwick, S.; Speller, R.

2009-05-01

Illicit drugs are imported into countries in myriad ways, including via the postal system and courier services. An automated system is required to detect drugs in parcels for which X-ray diffraction is a suitable technique as it is non-destructive, material specific and uses X-rays of sufficiently high energy to penetrate parcels containing a range of attenuating materials. A database has been constructed containing the measured powder diffraction profiles of several thousand materials likely to be found in parcels. These include drugs, cutting agents, packaging and other innocuous materials. A software model has been developed using these data to predict the diffraction profiles which would be obtained by X-ray diffraction systems with a range of suggested detector (high purity germanium, CZT and scintillation), source and collimation options. The aim of the model was to identify the most promising system geometries, which was done with the aid of multivariate analysis (MVA). The most promising systems were constructed and tested. The diffraction profiles of a range of materials have been measured and used to both validate the model and to identify the presence of drugs in sample packages.

EEL spectroscopic tomography: towards a new dimension in nanomaterials analysis.

PubMed

Yedra, Lluís; Eljarrat, Alberto; Arenal, Raúl; Pellicer, Eva; Cabo, Moisés; López-Ortega, Alberto; Estrader, Marta; Sort, Jordi; Baró, Maria Dolors; Estradé, Sònia; Peiró, Francesca

2012-11-01

Electron tomography is a widely spread technique for recovering the three dimensional (3D) shape of nanostructured materials. Using a spectroscopic signal to achieve a reconstruction adds a fourth chemical dimension to the 3D structure. Up to date, energy filtering of the images in the transmission electron microscope (EFTEM) is the usual spectroscopic method even if most of the information in the spectrum is lost. Unlike EFTEM tomography, the use of electron energy-loss spectroscopy (EELS) spectrum images (SI) for tomographic reconstruction retains all chemical information, and the possibilities of this new approach still remain to be fully exploited. In this article we prove the feasibility of EEL spectroscopic tomography at low voltages (80 kV) and short acquisition times from data acquired using an aberration corrected instrument and data treatment by Multivariate Analysis (MVA), applied to Fe(x)Co((3-x))O(4)@Co(3)O(4) mesoporous materials. This approach provides a new scope into materials; the recovery of full EELS signal in 3D. Copyright © 2012 Elsevier B.V. All rights reserved.

Infectivity of attenuated poxvirus vaccine vectors and immunogenicity of a raccoonpox vectored rabies vaccine in the Brazilian Free-tailed bat (Tadarida brasiliensis)

USGS Publications Warehouse

Stading, Benjamin; Osorio, Jorge E.; Velasco-Villa, Andres; Smotherman, Michael; Kingstad-Bakke, Brock; Rocke, Tonie E.

2016-01-01

Bats (Order Chiroptera) are an abundant group of mammals with tremendous ecological value as insectivores and plant dispersers, but their role as reservoirs of zoonotic diseases has received more attention in the last decade. With the goal of managing disease in free-ranging bats, we tested modified vaccinia Ankara (MVA) and raccoon poxvirus (RCN) as potential vaccine vectors in the Brazilian Free-tailed bat (Tadarida brasiliensis), using biophotonic in vivo imaging and immunogenicity studies. Animals were administered recombinant poxviral vectors expressing the luciferase gene (MVA-luc, RCN-luc) through oronasal (ON) or intramuscular (IM) routes and subsequently monitored for bioluminescent signal indicative of viral infection. No clinical illness was noted after exposure to any of the vectors, and limited luciferase expression was observed. Higher and longer levels of expression were observed with the RCN-luc construct. When given IM, luciferase expression was limited to the site of injection, while ON exposure led to initial expression in the oral cavity, often followed by secondary replication at another location, likely the gastric mucosa or gastric associated lymphatic tissue. Viral DNA was detected in oral swabs up to 7 and 9 days post infection (dpi) for MVA and RCN, respectively. While no live virus was detected in oral swabs from MVA-infected bats, titers up to 3.88 x 104 PFU/ml were recovered from oral swabs of RCN-infected bats. Viral DNA was also detected in fecal samples from two bats inoculated IM with RCN, but no live virus was recovered. Finally, we examined the immunogenicity of a RCN based rabies vaccine (RCN-G) following ON administration. Significant rabies neutralizing antibody titers were detected in the serum of immunized bats using the rapid fluorescence focus inhibition test (RFFIT). These studies highlight the safety and immunogenicity of attenuated poxviruses and their potential use as vaccine vectors in bats.

MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults

PubMed Central

La Rosa, Corinna; Longmate, Jeff; Martinez, Joy; Zhou, Qiao; Kaltcheva, Teodora I.; Tsai, Weimin; Drake, Jennifer; Carroll, Mary; Wussow, Felix; Chiuppesi, Flavia; Hardwick, Nicola; Dadwal, Sanjeet; Aldoss, Ibrahim; Nakamura, Ryotaro; Zaia, John A.

2017-01-01

Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered IM in 8 subjects/DL, with an identical booster injection 28 days later and 1-year follow-up. Vaccinations at all DL were safe with no dose-limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity was transient and self-limiting. Robust, functional, and durable Triplex-driven expansions of CMV-specific T cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and interferon-γ production. Marked and durable CMV-specific T-cell responses were also detected in Triplex-vaccinated CMV-seronegatives, and in DryVax-vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection, was predominantly found on the membrane of CMV-specific and functional T cells, whereas off-target vaccine responses activating memory T cells from the related herpesvirus Epstein-Barr virus remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant (HCT) recipients and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This trial was registered at www.clinicaltrials.gov as #NCT02506933. PMID:27760761

Process of assay selection and optimization for the study of case and control samples from a phase IIb efficacy trial of a candidate tuberculosis vaccine, MVA85A.

PubMed

Harris, Stephanie A; Satti, Iman; Matsumiya, Magali; Stockdale, Lisa; Chomka, Agnieszka; Tanner, Rachel; O'Shea, Matthew K; Manjaly Thomas, Zita-Rose; Tameris, Michele; Mahomed, Hassan; Scriba, Thomas J; Hanekom, Willem A; Fletcher, Helen A; McShane, Helen

2014-07-01

The first phase IIb safety and efficacy trial of a new tuberculosis vaccine since that for BCG was completed in October 2012. BCG-vaccinated South African infants were randomized to receive modified vaccinia virus Ankara, expressing the Mycobacterium tuberculosis antigen 85A (MVA85A), or placebo. MVA85A did not significantly boost the protective effect of BCG. Cryopreserved samples provide a unique opportunity for investigating the correlates of the risk of tuberculosis disease in this population. Due to the limited amount of sample available from each infant, preliminary work was necessary to determine which assays and conditions give the most useful information. Peripheral blood mononuclear cells (PBMC) were stimulated with antigen 85A (Ag85A) and purified protein derivative from M. tuberculosis in an ex vivo gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) and a Ki67 proliferation assay. The effects of a 2-h or overnight rest of thawed PBMC on ELISpot responses and cell populations were determined. Both the ELISpot and Ki67 assays detected differences between the MVA85A and placebo groups, and the results correlated well. The cell numbers and ELISpot responses decreased significantly after an overnight rest, and surface flow cytometry showed a significant loss of CD4(+) and CD8(+) T cells. Of the infants tested, 50% had a positive ELISpot response to a single pool of flu, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (FEC) peptides. This pilot work has been essential in determining the assays and conditions to be used in the correlate study. Moving forward, PBMC will be rested for 2 h before assay setup. The ELISpot assay, performed in duplicate, will be selected over the Ki67 assay, and further work is needed to evaluate the effect of high FEC responses on vaccine-induced immunity and susceptibility to tuberculosis disease. Copyright © 2014 Harris et al.

Infectivity of attenuated poxvirus vaccine vectors and immunogenicity of a raccoonpox vectored rabies vaccine in the Brazilian Free-tailed bat (Tadarida brasiliensis)

PubMed Central

Stading, Ben R.; Osorio, Jorge E.; Velasco-Villa, Andres; Smotherman, Michael; Kingstad-Bakke, Brock

2017-01-01

Bats (Order Chiroptera) are an abundant group of mammals with tremendous ecological value as insectivores and plant dispersers, but their role as reservoirs of zoonotic diseases has received more attention in the last decade. With the goal of managing disease in free-ranging bats, we tested modified vaccinia Ankara (MVA) and raccoon poxvirus (RCN) as potential vaccine vectors in the Brazilian Free-tailed bat (Tadarida brasiliensis), using biophotonic in vivo imaging and immunogenicity studies. Animals were administered recombinant poxviral vectors expressing the luciferase gene (MVA-luc, RCN-luc) through oronasal (ON) or intramuscular (IM) routes and subsequently monitored for bioluminescent signal indicative of viral infection. No clinical illness was noted after exposure to any of the vectors, and limited luciferase expression was observed. Higher and longer levels of expression were observed with the RCN-luc construct. When given IM, luciferase expression was limited to the site of injection, while ON exposure led to initial expression in the oral cavity, often followed by secondary replication at another location, likely the gastric mucosa or gastric associated lymphatic tissue. Viral DNA was detected in oral swabs up to 7 and 9 days post infection (dpi) for MVA and RCN, respectively. While no live virus was detected in oral swabs from MVA-infected bats, titers up to 3.88 × 104 PFU/ml were recovered from oral swabs of RCN-infected bats. Viral DNA was also detected in fecal samples from two bats inoculated IM with RCN, but no live virus was recovered. Finally, we examined the immunogenicity of a RCN based rabies vaccine (RCN-G) following ON administration. Significant rabies neutralizing antibody titers were detected in the serum of immunized bats using the rapid fluorescence focus inhibition test (RFFIT). These studies highlight the safety and immunogenicity of attenuated poxviruses and their potential use as vaccine vectors in bats. PMID:27650872

A small antigenic determinant of the Chikungunya virus E2 protein is sufficient to induce neutralizing antibodies which are partially protective in mice.

PubMed

Weber, Christopher; Büchner, Sarah M; Schnierle, Barbara S

2015-04-01

The mosquito-borne Chikungunya virus (CHIKV) causes high fever and severe joint pain in humans. It is expected to spread in the future to Europe and has recently reached the USA due to globalization, climate change and vector switch. Despite this, little is known about the virus life cycle and, so far, there is no specific treatment or vaccination against Chikungunya infections. We aimed here to identify small antigenic determinants of the CHIKV E2 protein able to induce neutralizing immune responses. E2 enables attachment of the virus to target cells and a humoral immune response against E2 should protect from CHIKV infections. Seven recombinant proteins derived from E2 and consisting of linear and/or structural antigens were created, and were expressed in and purified from E. coli. BALB/c mice were vaccinated with these recombinant proteins and the mouse sera were screened for neutralizing antibodies. Whereas a linear N-terminally exposed peptide (L) and surface-exposed parts of the E2 domain A (sA) alone did not induce neutralizing antibodies, a construct containing domain B and a part of the β-ribbon (called B+) was sufficient to induce neutralizing antibodies. Furthermore, domain sA fused to B+ (sAB+) induced the highest amount of neutralizing antibodies. Therefore, the construct sAB+ was used to generate a recombinant modified vaccinia virus Ankara (MVA), MVA-CHIKV-sAB+. Mice were vaccinated with MVA-CHIKV-sAB+ and/or the recombinant protein sAB+ and were subsequently challenged with wild-type CHIKV. Whereas four vaccinations with MVA-CHIKV-sAB+ were not sufficient to protect mice from a CHIKV infection, protein vaccination with sAB+ markedly reduced the viral titers of vaccinated mice. The recombinant protein sAB+ contains important structural antigens for a neutralizing antibody response in mice and its formulation with appropriate adjuvants might lead to a future CHIKV vaccine.

Intradermal HIV-1 DNA Immunization Using Needle-Free Zetajet Injection Followed by HIV-Modified Vaccinia Virus Ankara Vaccination Is Safe and Immunogenic in Mozambican Young Adults: A Phase I Randomized Controlled Trial.

PubMed

Viegas, Edna Omar; Tembe, Nelson; Nilsson, Charlotta; Meggi, Bindiya; Maueia, Cremildo; Augusto, Orvalho; Stout, Richard; Scarlatti, Gabriella; Ferrari, Guido; Earl, Patricia L; Wahren, Britta; Andersson, Sören; Robb, Merlin L; Osman, Nafissa; Biberfeld, Gunnel; Jani, Ilesh; Sandström, Eric

2017-11-27

We assessed the safety and immunogenicity of HIV-DNA priming using Zetajet™, a needle-free device intradermally followed by intramuscular HIV-MVA boosts, in 24 healthy Mozambicans. Volunteers were randomized to receive three immunizations of 600 μg (n = 10; 2 × 0.1 ml) or 1,200 μg (n = 10; 2 × 0.2 ml) of HIV-DNA (3 mg/ml), followed by two boosts of 10 8 pfu HIV-MVA. Four subjects received placebo saline injections. Vaccines and injections were safe and well tolerated with no difference between the two priming groups. After three HIV-DNA immunizations, IFN-γ ELISpot responses to Gag were detected in 9/17 (53%) vaccinees, while none responded to Envelope (Env). After the first HIV-MVA, the overall response rate to Gag and/or Env increased to 14/15 (93%); 14/15 (93%) to Gag and 13/15 (87%) to Env. There were no significant differences between the immunization groups in frequency of response to Gag and Env or magnitude of Gag responses. Env responses were significantly higher in the higher dose group (median 420 vs. 157.5 SFC/million peripheral blood mononuclear cell, p = .014). HIV-specific antibodies to subtype C gp140 and subtype B gp160 were elicited in all vaccinees after the second HIV-MVA, without differences in titers between the groups. Neutralizing antibody responses were not detected. Two (13%) of 16 vaccinees, one in each of the priming groups, exhibited antibodies mediating antibody-dependent cellular cytotoxicity to CRF01_AE. In conclusion, HIV-DNA vaccine delivered intradermally in volumes of 0.1-0.2 ml using Zetajet was safe and well tolerated. Priming with the 1,200 μg dose of HIV-DNA generated higher magnitudes of ELISpot responses to Env.

A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis.

PubMed

Bull, Tim J; Gilbert, Sarah C; Sridhar, Saranya; Linedale, Richard; Dierkes, Nicola; Sidi-Boumedine, Karim; Hermon-Taylor, John

2007-11-28

Mycobacterium avium subspecies paratuberculosis causes systemic infection and chronic intestinal inflammation in many species including primates. Humans are exposed through milk and from sources of environmental contamination. Hitherto, the only vaccines available against Mycobacterium avium subspecies paratuberculosis have been limited to veterinary use and comprised attenuated or killed organisms. We developed a vaccine comprising a fusion construct designated HAV, containing components of two secreted and two cell surface Mycobacterium avium subspecies paratuberculosis proteins. HAV was transformed into DNA, human Adenovirus 5 (Ad5) and Modified Vaccinia Ankara (MVA) delivery vectors. Full length expression of the predicted 95 kDa fusion protein was confirmed. Vaccination of naïve and Mycobacterium avium subspecies paratuberculosis infected C57BL/6 mice using DNA-prime/MVA-boost or Ad5-prime/MVA-boost protocols was highly immunogenic resulting in significant IFN-gamma ELISPOT responses by splenocytes against recombinant vaccine antigens and a range of HAV specific peptides. This included strong recognition of a T-cell epitope GFAEINPIA located near the C-terminus of the fusion protein. Antibody responses to recombinant vaccine antigens and HAV specific peptides but not GFAEINPIA, also occurred. No immune recognition of vaccine antigens occurred in any sham vaccinated Mycobacterium avium subspecies paratuberculosis infected mice. Vaccination using either protocol significantly attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection measured by qPCR in spleen and liver and the Ad5-prime/MVA-boost protocol also conferred some protection against subsequent challenge. No adverse effects of vaccination occurred in any of the mice. A range of modern veterinary and clinical vaccines for the treatment and prevention of disease caused by Mycobacterium avium subspecies paratuberculosis are needed. The present vaccine proved to be highly immunogenic without adverse effect in mice and both attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection and conferred protection against subsequent challenge. Further studies of the present vaccine in naturally infected animals and humans are indicated.

Regression equations for calculation of z scores for echocardiographic measurements of left heart structures in healthy Han Chinese children.

PubMed

Wang, Shan-Shan; Hong, Wen-Jing; Zhang, Yu-Qi; Chen, Shu-Bao; Huang, Guo-Ying; Zhang, Hong-Yan; Chen, Li-Jun; Wu, Lan-Ping; Shen, Rong; Liu, Yi-Qing; Zhu, Jun-Xue

2018-06-01

Clinical decision making in children with heart disease relies on detailed measurements of cardiac structures using two-dimensional and M-mode echocardiography. However, no echocardiographic reference values are available for the Chinese children. We aimed to establish z-score regression equations for left heart structures in a population-based cohort of healthy Chinese Han children. Echocardiography was performed in 545 children with a normal heart. The dimensions of the aortic valve annulus (AVA), aortic sinuses of Valsalva (ASV), sinotubular junction (STJ), ascending aorta (AAO), left atrium (LA), mitral valve annulus (MVA), interventricular septal end-diastolic thickness (IVSd), interventricular septal end-systolic thickness (IVSs), left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), left ventricular posterior wall end-diastolic thickness (LVPWd), left ventricular posterior wall end-systolic thickness (LVPWs) were measured. Regression analyses were conducted to relate the measurements of left heart structures to body surface area (BSA). Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were calculated. Several models were used, and the adjusted R2 values were compared for each model. AVA, ASV, STJ, AAO, LA, MVA, IVSd, IVSs, LVIDd, LVIDs, LVPWd, and LVPWs had a cubic relationship with BSA. LVEF and LVFS fell within a narrow range. Our results provide reference values for z scores and regression equations for left heart structures in Han Chinese children. These data may help make a quick and accurate judgment of the routine clinical measurement of left heart structures in children with heart disease. © 2018 Wiley Periodicals, Inc.

Correlation Study of the UH-1B Helicopter Blast Test Results from the DICE-THROW Event

DTIC Science & Technology

1977-10-01

histories using the digital computer for numerical computations and plotting. The data reduction system and procedure are essentially those of...as low as 0 = -0.8 deg) due to a significant move- ment of the remote F/A (fore-and-aft) stick. The time history of this remote control is depicted...I I I 5930 ’ yfv ,y ’N0I1VIA30 MVA oo I idSn 3S0N- 124 -iH9l8 3S0N ■03S/S93a ’-I 󈧣Va MVA J.i3T 3S0N ■ 125 r- 1 1 r r 1 ■ 1

Glioblastoma multiforme (GBM) in the elderly: initial treatment strategy and overall survival.

PubMed

Glaser, Scott M; Dohopolski, Michael J; Balasubramani, Goundappa K; Flickinger, John C; Beriwal, Sushil

2017-08-01

The EORTC trial which solidified the role of external beam radiotherapy (EBRT) plus temozolomide (TMZ) in the management of GBM excluded patients over age 70. Randomized studies of elderly patients showed that hypofractionated EBRT (HFRT) alone or TMZ alone was at least equivalent to conventionally fractionated EBRT (CFRT) alone. We sought to investigate the practice patterns and survival in elderly patients with GBM. We identified patients age 65-90 in the National Cancer Data Base (NCDB) with histologically confirmed GBM from 1998 to 2012 and known chemotherapy and radiotherapy status. We analyzed factors predicting treatment with EBRT alone vs. EBRT plus concurrent single-agent chemotherapy (CRT) using multivariable logistic regression. Similarly, within the EBRT alone cohort we compared CFRT (54-65 Gy at 1.7-2.1 Gy/fraction) to HFRT (34-60 Gy at 2.5-5 Gy/fraction). Multivariable Cox proportional hazards model (MVA) with propensity score adjustment was used to compare survival. A total of 38,862 patients were included. Initial treatments for 1998 versus 2012 were: EBRT alone = 50 versus 10%; CRT = 6 versus 50%; chemo alone = 1.6% (70% single-agent) versus 3.2% (94% single-agent). Among EBRT alone patients, use of HFRT (compared to CFRT) increased from 13 to 41%. Numerous factors predictive for utilization of CRT over EBRT alone and for HFRT over CFRT were identified. Median survival and 1-year overall survival were higher in the CRT versus EBRT alone group at 8.6 months vs. 5.1 months and 36.0 versus 15.7% (p < 0.0005 by log-rank, multivariable HR 0.65 [95% CI = 0.61-0.68, p < 0.0005], multivariable HR with propensity adjustment 0.66 [95% CI = 0.63-0.70, p < 0.0005]). For elderly GBM patients in the United States, CRT is the most common initial treatment and appears to offer a survival advantage over EBRT alone. Adoption of hypofractionation has increased over time but continues to be low.

Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma.

PubMed

Jackson, William C; Tsien, Christina I; Junck, Larry; Leung, Denise; Hervey-Jumper, Shawn; Orringer, Daniel; Heth, Jason; Wahl, Daniel R; Spratt, Daniel E; Cao, Yue; Lawrence, Theodore S; Kim, Michelle M

2018-05-01

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

Dose-Volume Analysis of Predictors for Gastrointestinal Toxicity After Concurrent Full-Dose Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma

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

Huang Jiayi; Robertson, John M., E-mail: jrobertson@beaumont.edu; Ye Hong

2012-07-15

Purpose: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT). Methods and Materials: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meiermore » and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity. Results: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V{sub 20Gy} to V{sub 35Gy} of duodenum were significantly associated with GI toxicity (all p {<=} 0.05). On MVA, the V{sub 25Gy} of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V{sub 25Gy} of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V{sub 25Gy} {<=} 45% and V{sub 25Gy} > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V{sub 35Gy} is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V{sub 35Gy} {<=} 20% and V{sub 35Gy} > 20%, respectively (p = 0.04). Conclusions: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity.« less

Radiation therapy dose is associated with improved survival for unresected anaplastic thyroid carcinoma: Outcomes from the National Cancer Data Base.

PubMed

Pezzi, Todd A; Mohamed, Abdallah S R; Sheu, Tommy; Blanchard, Pierre; Sandulache, Vlad C; Lai, Stephen Y; Cabanillas, Maria E; Williams, Michelle D; Pezzi, Christopher M; Lu, Charles; Garden, Adam S; Morrison, William H; Rosenthal, David I; Fuller, Clifton D; Gunn, G Brandon

2017-05-01

The outcomes of patients with unresected anaplastic thyroid carcinoma (ATC) from the National Cancer Data Base (NCDB) were assessed, and potential correlations were explored between radiation therapy (RT) dose and overall survival (OS). The study cohort was comprised of patients who underwent either no surgery or grossly incomplete resection. Correlates of OS were explored using univariate analysis and multivariable analysis (MVA). In total, 1288 patients were analyzed. The mean patient age was 70.2 years, 59.7% of patients were women, and 47.6% received neck RT. The median OS was 2.27 months, and 11% of patients remained alive at 1 year. A positive RT dose-survival correlation was observed for the entire study cohort, for those who received systemic therapy, and for those with stage IVA/IVB and IVC disease. On MVA, older age (hazard ratio [HR], 1.317; 95% confidence interval [CI], 1.137-1.526), ≥ 1 comorbidity (HR, 1.587; 95% CI, 1.379-1.827), distant metastasis (HR, 1.385; 95% CI, 1.216-1.578), receipt of systemic therapy (HR, 0.637; 95% CI, 0.547-0.742), and receipt of RT compared with no RT (<45 grays [Gy]:HR, 0.843; 95% CI, 0.718-0.988; 45-59.9 Gy: HR, 0.596; 95% CI, 0.479-0.743; 60-75 Gy: HR, 0.419; 95% CI, 0.339-0.517) correlated with OS. The RT dose-survival correlation for patients who received higher (60-75 Gy) versus lower (45-59.9 Gy) therapeutic doses was confirmed by propensity-score matching. Survival was poor in this cohort of patients with unresected ATC, and more effective therapies are needed. However, the association of RT dose with OS highlights the importance of identifying patients with unresected ATC who may still yet benefit from multimodal locoregional treatment that incorporates higher dose RT. Cancer 2017;123:1653-1661. © 2017 American Cancer Society. © 2016 American Cancer Society.

Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

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

Modh, Ankit; Rimner, Andreas; Williams, Eric

2014-12-01

Purpose: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. Methods and Materials: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonarymore » toxicity. Results: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT (“no-fly-zone” [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. Conclusions: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ and severe pulmonary toxicity. Esophageal toxicity may be an underappreciated risk, particularly when PTV overlaps the esophagus.« less

Risk of second malignancies in patients with early-stage classical Hodgkin's lymphoma treated in a modern era.

PubMed

LeMieux, Melissa H; Solanki, Abhishek A; Mahmood, Usama; Chmura, Steven J; Koshy, Matthew

2015-04-01

Second malignancies remain an issue affecting morbidity and mortality in long-term survivors of early stage Hodgkin's lymphoma (HL). We undertook this study to determine if treatment in the modern era resulted in decreased second malignancies. Patients diagnosed with stage I-II cHL between 1988 and 2009 who received radiation therapy (RT) were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Freedom from second malignancy (FFSM) was estimated using the Kaplan-Meier method. Univariate analysis (UVA) was performed using the Log-Rank test, and included age, gender, year of diagnosis, and stage. Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling. The study cohort included 8807 patients. The median age at diagnosis was 32 years (range: 2-85). The majority of patients had stage II disease (n = 6044, 69%), 597 (7%) had extranodal involvement (ENI), and 1925 (22%) had B symptoms. Median follow-up for the entire cohort was 7.2 years (range: 0-22). Five hundred twenty-three (6%) patients developed a second malignancy. Median latency to second malignancy was 5.8 years (range: 0.1-21.5). Of the 523 patients that developed a second malignancy, 228 (44%) occurred in the first 5 years, 139 (27%) were diagnosed between years 5-10, and 156 (30%) beyond 10 years. The 10 year FFSM for patients treated between 1988 and 1999 was 93.0% versus 95.1% for patients treated between 2000 and 2009 (P = 0.04), On MVA, treatment between 2000 and 2009 was associated with a HR for second malignancy of 0.77 (95% Confidence Interval: 0.62-0.96, P = 0.02) compared to the treatment between 1988 and 1999. Our analysis suggests that in patients treated with RT for stage I or II cHL, treatment prior to 2000 had a slightly higher risk of second malignancy compared to treatment in 2000 and later. Further studies, with longer follow-up of patients treated in the modern era are needed to confirm these findings. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Physical activity, black carbon exposure and airway inflammation in an urban adolescent cohort.

PubMed

Lovinsky-Desir, Stephanie; Jung, Kyung Hwa; Rundle, Andrew G; Hoepner, Lori A; Bautista, Joshua B; Perera, Frederica P; Chillrud, Steven N; Perzanowski, Matthew S; Miller, Rachel L

2016-11-01

Regular physical activity can improve cardiopulmonary health; however, increased respiratory rates and tidal volumes during activity may increase the effective internal dose of air pollution exposure. Our objective was to investigate the impact of black carbon (BC) measured by personal sampler on the relationship between physical activity and fractional exhaled nitric oxide (FeNO), a marker of airway inflammation. We hypothesized that higher personal BC would attenuate the protective effect of physical activity on airway inflammation. We performed a cross-sectional study nested in a birth cohort of African American and Dominican children living in the Bronx and Northern Manhattan, New York City. Children were recruited based on age (target 9-14 year olds) and presence (n=70) or absence (n=59) of current asthma. Children wore wrist mounted accelerometers for 6 days and were classified as 'active' if they had ≥60min of moderate-to-vigorous activity (MVA) each day and 'non-active' if they had <60min of MVA on any given day, based on CDC guidelines. Personal BC measured using a MicroAeth, was assessed during two 24-h periods, at the beginning and end of physical activity assessment. High BC was defined as the upper tertile of BC measured with personal sampler. FeNO measurements were sampled at the beginning and end of the of physical activity assessment. In multivariable linear regression models, 'active' children had 25% higher personal BC concentrations (p=0.02) and 20% lower FeNO (p=0.04) compared to 'non-active' children. Among children with high personal BC (n=33), there was no relationship between activity and FeNO (p=1.00). The significant protective relationship between activity and airway inflammation was largely driven by children with lower personal BC (n=96, p=0.04). Children that live in an urban environment and are physically active on a daily basis have higher personal exposure to BC. High BC offsets the protective relationship between physical activity and airway inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

Development and Validation of a Combined Methodology for Assessing the Total Quality Control of Herbal Medicinal Products – Application to Oleuropein Preparations

PubMed Central

Lemonakis, Nikolaos; Gikas, Evagelos; Halabalaki, Maria; Skaltsounis, Alexios-Leandros

2013-01-01

Oleuropein (OE) is a secoiridoid glycoside, which occurs mostly in the Oleaceae family presenting several pharmacological properties, including antioxidant, cardio-protective, anti-atherogenic effects etc. Based on these findings OE is commercially available, as Herbal Medicinal Product (HMP), claimed for its antioxidant effects. As there are general provisions of the medicine regulating bodies e.g. European Medicines Agency, the quality of the HMP’s must always be demonstrated. Therefore, a novel LC-MS methodology was developed and validated for the simultaneous quantification of OE and its main degradation product, hydroxytyrosol (HT), for the relevant OE claimed HMP’s. The internal standard (IS) methodology was employed and separation of OE, HT and IS was achieved on a C18 Fused Core column with 3.1 min overall run time employing the SIM method for the analytical signal acquisition. The method was validated according to the International Conference on Harmonisation requirements and the results show adequate linearity (r2 > 0.99) over a wide concentration range [0.1–15 μg/mL (n=12)] and a LLOQ value of 0.1 μg/mL, for both OE and HT. Furthermore, as it would be beneficial to control the quality taking into account all the substances of the OE claimed HMP’s; a metabolomics-like approach has been developed and applied for the total quality control of the different preparations employing UHPLC-HRMS-multivariate analysis (MVA). Four OE-claimed commercial HMP’s have been randomly selected and MVA similarity-based measurements were performed. The results showed that the examined samples could also be differentiated as evidenced according to their scores plot. Batch to batch reproducibility between the samples of the same brand has also been determined and found to be acceptable. Overall, the developed combined methodology has been found to be an efficient tool for the monitoring of the HMP’s total quality. Only one OE HMP has been found to be consistent to its label claim. PMID:24205178

Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates

PubMed Central

Pierantoni, Angiolo; Esposito, Maria Luisa; Ammendola, Virginia; Napolitano, Federico; Grazioli, Fabiana; Abbate, Adele; del Sorbo, Mariarosaria; Siani, Loredana; D’Alise, Anna Morena; Taglioni, Alessandra; Perretta, Gemma; Siccardi, Antonio; Soprana, Elisa; Panigada, Maddalena; Thom, Michelle; Scarselli, Elisa; Folgori, Antonella; Colloca, Stefano; Taylor, Geraldine; Cortese, Riccardo; Nicosia, Alfredo; Capone, Stefania; Vitelli, Alessandra

2015-01-01

Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing. PMID:26015988

Enhanced Vaccine-Induced CD8+ T Cell Responses to Malaria Antigen ME-TRAP by Fusion to MHC Class II Invariant Chain

PubMed Central

Spencer, Alexandra J.; Cottingham, Matthew G.; Jenks, Jennifer A.; Longley, Rhea J.; Capone, Stefania; Colloca, Stefano; Folgori, Antonella; Cortese, Riccardo; Nicosia, Alfredo; Bregu, Migena; Hill, Adrian V. S.

2014-01-01

The orthodox role of the invariant chain (CD74; Ii) is in antigen presentation to CD4+ T cells, but enhanced CD8+ T cells responses have been reported after vaccination with vectored viral vaccines encoding a fusion of Ii to the antigen of interest. In this study we assessed whether fusion of the malarial antigen, ME-TRAP, to Ii could increase the vaccine-induced CD8+ T cell response. Following single or heterologous prime-boost vaccination of mice with a recombinant chimpanzee adenovirus vector, ChAd63, or recombinant modified vaccinia virus Ankara (MVA), higher frequencies of antigen-specific CD4+ and CD8+ T cells were observed, with the largest increases observed following a ChAd63-MVA heterologous prime-boost regimen. Studies in non-human primates confirmed the ability of Ii-fusion to augment the T cell response, where a 4-fold increase was maintained up to 11 weeks after the MVA boost. Of the numerous different approaches explored to increase vectored vaccine induced immunogenicity over the years, fusion to the invariant chain showed a consistent enhancement in CD8+ T cell responses across different animal species and may therefore find application in the development of vaccines against human malaria and other diseases where high levels of cell-mediated immunity are required. PMID:24945248

Immunogenicity of modified vaccinia virus Ankara expressing the hemagglutinin stalk domain of pandemic (H1N1) 2009 influenza virus.

PubMed

Di Mario, Giuseppina; Soprana, Elisa; Gubinelli, Francesco; Panigada, Maddalena; Facchini, Marzia; Fabiani, Concetta; Garulli, Bruno; Basileo, Michela; Cassone, Antonio; Siccardi, Antonio; Donatelli, Isabella; Castrucci, Maria R

2017-03-01

Vaccination offers protection against influenza, although current vaccines need to be reformulated each year. The development of a broadly protective influenza vaccine would guarantee the induction of heterosubtypic immunity also against emerging influenza viruses of a novel subtype. Vaccine candidates based on the stalk region of the hemagglutinin (HA) have the potential to induce broad and persistent protection against diverse influenza A viruses. Modified vaccinia virus Ankara (MVA) expressing a headless HA (hlHA) of A/California/4/09 (CA/09) virus was used as a vaccine to immunize C57BL/6 mice. Specific antibody and cell-mediated immune responses were determined, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus. Immunization of mice with CA/09-derived hlHA, vectored by MVA, was able to elicit influenza-specific broad cross-reactive antibodies and cell-mediated immune responses, but failed to induce neutralizing antibodies and did not protect mice against virus challenge. Although highly immunogenic, our vaccine was unable to induce a protective immunity against influenza. A misfolded and unstable conformation of the hlHA molecule may have affected its capacity of inducing neutralizing antiviral, conformational antibodies. Design of stable hlHA-based immunogens and their delivery by recombinant MVA-based vectors has the potential of improving this promising approach for a universal influenza vaccine.

Is less more? Comparing chemotherapy alone with chemotherapy and radiation for high-risk grade 2 glioma: An analysis of the National Cancer Data Base.

PubMed

Jhaveri, Jaymin; Liu, Yuan; Chowdhary, Mudit; Buchwald, Zachary S; Gillespie, Theresa W; Olson, Jeffrey J; Voloschin, Alfredo D; Eaton, Bree R; Shu, Hui-Kuo G; Crocker, Ian R; Curran, Walter J; Patel, Kirtesh R

2018-03-15

The addition of chemotherapy to adjuvant radiotherapy (chemotherapy and radiation therapy [CRT]) improves overall survival (OS) for patients with high-risk grade 2 gliomas; however, the impact of chemotherapy alone (CA) is unknown. This study compares the OS of patients with high-risk grade 2 gliomas treated with CA versus CRT. Patients with high-risk grade 2 gliomas (subtotal resection or age ≥ 40 years) with oligodendrogliomas, astrocytomas, or mixed tumors were identified with the National Cancer Data Base. Patients were grouped into CA and CRT cohorts. Univariate analyses and multivariate analyses (MVAs) were performed. Propensity score (PS) matching was also implemented. The Kaplan-Meier method was used to analyze OS. A total of 1054 patients with high-risk grade 2 gliomas were identified: 496 (47.1%) received CA, and 558 (52.9%) received CRT. Patients treated with CA were more likely (all P values < .05) to have oligodendroglioma histology (65.5% vs 34.2%), exhibit a 1p/19q codeletion (22.8% vs 7.5%), be younger (median age, 47.0 vs 48.0 years), and receive treatment at an academic facility (65.2% vs 50.3%). The treatment type was not a significant predictor for OS (P = .125) according to the MVA; a tumor size > 6 cm, astrocytoma histology, and older age were predictors for worse OS (all P values < .05). After 1:1 PS matching (n = 331 for each cohort), no OS difference was seen (P = .696) between the CA and CRT cohorts at 5 (69.3% vs 67.4%) and 8 years (52.8% vs 56.7%). No long-term OS difference was seen in patients with high-risk grade 2 gliomas treated with CA versus CRT. These findings are hypothesis-generating, and prospective clinical trials comparing these treatment paradigms are warranted. Cancer 2018;124:1169-78. © 2017 American Cancer Society. © 2017 American Cancer Society.

Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses.

PubMed

Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W; Hewson, Roger

2016-01-01

Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge.

Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses

PubMed Central

Dowall, Stuart D.; Graham, Victoria A.; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W.; Hewson, Roger

2016-01-01

Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge. PMID:27272940

SU-F-R-07: Radiomics of CT Features and Associations and Correlation with Outcomes Following Lung SBRT

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

Schreibmann, E; Iwinski Sutter, A; Whitaker, D

Objective: To investigate the prognostic significance of image gradients and in predicting clinical outcomes in a patients with non-small cell lung cancer treated with stereotactic body radiotherapy (SBRT) on 71 patients with 83 treated lesions. Methods: The records of patients treated with lung SBRT were retrospectively reviewed. When applicable, SBRT target volumes were modified to exclude any overlap with pleura, chestwall, or mediastinum. The ITK software package was utilized to generate quantitative measures of image intensity, inhomogeneity, shape morphology and first and second-order CT textures. Multivariate and univariate models containing CT features were generated to assess associations with clinicopathologic factors.more » Results: On univariate analysis, tumor size (HR 0.54, p=0.045) sumHU (HR 0.31, p=0.044) and short run grey level emphasis STD (HR 0.22, p=0.019) were associated with regional failure-free survival; meanHU (HR 0.30, p=0.035), long run emphasis (HR 0.21, p=0.011) and long run low grey level emphasis (HR 0.14, p=0.005) was associated with distant failure-free survival (DFFS). No features were significant on multivariate modeling however long run low grey level emphasis had a hazard ratio of 0.12 (p=0.061) for DFFS. Adenocarcinoma and squamous cell carcinoma differed with respect to long run emphasis STD (p=0.024), short run low grey level emphasis STD (p<0.001), and long run low grey level emphasis STD (p=0.024). Multivariate modeling of texture features associated with tumor histology was used to estimate histologies of 18 lesions treated without histologic confirmation. Of these, MVA suggested the same histology as a prior metachronous lung malignancy in 3/7 patients. Conclusion: Extracting radiomics features on clinical datasets was feasible with the ITK package with minimal effort to identify pre-treatment quantitative CT features with prognostic factors for distant control after lung SBRT.« less

Association Of Tricuspid Regurgitation And Severity Of Mitral Stenosis In Patients With Rheumatic Heart Disease.

PubMed

Ahmed, Rehan; Kazmi, Nasir; Naz, Farhat; Malik, Saqib; Gillani, Saima

2016-01-01

Rheumatic heart disease is a common ailment in Pakistan and Mitral stenosis is its flag bearer Severity of mitral stenosis is the key factor in deciding for mitral valve surgery. This case series study was conducted at Ayub Teaching Hospital .Cases of Rheumatic heart disease with mitral stenosis were diagnosed clinically. 2D echocardiography was used to find severity of mitral stenosis. Data was entered into SPSS-17.0 and results were recorded and analysed. Pearson's two tailed correlation was used to find the correlation between presence of tricuspid regurgitation in patients with severe mitral stenosis, p was <0.05. A total 35 patients with pure mitral stenosis were included in study, out of which 8 were male and 27 were females. Mean age in males was 34.5±15.85 years while in females it was 31±8 years. Twenty-two out of 35 (62.86%) patients had tricuspid regurgitation while 13 out 35 (37.14%) had no tricuspid regurgitation. Mean (MVA) mitral valve area in patients with tricuspid regurgitation was 0.84±0.3 cm2 while mean (MVA) mitral valve area in patients without tricuspid regurgitation was 1.83±0.7 cm2. Mean left atrial (L.A) size was 45.23±1.5 mm2 in patients with tricuspid regurgitation, while it was 44.13±6.14 mm2 in patients without tricuspid regurgitation. Mean RSVP was 57.5mmHg in patients with tricuspid regurgitation while RSVP could not be calculated in patients without tricuspid regurgitation. It was concluded that tricuspid regurgitation was strongly associated with severe mitral stenosis as almost all patients with severe mitral stenosis had tricuspid regurgitation and none of the patients with mild mitral stenosis had tricuspid regurgitation.

'It's a very complicated issue here': understanding the limited and declining use of manual vacuum aspiration for postabortion care in Malawi: a qualitative study.

PubMed

Cook, Sinead; de Kok, Bregje; Odland, Maria Lisa

2017-04-01

Malawi has one of the highest maternal mortality ratios in the world. Unsafe abortions are an important contributor to Malawi's maternal mortality and morbidity, where abortion is illegal except to save the woman's life. Postabortion care (PAC) aims to reduce adverse consequences of unsafe abortions, in part by treating incomplete abortions. Although global and national PAC policies recommend manual vacuum aspiration (MVA) for treatment of incomplete abortion, usage in Malawi is low and appears to be decreasing, with sharp curettage being used in preference. There is limited evidence regarding what influences rejection of recommended PAC innovations. Hence, drawing on Greenhalgh et al. 's (2004. Diffusion of innovations in service organizations: systematic review and recommendations. Milbank Quarterly 82: 581-629.) diffusion of healthcare innovation framework, this qualitative study aimed to investigate factors contributing to the limited and declining use of MVA in Malawi. Semi-structured interviews with 17 PAC providers in a central hospital and a district hospital indicate that a range of factors coalesce and influence PAC and MVA use in Malawi. Factors pertain to four main domains: the system (shortages of material and human resources; lack of training, supervision and feedback), relationships (power dynamics; expected job roles), the health workers (attitudes towards abortion and PAC; prioritization of PAC) and the innovation (perceived risks and benefits of MVA use). Effective and sustainable PAC policy must adopt a broader people-centred health systems approach which considers all these factors, their interactions and the wider socio-cultural, legal and political context of abortion and PAC. The study showed the value of using Greenhalgh et al. 's (2004. Diffusion of innovations in service organizations: systematic review and recommendations. Milbank Quarterly 82: 581-629.) framework to consider the complex interaction of factors surrounding innovation use (or lack of), but provided more insights into rejections of innovations and, particularly, a low- and middle-income country perspective. © The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Mitral Regurgitation after Percutaneous Balloon Mitral Valvotomy in Patients with Rheumatic Mitral Stenosis: A Single-Center Study

PubMed Central

Aslanabadi, Naser; Toufan, Mehrnoush; Salehi, Rezvaneyeh; Alizadehasl, Azin; Ghaffari, Samad; Sohrabi, Bahram; Separham, Ahmad; Manafi, Ataolaah; Mehdizadeh, Mohammad Bagher; Habibzadeh, Afshin

2014-01-01

Abstract Background: Percutaneous balloon mitral valvotomy (BMV) is the gold standard treatment for rheumatic mitral stenosis (MS) in that it causes significant changes in mitral valve area (MVA) and improves leaflet mobility. Development of or increase in mitral regurgitation (MR) is common after BMV. This study evaluated MR severity and its changes after BMV in Iranian patients. Methods: We prospectively evaluated consecutive patients with severe rheumatic MS undergoing BMV using the Inoue balloon technique between February 2010 and January 2013 in Madani Heart Center, Tabriz, Iran. New York Heart Association (NYHA) functional class and echocardiographic and catheterization data, including MVA, mitral valve mean and peak gradient (MVPG and MVMG), left atrial (LA) pressure, pulmonary artery systolic pressure (PAPs), and MR severity before and after BMV, were evaluated. Results: Totally, 105 patients (80% female) at a mean age of 45.81 ± 13.37 years were enrolled. NYHA class was significantly improved after BMV: 55.2% of the patients were in NYHA functional class III before BMV compared to 36.2% after the procedure (p value < 0.001). MVA significantly increased (mean area = 0.64 ± 0.29 cm2 before BMV vs. 1.90 ± 0.22 cm2 after BMV; p value < 0.001) and PAPs, LA pressure, MVPG, and MVMG significantly decreased. MR severity did not change in 82 (78.1%) patients, but it increased in 18 (17.1%) and decreased in 5 (4.8%) patients. Patients with increased MR had a significantly higher calcification score (2.03 ± 0.53 vs.1.50 ± 0.51; p value < 0.001) and lower MVA before BMV (0.81 ± 0.23 vs.0.94 ± 0.18; p value = 0.010). There were no major complications. Conclusion: In our study, BMV had excellent immediate hemodynamic and clinical results inasmuch as MR severity increased only in some patients and, interestingly, decreased in a few. Our results, underscore BMV efficacy in severe MS. The echocardiographic calcification score was useful for identifying patients likely to have MR development or MR increase after BMV. PMID:25870627

Feasibility study of new energy projects on three-level indicator system

NASA Astrophysics Data System (ADS)

Zhan, Zhigang

2018-06-01

With the rapid development of new energy industry, many new energy development projects are being carried out all over the world. To analyze the feasibility of the project. we build feasibility of new energy projects assessment model, based on the gathered abundant data about progress in new energy projects.12 indicators are selected by principal component analysis(PCA). Then we construct a new three-level indicator system, where the first level has 1 indicator, the second level has 5 indicators and the third level has 12 indicators to evaluate. Moreover, we use the entropy weight method (EWM) to get weight vector of the indicators in the third level and the multivariate statistical analysis(MVA)to get the weight vector of indicators in the second-class. We use this evaluation model to evaluate the feasibility of the new energy project and make a reference for the subsequent new energy investment. This could be a contribution to the world's low-carbon and green development by investing in sustainable new energy projects. We will introduce new variables and improve the weight model in the future. We also conduct a sensitivity analysis of the model and illustrate the strengths and weaknesses.

Influence of adenovirus and MVA vaccines on the breadth and hierarchy of T cell responses.

PubMed

Rollier, Christine S; Hill, Adrian V S; Reyes-Sandoval, Arturo

2016-08-31

Viral-vectored vaccines are in clinical development for several infectious diseases where T-cell responses can mediate protection, and responses to sub-dominant epitopes is needed. Little is known about the influence of MVA or adenoviral vectors on the hierarchy of the dominant and sub-dominant T-cell epitopes. We investigated this aspect in mice using a malaria immunogen. Our results demonstrate that the T-cell hierarchy is influenced by the timing of analysis, rather than by the vector after a single immunization, with hierarchy changing over time. Repeated homologous immunization reduced the breadth of responses, while heterologous prime-boost induced the strongest response to the dominant epitope, albeit with only modest response to the sub-dominant epitopes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

An audit of a hospital-based Doppler ultrasound quality control protocol using a commercial string Doppler phantom.

PubMed

Cournane, S; Fagan, A J; Browne, J E

2014-05-01

Results from a four-year audit of a Doppler quality assurance (QA) program using a commercially available Doppler string phantom are presented. The suitability of the phantom was firstly determined and modifications were made to improve the reliability and quality of the measurements. QA of Doppler ultrasound equipment is very important as data obtained from these systems is used in patient management. It was found that if the braided-silk filament of the Doppler phantom was exchanged with an O-ring rubber filament and the velocity range below 50 cm/s was avoided for Doppler quality control (QC) measurements, then the maximum velocity accuracy (MVA) error and intrinsic spectral broadening (ISB) results obtained using this device had a repeatability of 18 ± 3.3% and 19 ± 3.5%, respectively. A consistent overestimation of the MVA of between 12% and 56% was found for each of the tested ultrasound systems. Of more concern was the variation of the overestimation within each respective transducer category: MVA errors of the linear, curvilinear and phased array probes were in the range 12.3-20.8%, 32.3-53.8% and 27-40.7%, respectively. There is a dearth of QA data for Doppler ultrasound; it would be beneficial if a multicentre longitudinal study was carried out using the same Doppler ultrasound test object to evaluate sensitivity to deterioration in performance measurements. Copyright © 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.

PubMed

Pearson, Frances E; O'Mahony, Conor; Moore, Anne C; Hill, Adrian V S

2015-06-22

There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review.

PubMed

Cho, Chi Hyun; Oh, Min-Jeong; Lim, Chae Seung; Lee, Chang Kyu; Cho, Yunjung; Yoon, Soo-Young

2015-01-01

Mosaic variegated aneuploidy (MVA) is a recessive condition characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple chromosomes and tissues. The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer. We report a case of true fetal mosaicism for variegated aneuploidies detected in amniotic fluid cells. A 33-year-old primigravida woman at 5 weeks 1 day of gestation was referred to our tertiary hospital because of a high-risk pregnancy associated with IgA nephropathy. In a quadruple screening test performed at the 15(th) week of gestation, alpha fetoprotein was 73.4 IU/mL (2.792 MoM), suggesting that she was at high risk of neural tube defect. Following amniocentesis performed at the 17 weeks' gestation, chromosome examination of amniocyte culture showed premature chromatic separation in 63% of the metaphases (58/92) and a high frequency of gain and loss of chromosomes. Repeat amniocentesis at 21 weeks' gestation consistently showed the presence of multiple mosaic autosomal variegated aneuploidies. Ultrasonography at 21 weeks' gestation revealed relatively small head circumference for gestational age (<3%) and vermis defect, suggesting that the fetus would have microcephaly and Dandy-Walker malformation. Cytogenetic analysis with peripheral blood of the parents showed normal karyotype. In summary, we hereby report the cytogenetic analysis and prenatal findings of MVA. © 2015 by the Association of Clinical Scientists, Inc.

Atrial contribution to ventricular filling in mitral stenosis.

PubMed

Meisner, J S; Keren, G; Pajaro, O E; Mani, A; Strom, J A; Frater, R W; Laniado, S; Yellin, E L

1991-10-01

The importance of the contribution of atrial systole to ventricular filling in mitral stenosis is controversial. The cause of reduced cardiac output following the onset of atrial fibrillation may be due to an increased heart rate, a loss of booster pump function, or both. We studied the atrial contribution to filling under a variety of conditions by combining noninvasive studies of patients with computer modeling. Thirty patients in sinus rhythm with mild-to-severe stenosis were studied with two-dimensional and Doppler echocardiography for measurement of mitral flow velocity and mitral valve area (MVA). The mean +/- SD atrial contribution to left ventricular filling volume was 18 +/- 10% and varied inversely with mitral resistance. Patients with mild mitral stenosis (MVA, 1.8 +/- 0.7 cm2) and severe mitral stenosis (MVA, 0.9 +/- 0.2 cm2) had atrial contributions of 29 +/- 4% and 9 +/- 5%, respectively. The pathophysiological mechanisms responsible for these trends were further investigated by the computer model. In modeled severe mitral stenosis, increasing heart rate from 75 to 150 beats/min caused an increase of 5.2 mm Hg in mean left atrial pressure, whereas loss of atrial contraction at a heart rate of 150 beats/min caused only a 1.3 mm Hg increase. The atrial booster pump contributes less to ventricular filling in mitral stenosis than in the normal heart, and the loss of atrial pump function is less important than the effect of increasing heart rate as the cause of decompensation during atrial fibrillation.

Service users' attributes associated with the uptake of medical versus surgical abortion at public health facilities in Vietnam.

PubMed

Ngo, Thoai D; Free, Caroline; Le, Hoan T; Edwards, Phil; Pham, Kiet H T; Nguyen, Yen B T; Nguyen, Thang H

2014-06-01

To investigate the attributes of service users associated with uptake of medical abortion (MA) versus manual vacuum aspiration (MVA) at public health facilities in Vietnam. Structured exit interviews were conducted among women who underwent termination at 62 public health facilities in Hanoi, Khanh Hoa, and Ho Chi Minh City (HCMC) between August and December 2011. Data on sociodemographic, abortion-related, and service-related factors were compared between women who underwent MVA versus MA. Overall, 1233 women completed the study survey: 541 (43.9%) from Hanoi; 163 (13.2%) from Khanh Hoa; and 529 (42.9%) from HCMC. Almost one-quarter of women (23.1%) had chosen MA. After controlling for sociodemographic factors, women living in Khanh Hoa (odds ratio [OR], 13.4; 95% confidence interval [CI], 5.3-33.8) and HCMC (OR, 5.8; 95% CI, 2.1-15.9) were more likely to have undergone MA than women in Hanoi. Older women were less likely to have undergone MA (P < 0.05), and those who had previously heard of MA were twice as likely to have undergone MA (P = 0.020). Uptake of MA was lower than that of MVA and varied by province. Women in Vietnam will make their own judgment about which method to choose if they have prior knowledge of both. Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.

PubMed

Sheehy, Susanne H; Duncan, Christopher J A; Elias, Sean C; Choudhary, Prateek; Biswas, Sumi; Halstead, Fenella D; Collins, Katharine A; Edwards, Nick J; Douglas, Alexander D; Anagnostou, Nicholas A; Ewer, Katie J; Havelock, Tom; Mahungu, Tabitha; Bliss, Carly M; Miura, Kazutoyo; Poulton, Ian D; Lillie, Patrick J; Antrobus, Richard D; Berrie, Eleanor; Moyle, Sarah; Gantlett, Katherine; Colloca, Stefano; Cortese, Riccardo; Long, Carole A; Sinden, Robert E; Gilbert, Sarah C; Lawrie, Alison M; Doherty, Tom; Faust, Saul N; Nicosia, Alfredo; Hill, Adrian V S; Draper, Simon J

2012-12-01

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Comparative multivariate analyses of transient otoacoustic emissions and distorsion products in normal and impaired hearing.

PubMed

Stamate, Mirela Cristina; Todor, Nicolae; Cosgarea, Marcel

2015-01-01

The clinical utility of otoacoustic emissions as a noninvasive objective test of cochlear function has been long studied. Both transient otoacoustic emissions and distorsion products can be used to identify hearing loss, but to what extent they can be used as predictors for hearing loss is still debated. Most studies agree that multivariate analyses have better test performances than univariate analyses. The aim of the study was to determine transient otoacoustic emissions and distorsion products performance in identifying normal and impaired hearing loss, using the pure tone audiogram as a gold standard procedure and different multivariate statistical approaches. The study included 105 adult subjects with normal hearing and hearing loss who underwent the same test battery: pure-tone audiometry, tympanometry, otoacoustic emission tests. We chose to use the logistic regression as a multivariate statistical technique. Three logistic regression models were developed to characterize the relations between different risk factors (age, sex, tinnitus, demographic features, cochlear status defined by otoacoustic emissions) and hearing status defined by pure-tone audiometry. The multivariate analyses allow the calculation of the logistic score, which is a combination of the inputs, weighted by coefficients, calculated within the analyses. The accuracy of each model was assessed using receiver operating characteristics curve analysis. We used the logistic score to generate receivers operating curves and to estimate the areas under the curves in order to compare different multivariate analyses. We compared the performance of each otoacoustic emission (transient, distorsion product) using three different multivariate analyses for each ear, when multi-frequency gold standards were used. We demonstrated that all multivariate analyses provided high values of the area under the curve proving the performance of the otoacoustic emissions. Each otoacoustic emission test presented high values of area under the curve, suggesting that implementing a multivariate approach to evaluate the performances of each otoacoustic emission test would serve to increase the accuracy in identifying the normal and impaired ears. We encountered the highest area under the curve value for the combined multivariate analysis suggesting that both otoacoustic emission tests should be used in assessing hearing status. Our multivariate analyses revealed that age is a constant predictor factor of the auditory status for both ears, but the presence of tinnitus was the most important predictor for the hearing level, only for the left ear. Age presented similar coefficients, but tinnitus coefficients, by their high value, produced the highest variations of the logistic scores, only for the left ear group, thus increasing the risk of hearing loss. We did not find gender differences between ears for any otoacoustic emission tests, but studies still debate this question as the results are contradictory. Neither gender, nor environment origin had any predictive value for the hearing status, according to the results of our study. Like any other audiological test, using otoacoustic emissions to identify hearing loss is not without error. Even when applying multivariate analysis, perfect test performance is never achieved. Although most studies demonstrated the benefit of using the multivariate analysis, it has not been incorporated into clinical decisions maybe because of the idiosyncratic nature of multivariate solutions or because of the lack of the validation studies.

Comparative multivariate analyses of transient otoacoustic emissions and distorsion products in normal and impaired hearing

PubMed Central

STAMATE, MIRELA CRISTINA; TODOR, NICOLAE; COSGAREA, MARCEL

2015-01-01

Background and aim The clinical utility of otoacoustic emissions as a noninvasive objective test of cochlear function has been long studied. Both transient otoacoustic emissions and distorsion products can be used to identify hearing loss, but to what extent they can be used as predictors for hearing loss is still debated. Most studies agree that multivariate analyses have better test performances than univariate analyses. The aim of the study was to determine transient otoacoustic emissions and distorsion products performance in identifying normal and impaired hearing loss, using the pure tone audiogram as a gold standard procedure and different multivariate statistical approaches. Methods The study included 105 adult subjects with normal hearing and hearing loss who underwent the same test battery: pure-tone audiometry, tympanometry, otoacoustic emission tests. We chose to use the logistic regression as a multivariate statistical technique. Three logistic regression models were developed to characterize the relations between different risk factors (age, sex, tinnitus, demographic features, cochlear status defined by otoacoustic emissions) and hearing status defined by pure-tone audiometry. The multivariate analyses allow the calculation of the logistic score, which is a combination of the inputs, weighted by coefficients, calculated within the analyses. The accuracy of each model was assessed using receiver operating characteristics curve analysis. We used the logistic score to generate receivers operating curves and to estimate the areas under the curves in order to compare different multivariate analyses. Results We compared the performance of each otoacoustic emission (transient, distorsion product) using three different multivariate analyses for each ear, when multi-frequency gold standards were used. We demonstrated that all multivariate analyses provided high values of the area under the curve proving the performance of the otoacoustic emissions. Each otoacoustic emission test presented high values of area under the curve, suggesting that implementing a multivariate approach to evaluate the performances of each otoacoustic emission test would serve to increase the accuracy in identifying the normal and impaired ears. We encountered the highest area under the curve value for the combined multivariate analysis suggesting that both otoacoustic emission tests should be used in assessing hearing status. Our multivariate analyses revealed that age is a constant predictor factor of the auditory status for both ears, but the presence of tinnitus was the most important predictor for the hearing level, only for the left ear. Age presented similar coefficients, but tinnitus coefficients, by their high value, produced the highest variations of the logistic scores, only for the left ear group, thus increasing the risk of hearing loss. We did not find gender differences between ears for any otoacoustic emission tests, but studies still debate this question as the results are contradictory. Neither gender, nor environment origin had any predictive value for the hearing status, according to the results of our study. Conclusion Like any other audiological test, using otoacoustic emissions to identify hearing loss is not without error. Even when applying multivariate analysis, perfect test performance is never achieved. Although most studies demonstrated the benefit of using the multivariate analysis, it has not been incorporated into clinical decisions maybe because of the idiosyncratic nature of multivariate solutions or because of the lack of the validation studies. PMID:26733749

Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

PubMed

Osaki, Yoshinori; Nakagawa, Yoshimi; Miyahara, Shoko; Iwasaki, Hitoshi; Ishii, Akiko; Matsuzaka, Takashi; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Sone, Hirohito; Ohashi, Ken; Ishibashi, Shun; Yamada, Nobuhiro; Shimano, Hitoshi

2015-10-23

HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs. Copyright © 2015 Elsevier Inc. All rights reserved.

Optical quasi-distributed simultaneous vibration and temperature sensing in stator bars of a 370-MVA electric generator

NASA Astrophysics Data System (ADS)

Dreyer, Uilian José; Vagner da Silva, Erlon; Martelli, Cicero; Cardozo da Silva, Jean Carlos

2017-08-01

In this paper, we propose a new multiparametric optical fiber transducer applied to an electric generator of 370 MVA. The optical transducer has three multiplexed FBGs in the same optical fiber as the sensing element. The FBG sensors can simultaneously measure both the temperature and vibration independently of the other multiplexed FBGs. The installation in the power plant was performed using six transducers and it was obtained 23 hours of simultaneous vibration and temperature measurement. All the FBGs used to monitor generator vibration were able to monitor the frequency of mechanical and electromagnetic vibrations, which were measured at 2 Hz and 120 Hz, respectively. During the measurement, the machine was turned off due to a failure and all the FBGs sensed temperature changes, as well as frequency vibration changes. The largest temperature difference measured between the FBGs during the test is approximately 2°C.

The Future of Smallpox Vaccination: is MVA the key?

PubMed Central

Slifka, Mark K

2005-01-01

Eradication of the smallpox virus through extensive global vaccination efforts has resulted in one of the most important breakthroughs in medical history, saving countless lives from the severe morbidity and mortality that is associated with this disease. Although smallpox is now extinct in nature, laboratory stocks of this virus still remain and the subject of smallpox vaccination has gained renewed attention due to the potential risk that smallpox may be used as a biological weapon by terrorists or rogue states. Despite having the longest history of any modern vaccine, there is still much to be learned about smallpox vaccination and the correlates of protection remain to be formally defined. This Commentary will discuss the strengths and weaknesses of traditional smallpox vaccination in comparison with immunization using modified vaccinia virus Ankura (MVA), a non-replicating virus with a strong safety record but weakened immunogenicity. PMID:15740619

Sampling effort affects multivariate comparisons of stream assemblages

USGS Publications Warehouse

Cao, Y.; Larsen, D.P.; Hughes, R.M.; Angermeier, P.L.; Patton, T.M.

2002-01-01

Multivariate analyses are used widely for determining patterns of assemblage structure, inferring species-environment relationships and assessing human impacts on ecosystems. The estimation of ecological patterns often depends on sampling effort, so the degree to which sampling effort affects the outcome of multivariate analyses is a concern. We examined the effect of sampling effort on site and group separation, which was measured using a mean similarity method. Two similarity measures, the Jaccard Coefficient and Bray-Curtis Index were investigated with 1 benthic macroinvertebrate and 2 fish data sets. Site separation was significantly improved with increased sampling effort because the similarity between replicate samples of a site increased more rapidly than between sites. Similarly, the faster increase in similarity between sites of the same group than between sites of different groups caused clearer separation between groups. The strength of site and group separation completely stabilized only when the mean similarity between replicates reached 1. These results are applicable to commonly used multivariate techniques such as cluster analysis and ordination because these multivariate techniques start with a similarity matrix. Completely stable outcomes of multivariate analyses are not feasible. Instead, we suggest 2 criteria for estimating the stability of multivariate analyses of assemblage data: 1) mean within-site similarity across all sites compared, indicating sample representativeness, and 2) the SD of within-site similarity across sites, measuring sample comparability.

Translating the Immunogenicity of Prime-boost Immunization With ChAd63 and MVA ME-TRAP From Malaria Naive to Malaria-endemic Populations

PubMed Central

Kimani, Domtila; Jagne, Ya Jankey; Cox, Momodou; Kimani, Eva; Bliss, Carly M; Gitau, Evelyn; Ogwang, Caroline; Afolabi, Muhammed O; Bowyer, Georgina; Collins, Katharine A; Edwards, Nick; Hodgson, Susanne H; Duncan, Christopher J A; Spencer, Alexandra J; Knight, Miguel G; Drammeh, Abdoulie; Anagnostou, Nicholas A; Berrie, Eleanor; Moyle, Sarah; Gilbert, Sarah C; Soipei, Peninah; Okebe, Joseph; Colloca, Stefano; Cortese, Riccardo; Viebig, Nicola K; Roberts, Rachel; Lawrie, Alison M; Nicosia, Alfredo; Imoukhuede, Egeruan B; Bejon, Philip; Chilengi, Roma; Bojang, Kalifa; Flanagan, Katie L; Hill, Adrian V S; Urban, Britta C; Ewer, Katie J

2014-01-01

To induce a deployable level of efficacy, a successful malaria vaccine would likely benefit from both potent cellular and humoral immunity. These requirements are met by a heterologous prime-boost immunization strategy employing a chimpanzee adenovirus vector followed by modified vaccinia Ankara (MVA), both encoding the pre-erythrocytic malaria antigen ME-thrombospondin-related adhesive protein (TRAP), with high immunogenicity and significant efficacy in UK adults. We undertook two phase 1b open-label studies in adults in Kenya and The Gambia in areas of similar seasonal malaria transmission dynamics and have previously reported safety and basic immunogenicity data. We now report flow cytometry and additional interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) data characterizing pre-existing and induced cellular immunity as well as anti-TRAP IgG responses. T-cell responses induced by vaccination averaged 1,254 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMC) across both trials and flow cytometry revealed cytokine production from both CD4+ and CD8+ T cells with the frequency of CD8+ IFN-γ-secreting monofunctional T cells (previously shown to associate with vaccine efficacy) particularly high in Kenyan adults. Immunization with ChAd63 and MVA ME-TRAP induced strong cellular and humoral immune responses in adults living in two malaria-endemic regions of Africa. This prime-boost approach targeting the pre-erythrocytic stage of the malaria life-cycle is now being assessed for efficacy in a target population. PMID:24930599

Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA

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

Wyatt, Linda S.; Belyakov, Igor M.; Earl, Patricia L.

2008-03-15

During propagation of modified vaccinia virus Ankara (MVA) encoding HIV 89.6 Env, a few viral foci stained very prominently. Virus cloned from such foci replicated to higher titers than the parent and displayed enhanced genetic stability on passage. Sequence analysis showed a single nucleotide deletion in the 89.6 env gene of the mutant that caused a frame shift and truncation of 115 amino acids from the cytoplasmic domain. The truncated Env was more highly expressed on the cell surface, induced higher antibody responses than the full-length Env, reacted with HIV neutralizing monoclonal antibodies and mediated CD4/co-receptor-dependent fusion. Intramuscular (IM), intradermalmore » (ID) needleless, and intrarectal (IR) catheter inoculations gave comparable serum IgG responses. However, intraoral (IO) needleless injector route gave the highest IgA in lung washings and IR gave the highest IgA and IgG responses in fecal extracts. Induction of CTL responses in the spleens of individual mice as assayed by intracellular cytokine staining was similar with both the full-length and truncated Env constructs. Induction of acute and memory CTL in the spleens of mice immunized with the truncated Env construct by ID, IO, and IR routes was comparable and higher than by the IM route, but only the IR route induced CTL in the gut-associated lymphoid tissue. Thus, truncation of Env enhanced genetic stability as well as serum and mucosal antibody responses, suggesting the desirability of a similar modification in MVA-based candidate HIV vaccines.« less

Trauma Related Guilt Inventory - psychometric properties of the Polish adaptation (TRGI-PL).

PubMed

Popiel, Agnieszka; Zawadzki, Bogdan

2015-01-01

AIM : Although various aspects of guilt are frequent problems of patients suffering from PTSD, they have been included into the diagnostic criteria for PTSD just in the present version DSM-5. Kubany proposed a cognitive conceptualization of guilt in PTSD followed by development of the Trauma Related Guilt Inventory (TRGI). The aim of the paper is to present psychometric properties of the Polish version of the inventory - the TRGI-PL. A Polish adaptation of the Trauma-Related Guilt Inventory was applied to a sample of 280 motor vehicle (MVA) participants (147 females, 133 males of age from 18 to 80 (M=34,93, SD=13,71) within 1-24 months after a MVA (M=10,18, SD=6,23). Validation of the Polish version was done by analyzing the internal structure of the instrument and comparing the emotional and cognitive aspects of guilt assessed by the TRGI with PTSD symptoms, post-traumatic cognitions and responsibility for MVA and subjective agreement with the judgment. The model with four latent factors: Distress, Hindsight-Bias/Responsibility, Wrongdoing and Insufficient Justification scales showed acceptable fit (Satorra-Bentler chi2=518,62, df=203, p<0,01, RMSEA=0,079, CFI=0,96, GFI=0,97), what confirms the four-factor structure of guilt, obtained in the studies on original TRGI version. Reliability coefficients are similar to original version. Correlations with other PTSD measures showed satisfactory convergent and discriminative validity. The Polish adaptation of the Trauma-Related Guilt Inventory is a reliable and valid tool for assessing guilt as a multidimensional phenomenon, comprising emotional and several cognitive characteristics, in trauma survivors.

Heterologous expression of the mevalonic acid pathway in cyanobacteria enhances endogenous carbon partitioning to isoprene.

PubMed

Bentley, Fiona K; Zurbriggen, Andreas; Melis, Anastasios

2014-01-01

Heterologous expression of the isoprene synthase gene in the cyanobacterium Synechocystis PCC 6803 conferred upon these microorganisms the property of photosynthetic isoprene (C₅H₈) hydrocarbons production. Continuous production of isoprene from CO₂ and H₂O was achieved in the light, occurring via the endogenous methylerythritol-phosphate (MEP) pathway, in tandem with the growth of Synechocystis. This work addressed the issue of photosynthetic carbon partitioning between isoprene and biomass in Synechocystis. Evidence is presented to show heterologous genomic integration and cellular expression of the mevalonic acid (MVA) pathway genes in Synechocystis endowing a non-native pathway for carbon flux amplification to isopentenyl-diphosphate (IPP) and dimethylallyl-diphosphate (DMAPP) precursors of isoprene. Heterologous expression of the isoprene synthase in combination with the MVA pathway enzymes resulted in photosynthetic isoprene yield improvement by approximately 2.5-fold, compared with that measured in cyanobacteria transformed with the isoprene synthase gene only. These results suggest that the MVA pathway introduces a bypass in the flux of endogenous cellular substrate in Synechocystis to IPP and DMAPP, overcoming flux limitations of the native MEP pathway. The work employed a novel chromosomal integration and expression of synthetic gene operons in Synechocystis, comprising up to four genes under the control of a single promoter, and expressing three operons simultaneously. This is the first time an entire biosynthetic pathway with seven recombinant enzymes has been heterologously expressed in a photosynthetic microorganism. It constitutes contribution to the genetic engineering toolkit of photosynthetic microorganisms and a paradigm in the pursuit of photosynthetic approaches for the renewable generation of high-impact products.

Toward industrial production of isoprenoids in Escherichia coli: Lessons learned from CRISPR-Cas9 based optimization of a chromosomally integrated mevalonate pathway.

PubMed

Alonso-Gutierrez, Jorge; Koma, Daisuke; Hu, Qijun; Yang, Yuchen; Chan, Leanne J G; Petzold, Christopher J; Adams, Paul D; Vickers, Claudia E; Nielsen, Lars K; Keasling, Jay D; Lee, Taek S

2018-04-01

Escherichia coli has been the organism of choice for the production of different chemicals by engineering native and heterologous pathways. In the present study, we simultaneously address some of the main issues associated with E. coli as an industrial platform for isoprenoids, including an inability to grow on sucrose, a lack of endogenous control over toxic mevalonate (MVA) pathway intermediates, and the limited pathway engineering into the chromosome. As a proof of concept, we generated an E. coli DH1 strain able to produce the isoprenoid bisabolene from sucrose by integrating the cscAKB operon into the chromosome and by expressing a heterologous MVA pathway under stress-responsive control. Production levels dropped dramatically relative to plasmid-mediated expression when the entire pathway was integrated into the chromosome. In order to optimize the chromosomally integrated MVA pathway, we established a CRISPR-Cas9 system to rapidly and systematically replace promoter sequences. This strategy led to higher pathway expression and a fivefold improvement in bisabolene production. More interestingly, we analyzed proteomics data sets to understand and address some of the challenges associated with metabolic engineering of the chromosomally integrated pathway. This report shows that integrating plasmid-optimized operons into the genome and making them work optimally is not a straightforward task and any poor engineering choices on the chromosome may lead to cell death rather than just resulting in low titers. Based on these results, we also propose directions for chromosomal metabolic engineering. © 2017 Wiley Periodicals, Inc.

Allocate carbon for a reason: priorities are reflected in the ¹³C/¹²C ratios of plant lipids synthesized via three independent biosynthetic pathways.

PubMed

Zhou, Youping; Stuart-Williams, Hilary; Grice, Kliti; Kayler, Zachary E; Zavadlav, Saša; Vogts, Angela; Rommerskirchen, Florian; Farquhar, Graham D; Gessler, Arthur

2015-03-01

It has long been theorized that carbon allocation, in addition to the carbon source and to kinetic isotopic effects associated with a particular lipid biosynthetic pathway, plays an important role in shaping the carbon isotopic composition ((13)C/(12)C) of lipids (Park and Epstein, 1961). If the latter two factors are properly constrained, valuable information about carbon allocation during lipid biosynthesis can be obtained from carbon isotope measurements. Published work of Chikaraishi et al. (2004) showed that leaf lipids isotopic shifts from bulk leaf tissue Δδ(13)C(bk-lp) (defined as δ(13)C(bulkleaftissue)-δ(13)C(lipid)) are pathway dependent: the acetogenic (ACT) pathway synthesizing fatty lipids has the largest isotopic shift, the mevalonic acid (MVA) pathway synthesizing sterols the lowest and the phytol synthesizing 1-deoxy-D-xylulose 5-phosphate (DXP) pathway gives intermediate values. The differences in Δδ(13)C(bk-lp) between C3 and C4 plants Δδ(13)C(bk-lp,C4-C3) are also pathway-dependent: Δδ(13)C(ACT)(bk-lp,C4-C3) > Δδ(13)C(DXP(bk-lp,C4-C3) > Δδ(13)C(MVA)(bk-lp,C4-C3). These pathway-dependent differences have been interpreted as resulting from kinetic isotopic effect differences of key but unspecified biochemical reactions involved in lipids biosynthesis between C3 and C4 plants. After quantitatively considering isotopic shifts caused by (dark) respiration, export-of-carbon (to sink tissues) and photorespiration, we propose that the pathway-specific differences Δδ(13)C(bk-lp,C4-C3) can be successfully explained by C4-C3 carbon allocation (flux) differences with greatest flux into the ACT pathway and lowest into the MVA pathways (when flux is higher, isotopic shift relative to source is smaller). Highest carbon allocation to the ACT pathway appears to be tied to the most stringent role of water-loss-minimization by leaf waxes (composed mainly of fatty lipids) while the lowest carbon allocation to the MVA pathway can be largely explained by the fact that sterols act as regulatory hormones and membrane fluidity modulators in rather low concentrations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Monocytes Phenotype and Cytokine Production in Human Immunodeficiency Virus-1 Infected Patients Receiving a Modified Vaccinia Ankara-Based HIV-1 Vaccine: Relationship to CD300 Molecules Expression.

PubMed

Vitallé, Joana; Zenarruzabeitia, Olatz; Terrén, Iñigo; Plana, Montserrat; Guardo, Alberto C; Leal, Lorna; Peña, José; García, Felipe; Borrego, Francisco

2017-01-01

A modified vaccinia Ankara-based HIV-1 vaccine clade B (MVA-B) has been tested for safety and immunogenicity in low-risk human immunodeficiency virus (HIV)-uninfected individuals and as a therapeutic vaccine in HIV-1-infected individuals on combined antiretroviral therapy (cART). As a therapeutic vaccine, MVA-B was safe and broadly immunogenic; however, patients still showed a viral rebound upon treatment interruption. Monocytes are an important part of the viral reservoir and several studies suggest that they are partly responsible for the chronic inflammation observed in cART-treated HIV-infected people. The CD300 family of receptors has an important role in several diseases, including viral infections. Monocytes express CD300a, c, e, and f molecules and lipopolysaccharide (LPS) and other stimuli regulate their expression. However, the expression and function of CD300 receptors on monocytes in HIV infection is still unknown. In this work, we investigated for the first time the expression of CD300 molecules and the cytokine production in response to LPS on monocytes from HIV-1-infected patients before and after vaccination with MVA-B. Our results showed that CD300 receptors expression on monocytes from HIV-1-infected patients correlates with markers of HIV infection progression and immune inflammation. Specifically, we observed a positive correlation between the expression of CD300e and CD300f receptors on monocytes with the number of CD4+ T cells of HIV-1-infected patients before vaccination. We also saw a positive correlation between the expression of the inhibitory receptor CD300f and the expression of CD163 on monocytes from HIV-1-infected individuals before and after vaccination. In addition, monocytes exhibited a higher cytokine production in response to LPS after vaccination, almost at the same levels of monocytes from healthy donors. Furthermore, we also described a correlation in the expression of CD300e and CD300f receptors with TNF-α production in response to LPS, only in monocytes of HIV-1-infected patients before vaccination. Altogether, our results describe the impact of HIV-1 and of the MVA-B vaccine in cytokine production and monocytes phenotype.

Second Malignancies After Adjuvant Radiation Therapy for Early Stage Breast Cancer: Is There Increased Risk With Addition of Regional Radiation to Local Radiation?

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

Hamilton, Sarah Nicole; Department of Radiation Oncology, British Columbia Cancer Agency-Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott, E-mail: styldesl@bccancer.bc.ca

2015-04-01

Purpose: This study was undertaken to determine whether there was an increased risk of second malignancies (SM), particularly lung cancer, in early stage breast cancer patients treated with the addition of nodal fields to breast and/or chest wall radiation therapy (RT). Materials and Methods: Subjects were stage I/II female breast cancer patients 20 to 79 years of age, diagnosed between 1989 and 2005 and treated with adjuvant RT at our institution. Patients were included if they survived and did not have SM within 3 years of diagnosis. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to compare SM incidencemore » to cancer incidence in the general sex- and age-matched populations. Secondary malignancy risks in patients treated with local RT (LRT) to the breast/chest wall were compared to those in patients treated with locoregional RT (LRRT) to the breast/chest wall and regional nodes, using multivariate regression analysis (MVA) to account for covariates. Results: The cohort included 12,836 patients with a median follow-up of 8.4 years. LRRT was used in 18% of patients. The SIR comparing patients treated with LRT to the general population was 1.29 (CI: 1.21-1.38). No statistically significant increased incidence of in-field malignancies (SIR, 1.04; CI: 0.87-1.23) and lung cancers (SIR, 1.06; CI: 0.88-1.26) was detected. The SIR comparing patients treated with LRRT to the general population was 1.39 (CI: 1.17-1.64). No statistically significant increased incidence of in-field malignancies (SIR, 1.26; CI: 0.77-1.94) and lung cancers (SIR, 1.27; CI: 0.76-1.98) was detected. On MVA comparing LRRT to LRT, the adjusted hazard ratio was 1.20 for in-field malignancies (CI: 0.68-2.16) and 1.26 for lung cancer (CI: 0.67-2.36). The excess attributable risk (EAR) to regional RT was 3.1 per 10,000 person years (CI: −8.7 to 9.9). Conclusions: No statistically significant increased risk of second malignancy was detected after LRRT relative to that for LRT. The upper limit of the EAR was approximately 1% at 10 years.« less

The Decoding Toolbox (TDT): a versatile software package for multivariate analyses of functional imaging data

PubMed Central

Hebart, Martin N.; Görgen, Kai; Haynes, John-Dylan

2015-01-01

The multivariate analysis of brain signals has recently sparked a great amount of interest, yet accessible and versatile tools to carry out decoding analyses are scarce. Here we introduce The Decoding Toolbox (TDT) which represents a user-friendly, powerful and flexible package for multivariate analysis of functional brain imaging data. TDT is written in Matlab and equipped with an interface to the widely used brain data analysis package SPM. The toolbox allows running fast whole-brain analyses, region-of-interest analyses and searchlight analyses, using machine learning classifiers, pattern correlation analysis, or representational similarity analysis. It offers automatic creation and visualization of diverse cross-validation schemes, feature scaling, nested parameter selection, a variety of feature selection methods, multiclass capabilities, and pattern reconstruction from classifier weights. While basic users can implement a generic analysis in one line of code, advanced users can extend the toolbox to their needs or exploit the structure to combine it with external high-performance classification toolboxes. The toolbox comes with an example data set which can be used to try out the various analysis methods. Taken together, TDT offers a promising option for researchers who want to employ multivariate analyses of brain activity patterns. PMID:25610393

Multivariate Models for Normal and Binary Responses in Intervention Studies

ERIC Educational Resources Information Center

Pituch, Keenan A.; Whittaker, Tiffany A.; Chang, Wanchen

2016-01-01

Use of multivariate analysis (e.g., multivariate analysis of variance) is common when normally distributed outcomes are collected in intervention research. However, when mixed responses--a set of normal and binary outcomes--are collected, standard multivariate analyses are no longer suitable. While mixed responses are often obtained in…

Differential Velocity between Solar Wind Protons and Alpha Particles in Pressure Balance Structures

NASA Technical Reports Server (NTRS)

Yamauchi, Yohei; Suess, Steven T.; Steinberg, John T.; Sakurai, Takashi

2004-01-01

Pressure balance structures (PBSs) are a common high-plasma beta feature in high-latitude, high-speed solar wind. They have been proposed as remnants of coronal plumes. If true, they should reflect the observation that plumes are rooted in unipolar magnetic flux concentrations in the photosphere and are heated as oppositely directed flux is advected into and reconnects with the flux concentration. A minimum variance analysis (MVA) of magnetic discontinuities in PBSs showed there is a larger proportion of tangential discontinuities than in the surrounding high-speed wind, supporting the hypothesis that plasmoids or extended current sheets are formed during reconnection at the base of plumes. To further evaluate the character of magnetic field discontinuities in PBSs, differential streaming between alpha particles and protons is analyzed here for the same sample of PBSs used in the MVA. Alpha particles in high-speed wind generally have a higher radial flow speed than protons. However, if the magnetic field is folded back on itself, as in a large-amplitude Alfven wave, alpha particles will locally have a radial flow speed less than protons. This characteristic is used here to distinguish between folded back magnetic fields (which would contain rotational discontinuities) and tangential discontinuities using Ulysses high-latitude, high-speed solar wind data. The analysis indicates that almost all reversals in the radial magnetic field in PBSs are folded back field lines. This is found to also be true outside PBSs, supporting existing results for typical high-speed, high-latitude wind. There remains a small number of cases that appear not to be folds in the magnetic field and which may be flux tubes with both ends rooted in the Sun. The distinct difference in MVA results inside and outside PBSs remains unexplained.

Differential Velocity Between Solar Wind Protons and Alpha Particles in Pressure Balance Structures

NASA Technical Reports Server (NTRS)

Yamauchi, Y.; Suess, S. T.; Steinberg, J. T.; Sakurai, T.

2003-01-01

Pressure balance structures (PBSs) are a common high plasma beta feature in high latitude, high speed solar wind. They have been proposed as remnants of coronal plumes. If true, they should reflect the observation that plumes are rooted in unipolar magnetic flux concentrations in the photosphere and are heated as oppositely directed flux is advected into and reconnects with the flux concentration. A minimum variance analysis (MVA) of magnetic discontinuities in PBSs showed there is a larger proportion of tangential discontinuities than in the surrounding high speed wind, supporting the hypothesis that plasmoids or extended current sheets are formed during reconnection at the base of plumes. To further evaluate the character of magnetic field discontinuities in PBSs, differential streaming between alpha particles and protons is analyzed here for the same sample of PBSs used in the MVA. Alpha particles in high speed wind generally have a higher radial flow speed than protons. However, if the magnetic field is folded back on itself, as in a large amplitude Alfven wave, alpha particles will locally have a radial flow speed less than protons. This characteristic is used here to distinguish between folded back magnetic fields (which would contain rotational discontinuities) and tangential discontinuities using Ulysses high latitude, high speed solar wind data. The analysis indicates that almost all reversals in the radial magnetic field in PBSs are folded back field lines. This is found to also be true outside PBSs, supporting existing results for typical high speed, high latitude wind. There remains a small number of cases that appear not to be folds in the magnetic field and which may be flux tubes with both ends rooted in the Sun. The distinct difference in MVA results inside and outside PBSs remains unexplained.

Gender and age interact to predict the development of posttraumatic stress disorder symptoms following a motor vehicle accident.

PubMed

Kobayashi, Ihori; Sledjeski, Eve M; Delahanty, Douglas L

2018-02-15

Women have a greater overall risk of developing posttraumatic stress disorder (PTSD) than men after exposure to trauma. In addition to gender, other sociodemographic factors have been identified as risk factors for PTSD; however, research has typically examined these factors separately. Age has been found to contribute to the development of psychiatric disorders, and both linear and curvilinear relationships have been reported between age and risk of developing PTSD. Recent research has suggested that this relationship may vary depending on gender. We performed a secondary analysis of data from a prospective study of 287 (164 men, 123 women) motor vehicle accident (MVA) patients (aged 18-81) who completed clinical interviews 6 weeks, 6 months, and/or 1 year after an MVA. Overall, women developed more severe PTSD symptoms than men; however, gender differences were small in the young (18-24 years) and the old (55 and older) groups. In women, age was not associated with PTSD symptoms at 6 weeks and 6 months; however, age was curvilinearly associated with PTSD severity at 1-year post-MVA such that middle-aged women reported greater symptom severity than younger and older women. Prior trauma exposure and social support mediated this relationship. In men, PTSD severity was not associated with age, but was related to income and social support. These findings highlight age-based subgroups of women at elevated risk for PTSD following a traumatic injury and suggest that psychosocial intervention with middle-aged women following trauma exposure may help reduce the risk of persistent PTSD symptoms. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Specificity and 6-Month Durability of Immune Responses Induced by DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-Like Particles

PubMed Central

Goepfert, Paul A.; Elizaga, Marnie L.; Seaton, Kelly; Tomaras, Georgia D.; Montefiori, David C.; Sato, Alicia; Hural, John; DeRosa, Stephen C.; Kalams, Spyros A.; McElrath, M. Juliana; Keefer, Michael C.; Baden, Lindsey R.; Lama, Javier R.; Sanchez, Jorge; Mulligan, Mark J.; Buchbinder, Susan P.; Hammer, Scott M.; Koblin, Beryl A.; Pensiero, Michael; Butler, Chris; Moss, Bernard; Robinson, Harriet L.; Donastorg, Yeycy; Qin, Li; Lawrence, Dale; Cardinali, Massimo; Bae, Jin; Holt, Renée; Redinger, Huguette; Johannessen, Jan; Broder, Gail; Moody-White, Jerri; McKay, Butch; Calazans, Gabriela; Bentley, Carter; Kakinami, Lisa; Skibinski, Katie; Estep, Scharla; Tseng, Jenny; Swenson, Molly; Madenwald, Tamra; Overton, Edgar Turner; Edupuganti, Srilatha; Rouphael, Nadine; Whitaker, Jennifer; Hay, C Mhorag; Bunce, Catherine A; Gonzales, Pedro; Hurtado, Juan Carlos; Dolin, Raphael; Mayer, Ken; Walsh, Steven; Johnson, Jennifer

2014-01-01

Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)–uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections. Results. At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4+ T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8+ T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4+ and CD8+ T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. Conclusions. DDMM and MMM vaccinations with virus-like particle–expressing immunogens elicited durable antibody and T-cell responses. PMID:24403557

Computerized whole slide quantification shows increased microvascular density in pT2 prostate cancer as compared to normal prostate tissue.

PubMed

van Niekerk, Cornelis G; van der Laak, Jeroen A W M; Börger, M Elisa; Huisman, Henk-Jan; Witjes, J Alfred; Barentsz, Jelle O; Hulsbergen-van de Kaa, Christina A

2009-01-01

Contrast enhanced imaging enables powerful, non-invasive diagnostics, important for detection and staging of early prostate cancer. The uptake of contrast agent is increased in prostate cancer as compared to normal prostate tissue. To reveal the underlying physiological mechanisms, quantification of tissue components in pathology specimens may yield important information. Aim of this study was to investigate whether microvascularity is increased in prostate confined cancer (pT2). Radical prostatectomy specimens of 26 patients were selected for organ confined peripheral zone tumors which were restricted to one side of the prostate. Microvessels were visualized by immunohistochemistry against CD31. Specimens were scanned using a computer controlled microscope and scanning stage and vessels were recognized automatically. Pseudocolor mappings were produced showing number of vascular profiles (MVD), vascular area (MVA) and perimeter (MVP) in an overview of the entire prostate transection. MVD is a common measure for vascularity, whereas MVA represents the 3D vascular volume and MVP the perfused surface area. Mean, coefficient of variation and 75th percentile of these parameters were calculated automatically in manually indicated areas, consisting of the entire tumor area and the corresponding normal area in the contra lateral side of the prostate. The mappings clearly indicate areas of increased vascularity in prostate transections. In tumor tissue an increase was found compared to normal tissue of 81%, 49%, and 62% for mean MVD, mean MVA and mean MVP, respectively (P < 0.001 for all comparisons). In contrast, the heterogeneity in tumor vasculature was significantly decreased as compared to normal prostate (P < 0.001). Characteristics of microvasculature deviated significantly in pT2 prostate tumor as compared to normal tissue. Copyright 2008 Wiley-Liss, Inc.

A retrospective study of oral and maxillofacial injuries in Seremban Hospital, Malaysia.

PubMed

Ramli, Roszalina; Rahman, Normastura Abdul; Rahman, Roslan Abdul; Hussaini, Haizal Mohd; Hamid, Abdul Latif Abdul

2011-04-01

Aetiology of oral and maxillofacial injuries in this country includes motorvehicle accident (MVA), fall, industrial accidents and others. Among these causes, MVA accident is the predominant cause of injury in Malaysia. A retrospective record review was carried out using hospital records of all patients who sustained oral and maxillofacial injury at the Department of Oral Surgery, Seremban Hospital, Negeri Sembilan, Malaysia between 1998 and 2002. Information related to demographics, aetiology of trauma, vehicles involved in collision, location of injuries and treatment modalities were reviewed. Two thousand nine hundred and eighty-six patients sustained oral and maxillofacial injuries. Of these patients, 79.2% were men and the remaining were women. Among all the races, Malays had the highest involvement (50.6%) followed by Indians (24.5%), Chinese (19.6%) and others (5.3%). There were statistically significant results on the association of aetiology and the ethnic groups, in the age group of 30 years or less and male gender (P < 0.001). The most common injury was the soft-tissue injury followed by dental and dentoalveolar injuries and bony fracture. Among all facial fractures, 66.3% were managed conservatively, 13% were treated surgically and 19.7% did not have any intervention. In relation to dental and dentoalveolar injuries, 64.8% had treatment in the form of splinting, restorations or dental extraction. The rest of the patients (35.2%) were referred to their dentists or did not have any active treatment at Seremban Hospital. Most of the dental and facial injuries in Seremban Hospital were caused by MVA and were predominantly managed using conservative methods. © 2011 John Wiley & Sons A/S.

Baclofen dosage after traumatic spinal cord injury: a multi-decade retrospective analysis.

PubMed

Veerakumar, Ashan; Cheng, Jennifer J; Sunshine, Abraham; Ye, Xiaobu; Zorowitz, Richard D; Anderson, William S

2015-02-01

To perform an analysis of oral baclofen dosage in patients with traumatic spinal cord injuries over time and to ascertain the clinical determinants of long-term baclofen dosage trends. Retrospective cohort study of patient records from the PM&R units at the Johns Hopkins Bayview Medical Center and the Johns Hopkins Hospital. A total of 115 PM&R patients suffering spinal cord injury due to trauma leading to either complete or incomplete paralysis. The modes of injury included were motor vehicle accidents (MVA) (n=39), gunshot wounds (GSW) (n=55), falls (n=17), diving (n=2), workplace (n=1) and swimming (n=1) accidents. The location of injury in the spinal cord was categorized into either cervical (n=52), thoracic (n=59), lumbar (n=2), or unspecified (n=2). From time of injury, an aggregate of all dosage assignments for each patient demonstrated a significant yearly increase in baclofen dosage (1.26 mg/year, p<0.01). Baclofen dosage for MVA cases were seen to rise at 4.99 mg/year (p<0.0001). Kaplan-Meier analysis revealed that GSW patients received their first baclofen dosage earlier than MVA patients (log-rank p<0.05, unadjusted). We observed a marginal increase in baclofen dosage over nearly 25 years in a single provider's patient database and observed different timings of first dose between two causes of traumatic SCI. These results provide an estimate of baclofen dosage trends over time after spinal cord injury and may be useful for patient counseling or as a method to assess costs of providing SCI patient care. Copyright © 2014 Elsevier B.V. All rights reserved.

Proteomic Analysis of Lettuce Seed Germination and Thermoinhibition by Sampling of Individual Seeds at Germination and Removal of Storage Proteins by Polyethylene Glycol Fractionation1

PubMed Central

Song, Bin-Yan; Deng, Zhi-Jun; Wang, Yue; Liu, Shu-Jun; Møller, Ian Max; Song, Song-Quan

2015-01-01

Germination and thermoinhibition in lettuce (Lactuca sativa ‘Jianyexianfeng No. 1’) seeds were investigated by a proteomic comparison among dry seeds, germinated seeds at 15°C, at 15°C after imbibition at 25°C for 48 h, or at 25°C in KNO3 (all sampled individually at germination), and ungerminated seeds at 25°C, a thermoinhibitory temperature. Before two-dimensional gel electrophoresis analysis, storage proteins (greater than 50% of total extractable protein) were removed by polyethylene glycol precipitation, which significantly improved the detection of less abundant proteins on two-dimensional gels. A total of 108 protein spots were identified to change more than 2-fold (P < 0.05) in abundance in at least one germination treatment. Nineteen proteins increasing and one protein decreasing in abundance during germination had higher abundance in germinated 15°C, 15°C after imbibition at 25°C for 48 h, and 25°C in KNO3 seeds than in ungerminated 25°C seeds. Gene expression of 12 of those proteins correlated well with the protein accumulation. Methionine metabolism, ethylene production, lipid mobilization, cell elongation, and detoxification of aldehydes were revealed to be potentially related to lettuce seed germination and thermoinhibition. Accumulation of three proteins and expression of five genes participating in the mevalonate (MVA) pathway of isoprenoid biosynthesis correlated positively with seed germinability. Inhibition of this pathway by lovastatin delayed seed germination and increased the sensitivity of germination to abscisic acid. MVA pathway-derived products, cytokinins, partially reversed the lovastatin inhibition of germination and released seed thermoinhibition at 25°C. We conclude that the MVA pathway for isoprenoid biosynthesis is involved in lettuce seed germination and thermoinhibition. PMID:25736209

Impact of preprocedural atrial fibrillation on immediate and long-term outcomes after successful percutaneous mitral valvuloplasty of significant mitral stenosis.

PubMed

Miura, Shiro; Arita, Takeshi; Domei, Takenori; Yamaji, Kyohei; Soga, Yoshimitsu; Hyodo, Makoto; Shirai, Shinichi; Ando, Kenji

2018-01-01

Optimal time to perform percutaneous mitral valvuloplasty (PMV) for patients with significant mitral stenosis (MS) and atrial fibrillation (AF) remains controversial. We sought to identify prognostic factors and evaluate long-term clinical outcomes after PMV of 77 consecutive patients with MS with a mitral valve area (MVA) <1.5 cm 2 . According to baseline heart rhythm, these patients were divided into sinus rhythm (SR; n = 24) and AF (n = 53) groups. The study endpoint was defined as a composite of all-cause mortality, admission for heart failure, mitral valve surgery, repeated PMV, and major cerebral vascular accident during follow-up. After successful PMV, there was no significant difference between the two groups in post-MVA and post-mitral mean pressure gradient. However, the New York Heart Association Functional Classification post-procedure was worse in the AF group (p < 0.01). In the AF group, event-free survival during follow-up was significantly lower compared with that of the SR group (p = 0.016). Independent predictors of clinical events were AF [hazard ratio (HR), 2.73; 95 % confidence interval (CI), 1.04-9.36; p = 0.03] and pulmonary artery systolic pressure (HR 2.57; 95 % CI 1.18-5.47; p = 0.017). Patients with AF at baseline were significantly associated with worse symptoms and higher event rates after successful PMV compared with those with SR. The clinical benefit of PMV may be considered for patients with MVA <1.5 cm 2 before the onset of AF.

Predictors of Very Late Events After Percutaneous Mitral Valvuloplasty in Patients With Mitral Stenosis.

PubMed

Jorge, Elisabete; Pan, Manuel; Baptista, Rui; Romero, Miguel; Ojeda, Soledad; Suárez de Lezo, Javier; Faria, Henrique; Calisto, João; Monteiro, Pedro; Pêgo, Mariano; Suárez de Lezo, José

2016-06-15

Data on long-term outcomes of percutaneous mitral valvuloplasty (PMV) are still scarce. In addition, the persistence of pulmonary hypertension (PH) after PMV is a complication for which mechanisms and prognostic implications are unclear. Our aims were (1) to report the long-term outcomes of patients with rheumatic mitral stenosis treated with PMV; (2) to determine the risk factors for long-term poor outcomes; and (3) to analyze the prevalence and predictors of persistent PH. We prospectively enrolled 532 patients who underwent PMV from 1987 to 2011 at 2 hospitals. The following end points were assessed after PMV: all-cause mortality, mitral reintervention, a composite end point of all-cause mortality and mitral reintervention, and PH persistence. Survival status was available for 97% patients; the median follow-up was 10 years (interquartile range 4 to 18 years). Procedural success was achieved in 85% patients. During the follow-up, 21% patients died and 27% required mitral reintervention. Before PMV, 74% patients had PH that persisted after PMV in 45% of patients (p <0.001). Unfavorable valve anatomy (Wilkins score >8) and post-PMV mean pulmonary arterial pressure (PAP) were independent predictors of all-cause mortality, mitral reintervention, and the composite end point. Post-PMV mean PAP was significantly correlated with a mitral valve area (MVA) <2.5 cm(2) (p <0.001); in addition, on the echocardiographic follow-up, MVA was an independent predictor of systolic PAP (p <0.001). In conclusion, PMV represents an advantageous therapeutic option for patients with mitral stenosis in terms of long-term outcomes. Unfavorable valve anatomy and persistent PH were the most important predictors of long-term outcomes. The persistence of PH is associated with the MVA obtained after PMV. Copyright © 2016 Elsevier Inc. All rights reserved.

Percutaneous transvenous mitral commissurotomy in juvenile mitral stenosis.

PubMed

Adhikari, Chandra Mani; Malla, Rabi; Rajbhandari, Rajib; Shakya, Urmila; Sharma, Poonam; Shrestha, Nagma; Kc, Bishal; Limbu, Deepak; Kc, Man Bahadur

2016-02-01

Percutaneous transvenous mitral commissurotomy (PTMC) is a valid alternative to surgical therapy in selected patients with mitral stenosis. Juvenile mitral stenosis (JMS) varies uniquely from adult rheumatic heart disease (RHD). We aimed to evaluate the efficacy of PTMC in JMS patients. It was a single centre, retrospective study conducted between July 2013 to June 2015 in Shahid Gangalal National Heart Centre, Kathmandu, Nepal. Medical records of all consecutive patients aged less than 21 years who underwent PTMC were included. Mitral valve area (MVA), left atrial pressure and mitral regurgitation (MR) were compared pre and post procedure. During the study period 131 JMS patients underwent PTMC. Seventy (53.4%) were female and 61 (46.6%) were male. Among the 131 patients, 40 (30.5%) patients were below the age of 15 years. Patient age ranged between 9 to 20 years with the mean of 16.3±2.9 years. Electrocardiography (ECG) findings were normal sinus rhythm in 115 (87.7%) patients and atrial fibrillation in 16 (12.3%) patients. Left atrial size ranged from 2.9 to 6.1 cm with the mean of 4.5±0.6 cm. The mean MVA increased from 0.8±0.1 cm(2) to 1.6±0.2 following PTMC. Mean left atrial pressure decreased from their pre-PTMC state of 27.5±8.6 to 14.1±5.8 mmHg. Successful results were observed in 115 (87.7%) patients. Suboptimal MVA <1.5 cm(2) in 11 (8.4%) patients and post-procedure MR of more than moderate MR in 5 (3.8%) patients was the reason for unsuccessful PTMC. PTMC in JMS is safe and effective.

Virus-Induced Silencing of Key Genes Leads to Differential Impact on Withanolide Biosynthesis in the Medicinal Plant, Withania somnifera.

PubMed

Agarwal, Aditya Vikram; Singh, Deeksha; Dhar, Yogeshwar Vikram; Michael, Rahul; Gupta, Parul; Chandra, Deepak; Trivedi, Prabodh Kumar

2018-02-01

Withanolides are a collection of naturally occurring, pharmacologically active, secondary metabolites synthesized in the medicinally important plant, Withania somnifera. These bioactive molecules are C28-steroidal lactone triterpenoids and their synthesis is proposed to take place via the mevalonate (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways through the sterol pathway using 24-methylene cholesterol as substrate flux. Although the phytochemical profiles as well as pharmaceutical activities of Withania extracts have been well studied, limited genomic information and difficult genetic transformation have been a major bottleneck towards understanding the participation of specific genes in withanolide biosynthesis. In this study, we used the Tobacco rattle virus (TRV)-mediated virus-induced gene silencing (VIGS) approach to study the participation of key genes from MVA, MEP and triterpenoid biosynthesis for their involvement in withanolide biosynthesis. TRV-infected W. somnifera plants displayed unique phenotypic characteristics and differential accumulation of total Chl as well as carotenoid content for each silenced gene suggesting a reduction in overall isoprenoid synthesis. Comprehensive expression analysis of putative genes of withanolide biosynthesis revealed transcriptional modulations conferring the presence of complex regulatory mechanisms leading to withanolide biosynthesis. In addition, silencing of genes exhibited modulated total and specific withanolide accumulation at different levels as compared with control plants. Comparative analysis also suggests a major role for the MVA pathway as compared with the MEP pathway in providing substrate flux for withanolide biosynthesis. These results demonstrate that transcriptional regulation of selected Withania genes of the triterpenoid biosynthetic pathway critically affects withanolide biosynthesis, providing new horizons to explore this process further, in planta.

Isolated Transverse Process Fractures and Markers of Associated Injuries: The Experience at University of California, Los Angeles.

PubMed

Bui, Timothy T; Nagasawa, Daniel T; Lagman, Carlito; Jacky Chen, Cheng Hao; Chung, Lawrance K; Voth, Brittany L; Beckett, Joel S; Tucker, Alexander M; Niu, Tianyi; Gaonkar, Bilwaj; Yang, Isaac; Macyszyn, Luke

2017-08-01

To report a single-institution experience with isolated transverse process fractures (ITPFs) and provide increasing support for the development of evidence-based guidelines. The authors also evaluated the presence of concerning symptoms or red flags that may indicate additional, underlying injuries in the setting of ITPFs. The Ronald Reagan UCLA Medical Center patient database was queried (years 2005-2016) using International Classification of Diseases, Ninth Revision, code 805: fracture of the vertebral column without mention of spinal cord injury. A total of 129 patients with ITPFs were identified. Mean age was 38.1 years (range 15-92 years). Women were more likely to present with abdominal pain and associated kidney injury (P = 0.018 and P = 0.012, respectively). Motor vehicle accident (MVA) was the most common mechanism of injury (n = 81, 62.8%) and was associated with thoracic (P = 0.032) and lower extremity pain/injury (P = 0.005). Back pain was the most common presenting symptom (n = 71, 64.6%) and was associated with intraabdominal and lower extremity injuries (P = 0.032 and P = 0.016, respectively). Chest and neck pain were associated with vascular injuries (P < 0.001 and P = 0.001, respectively). Spine consult (neurosurgery or orthopedic surgery) was frequent (n = 94, 72.9%) and was more common after MVA versus fall (P = 0.018). Several factors were identified as significant markers of associated injuries, including female sex, MVA, and presenting symptoms. Neck and chest pain were significantly associated with vascular injuries. Clinicians should maintain high indices of suspicion for associated injuries in patients with ITPFs, especially after high-velocity mechanisms. Copyright © 2017. Published by Elsevier Inc.

Predictors of Hypopituitarism in Patients with Traumatic Brain Injury.

PubMed

Silva, Paula P B; Bhatnagar, Saurabha; Herman, Seth D; Zafonte, Ross; Klibanski, Anne; Miller, Karen K; Tritos, Nicholas A

2015-11-15

Hypopituitarism may often occur in association with traumatic brain injury (TBI). Identification of reliable predictors of pituitary dysfunction is of importance in order to establish a rational testing approach. We searched the records of patients with TBI, who underwent neuroendocrine evaluation in our institution between 2007 and 2013. One hundred sixty-six adults (70% men) with TBI (median age: 41.6 years; range: 18-76) were evaluated at a median interval of 40.4 months (0.2-430.4).Of these, 31% had ≥1 pituitary deficiency, including 29% of patients with mild TBI and 35% with moderate/severe TBI. Growth hormone deficiency was the most common deficiency (21%); when body mass index (BMI)-dependent cutpoints were used, this was reduced to 15%. Central hypoadrenalism occurred in10%, who were more likely to have suffered a motor vehicle accident (MVA, p = 0.04), experienced post-traumatic seizures (p = 0.04), demonstrated any intracranial hemorrhage (p = 0.05), petechial brain hemorrhages (p = 0.017), or focal cortical parenchymal contusions (p = 0.02). Central hypothyroidism occurred in 8% and central hypogonadism in 12%; the latter subgroup had higher BMI (p = 0.03), were less likely to be working after TBI (p = 0.002), and had lower Global Assessment of Functioning (GAF) scores (p = 0.03). Central diabetes insipidus (DI) occurred in 6%, who were more likely to have experienced MVA (p < 0.001) or sustained moderate/severe TBI (p < 0.001). Patients with MVA and those with post-traumatic seizures, intracranial hemorrhage, petechial brain hemorrhages, and/or focal cortical contusions are at particular risk for serious pituitary dysfunction, including adrenal insufficiency and DI, and should be referred for neuroendocrine testing. However, a substantial proportion of patients without these risk factors also developed hypopituitarism.

A genomics resource for investigating regulation of essential oil production in Lavandula angustifolia.

PubMed

Lane, Alexander; Boecklemann, Astrid; Woronuk, Grant N; Sarker, Lukman; Mahmoud, Soheil S

2010-03-01

We are developing Lavandula angustifolia (lavender) as a model system for investigating molecular regulation of essential oil (a mixture of mono- and sesquiterpenes) production in plants. As an initial step toward building the necessary 'genomics toolbox' for this species, we constructed two cDNA libraries from lavender leaves and flowers, and obtained sequence information for 14,213 high-quality expressed sequence tags (ESTs). Based on homology to sequences present in GenBank, our EST collection contains orthologs for genes involved in the 1-deoxy-D: -xylulose-5-phosphate (DXP) and the mevalonic acid (MVA) pathways of terpenoid biosynthesis, and for known terpene synthases and prenyl transferases. To gain insight into the regulation of terpene metabolism in lavender flowers, we evaluated the transcriptional activity of the genes encoding for 1-deoxy-D: -xylulose-5-phosphate synthase (DXS) and HMG-CoA reductase (HMGR), which represent regulatory steps of the DXP and MVA pathways, respectively, in glandular trichomes (oil glands) by real-time PCR. While HMGR transcripts were barely detectable, DXS was heavily expressed in this tissue, indicating that essential oil constituents are predominantly produced through the DXP pathway in lavender glandular trichomes. As anticipated, the linalool synthase (LinS)-the gene responsible for the production of linalool, a major constituent of lavender essential oil-was also strongly expressed in glands. Surprisingly, the most abundant transcript in floral glandular trichomes corresponded to a sesquiterpene synthase (cadinene synthase, CadS), although sesquiterpenes are minor constituents of lavender essential oils. This result, coupled to the weak activity of the MVA pathway (the main route for sesquiterpene production) in trichomes, indicates that precursor supply may represent a bottleneck in the biosynthesis of sesquiterpenes in lavender flowers.

Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost.

PubMed

Ake, Julie A; Schuetz, Alexandra; Pegu, Poonam; Wieczorek, Lindsay; Eller, Michael A; Kibuuka, Hannah; Sawe, Fredrick; Maboko, Leonard; Polonis, Victoria; Karasavva, Nicos; Weiner, David; Sekiziyivu, Arthur; Kosgei, Josphat; Missanga, Marco; Kroidl, Arne; Mann, Philipp; Ratto-Kim, Silvia; Anne Eller, Leigh; Earl, Patricia; Moss, Bernard; Dorsey-Spitz, Julie; Milazzo, Mark; Laissa Ouedraogo, G; Rizvi, Farrukh; Yan, Jian; Khan, Amir S; Peel, Sheila; Sardesai, Niranjan Y; Michael, Nelson L; Ngauy, Viseth; Marovich, Mary; Robb, Merlin L

2017-11-27

We report the first-in-human safety and immunogenicity evaluation of PENNVAX-G DNA/modified vaccinia Ankara-Chiang Mai double recombinant (MVA-CMDR) prime-boost human immuonodeficiency virus (HIV) vaccine, with intramuscular DNA delivery by either Biojector 2000 needle-free injection system (Biojector) or CELLECTRA electroporation device. Healthy, HIV-uninfected adults were randomized to receive 4 mg of PENNVAX-G DNA delivered intramuscularly by Biojector or electroporation at baseline and week 4 followed by intramuscular injection of 108 plaque forming units of MVA-CMDR at weeks 12 and 24. The open-label part A was conducted in the United States, followed by a double-blind, placebo-controlled part B in East Africa. Solicited and unsolicited adverse events were recorded, and immune responses were measured. Eighty-eight of 100 enrolled participants completed all study injections, which were generally safe and well tolerated, with more immediate, but transient, pain in the electroporation group. Cellular responses were observed in 57% of vaccine recipients tested and were CD4 predominant. High rates of binding antibody responses to CRF01_AE antigens, including gp70 V1V2 scaffold, were observed. Neutralizing antibodies were detected in a peripheral blood mononuclear cell assay, and moderate antibody-dependent, cell-mediated cytotoxicity activity was demonstrated. The PVG/MVA-CMDR HIV-1 vaccine regimen is safe and immunogenic. Substantial differences in safety or immunogenicity between modes of DNA delivery were not observed. NCT01260727. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Vaccine Efficacy against Malaria by the Combination of Porcine Parvovirus-Like Particles and Vaccinia Virus Vectors Expressing CS of Plasmodium

PubMed Central

Rodríguez, Dolores; González-Aseguinolaza, Gloria; Rodríguez, Juan R.; Vijayan, Aneesh; Gherardi, Magdalena; Rueda, Paloma; Casal, J. Ignacio; Esteban, Mariano

2012-01-01

With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8+ T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8+ T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria. PMID:22529915

Histomorphometric Analysis of Angiogenesis using CD31 Immunomarker and Mast Cell Density in Oral Premalignant and Malignant Lesions: A Pilot Study.

PubMed

Jyothsna, M; Rammanohar, M; Kumar, Kiran

2017-01-01

Mast cells have been implicated in promoting angiogenesis in malignant tumors of lung, oesophagus and breast, but there are few studies on Oral Squamous Cell Carcinomas (OSCC). Most oral squamous cell carcinomas arise from pre-existing precancerous lesions exhibiting epithelial dysplasia. The present pilot study attempts to compare Mast Cell Density (MCD), Microvessel Density (MVD), Microvessel Area (MVA) histomorphometrically between normal buccal mucosa, severe epithelial dysplasia and OSCC and to correlate the role of mast cells and angiogenesis in tumor progression. The retrospective study was conducted on eight cases of OSCC, eight cases of severe epithelial dysplasia and five cases of normal buccal mucosa. Immunohistochemical staining with anti CD-31, to demonstrate angiogenesis and toluidine blue staining for mast cells were employed. MVA, MVD and MCD were calculated using the measurement tools of the image analysis software and compared between the groups. One way ANOVA (Analysis of Variance) was used for comparing the parameter for multiple groups followed by Games Howell test. To assess the relationship between micro vessel density and mast cell density, Karl Pearson's correlation was used. MCD and MVD increased with disease progression and were statistically higher in OSCC than in severe epithelial dysplasia and normal buccal mucosa (p<0.001). MVA increased from normal to severe dysplasia and decreased from dysplasia to OSCC, may be due to revascularization of tumor tissue. A positive correlation was observed between MCD and MVD in OSCC and dysplasia, though were not statistically significant. These findings suggest that mast cells may up regulate angiogenesis in OSCC. MCD and MVD may be used as indicators for disease progression.

Vaccine efficacy against malaria by the combination of porcine parvovirus-like particles and vaccinia virus vectors expressing CS of Plasmodium.

PubMed

Rodríguez, Dolores; González-Aseguinolaza, Gloria; Rodríguez, Juan R; Vijayan, Aneesh; Gherardi, Magdalena; Rueda, Paloma; Casal, J Ignacio; Esteban, Mariano

2012-01-01

With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8(+) T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8(+) T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria.

Towards a universal vaccine for avian influenza: Protective efficacy of modified Vaccinia virus Ankara and Adenovirus vaccines expressing conserved influenza antigens in chickens challenged with low pathogenic avian influenza virus

PubMed Central

Boyd, Amy C.; Ruiz-Hernandez, Raul; Peroval, Marylene Y.; Carson, Connor; Balkissoon, Devanand; Staines, Karen; Turner, Alison V.; Hill, Adrian V.S.; Gilbert, Sarah C.; Butter, Colin

2013-01-01

Current vaccines targeting surface proteins can drive antigenic variation resulting either in the emergence of more highly pathogenic viruses or of antigenically distinct viruses that escape control by vaccination and thereby persist in the host population. Influenza vaccines typically target the highly mutable surface proteins and do not provide protection against heterologous challenge. Vaccines which induce immune responses against conserved influenza epitopes may confer protection against heterologous challenge. We report here the results of vaccination with recombinant modified Vaccinia virus Ankara (MVA) and Adenovirus (Ad) expressing a fusion construct of nucleoprotein and matrix protein (NP + M1). Prime and boost vaccination regimes were trialled in different ages of chicken and were found to be safe and immunogenic. Interferon-γ (IFN-γ) ELISpot was used to assess the cellular immune response post secondary vaccination. In ovo Ad prime followed by a 4 week post hatch MVA boost was identified as the most immunogenic regime in one outbred and two inbred lines of chicken. Following vaccination, one inbred line (C15I) was challenged with low pathogenic avian influenza (LPAI) H7N7 (A/Turkey/England/1977). Birds receiving a primary vaccination with Ad-NP + M1 and a secondary vaccination with MVA-NP + M1 exhibited reduced cloacal shedding as measured by plaque assay at 7 days post infection compared with birds vaccinated with recombinant viruses containing irrelevant antigen. This preliminary indication of efficacy demonstrates proof of concept in birds; induction of T cell responses in chickens by viral vectors containing internal influenza antigens may be a productive strategy for the development of vaccines to induce heterologous protection against influenza in poultry. PMID:23200938

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

Behnke, M. R.; Bloethe, W.G.; Bradt, M.

Wind power plants use power transformers to step plant output from the medium voltage of the collector system to the HV or EHV transmission system voltage. This paper discusses the application of these transformers with regard to the selection of winding configuration, MVA rating, impedance, loss evaluation, on-load tapchanger requirements, and redundancy.

Delayed-onset post-traumatic headache after a motor vehicle collision: a case report

PubMed Central

Stupar, Maja; Kim, Peter SY

2007-01-01

Introduction Headaches are common after a motor vehicle accident (MVA). Post-traumatic headaches share many clinical symptoms including the clinical course of primary headaches. Secondary headaches (including those resulting from a subdural hematoma) are not as common, but should be considered in cases of post-traumatic events particularly if clinical symptoms progress. Clinical Features A case of a patient with a post-traumatic subdural hematoma demonstrates the importance of carefully examining, properly diagnosing and managing patients that experience headaches after MVAs. This patient presented with uncomplicated low back pain, neck pain and headache which progressed at one month to include focal neurological deficits. Since clinical examination alone may not be sufficient to diagnose secondary headaches, immediate referral to the emergency department may be required. Conclusion Primary contact practitioners should be aware of the various causes of headaches that result after a MVA. Headaches, which do not respond or progress, should be followed aggressively to determine their source. PMID:17657301

Anterior mitral valve aneurysm: a rare sequelae of aortic valve endocarditis.

PubMed

Janardhanan, Rajesh; Kamal, Muhammad Umar; Riaz, Irbaz Bin; Smith, M Cristy

2016-03-01

SummaryIn intravenous drug abusers, infective endocarditis usually involves right-sided valves, with Staphylococcus aureus being the most common etiologic agent. We present a patient who is an intravenous drug abuser with left-sided (aortic valve) endocarditis caused by Enterococcus faecalis who subsequently developed an anterior mitral valve aneurysm, which is an exceedingly rare complication. A systematic literature search was conducted which identified only five reported cases in the literature of mitral valve aneurysmal rupture in the setting of E. faecalis endocarditis. Real-time 3D-transesophageal echocardiography was critical in making an accurate diagnosis leading to timely intervention. Early recognition of a mitral valve aneurysm (MVA) is important because it may rupture and produce catastrophic mitral regurgitation (MR) in an already seriously ill patient requiring emergency surgery, or it may be overlooked at the time of aortic valve replacement (AVR).Real-time 3D-transesophageal echocardiography (RT-3DTEE) is much more advanced and accurate than transthoracic echocardiography for the diagnosis and management of MVA. © 2016 The authors.

Large Capacity SMES for Voltage Dip Compensation

NASA Astrophysics Data System (ADS)

Iwatani, Yu; Saito, Fusao; Ito, Toshinobu; Shimada, Mamoru; Ishida, Satoshi; Shimanuki, Yoshio

Voltage dips of power grids due to thunderbolts, snow damage, and so on, cause serious damage to production lines of precision instruments, for example, semiconductors. In recent years, in order to solve this problem, uninterruptible power supply systems (UPS) are used. UPS, however, has small capacity, so a great number of UPS are needed in large factories. Therefore, we have manufactured the superconducting magnetic energy storage (SMES) system for voltage dip compensation able to protect loads with large capacity collectively. SMES has advantages such as space conservation, long lifetime and others. In field tests, cooperating with CHUBU Electric Power Co., Inc. we proved that SMES is valuable for compensating voltage dips. Since 2007, 10MVA SMES improved from field test machines has been running in a domestic liquid crystal display plant, and in 2008, it protected plant loads from a number of voltage dips. In this paper, we report the action principle and components of the improved SMES for voltage dip compensation, and examples of waveforms when 10MVA SMES compensated voltage dips.

Micalastic high-voltage insulation: Design features and experience

NASA Astrophysics Data System (ADS)

Wichmann, A.

1981-12-01

High-quality mica, carefully selected epoxy resins and a well-matched vacuum/pressure impregnation process determine the characteristics of the MICALASTIC insulation for large turbine-generators. Logical development and process manufacturing quality control have led to an insulation system of high quality and operating reliability. The first winding of a turbine-generator being impregnated and cured under vacuum with solvent-free synthetic resin in 1958 was designed for 10.5 kV rated voltage. Ever since, Siemens AG and Kraftwerk Union AG have used this type of insulation for all direct-cooled windings and also for an increasing number of indirect-cooled windings. At present, 240 turbine-generators with a total of more than 115,000 MVA output have been built. Since 1960, this insulation system has been registered for Siemens AG under the trade name MICALASTIC. The stator windings of the largest, single-shaft generators to date, rated 1560 MVA, 27 kV, has been built with MICALASTIC insulation.

Use of Multivariate Linkage Analysis for Dissection of a Complex Cognitive Trait

PubMed Central

Marlow, Angela J.; Fisher, Simon E.; Francks, Clyde; MacPhie, I. Laurence; Cherny, Stacey S.; Richardson, Alex J.; Talcott, Joel B.; Stein, John F.; Monaco, Anthony P.; Cardon, Lon R.

2003-01-01

Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits. PMID:12587094

Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection Against Bovine Tuberculosis

USDA-ARS?s Scientific Manuscript database

Previous work in small animal laboratory models of tuberculosis have shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacille Calmette-Guerin (BCG) to prime and Modified Vaccinia Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad8...

Virulent poxviruses inhibit DNA sensing by preventing STING activation.

PubMed

Georgana, Iliana; Sumner, Rebecca P; Towers, Greg J; Maluquer de Motes, Carlos

2018-02-28

Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerised and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerisation and phosphorylation during infection and in response to transfected DNA and cGAMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence. IMPORTANCE Poxviruses are dsDNA viruses infecting a wide range of vertebrates and include the causative agent of smallpox (variola virus) and its vaccine vaccinia virus (VACV). Despite smallpox eradication VACV remains of interest as a therapeutic. Attenuated strains are popular vaccine candidates, whereas replication-competent strains are emerging as efficient oncolytics in virotherapy. The successful therapeutic use of VACV depends on a detailed understanding of its ability to modulate host innate immune responses. DNA sensing is a critical cellular mechanism for pathogen detection and activation of innate immunity that is centrally coordinated by the ER-resident protein STING. Here STING is shown to mediate immune activation in response to MVA, but not to virulent VACV strains or other virulent poxviruses, which prevent STING activation and DNA sensing during infection and after DNA transfection. These results provide new insights into poxvirus immune evasion and have implications in the rational design of VACV-based therapeutics. Copyright © 2018 Georgana et al.

Virulent Poxviruses Inhibit DNA Sensing by Preventing STING Activation

PubMed Central

Georgana, Iliana; Sumner, Rebecca P.; Towers, Greg J.

2018-01-01

ABSTRACT Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerizes and translocates from the endoplasmic reticulum (ER) to a perinuclear region to mediate IRF-3 activation. Poxviruses are double-stranded DNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here, we investigated the activation of innate immune signaling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerized and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerization and phosphorylation during infection and in response to transfected DNA and cyclic GMP-AMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence. IMPORTANCE Poxviruses are double-stranded DNA viruses infecting a wide range of vertebrates and include the causative agent of smallpox (variola virus) and its vaccine vaccinia virus (VACV). Despite smallpox eradication VACV remains of interest as a therapeutic. Attenuated strains are popular vaccine candidates, whereas replication-competent strains are emerging as efficient oncolytics in virotherapy. The successful therapeutic use of VACV depends on a detailed understanding of its ability to modulate host innate immune responses. DNA sensing is a critical cellular mechanism for pathogen detection and activation of innate immunity that is centrally coordinated by the endoplasmic reticulum-resident protein STING. Here, STING is shown to mediate immune activation in response to MVA, but not in response to virulent VACV strains or other virulent poxviruses, which prevent STING activation and DNA sensing during infection and after DNA transfection. These results provide new insights into poxvirus immune evasion and have implications in the rational design of VACV-based therapeutics. PMID:29491158

Review of High Power Density Superconducting Generators: Present State and Prospects for Incorporating YBCO Windings

DTIC Science & Technology

2005-01-01

Development of a 100 MVA high temperature super- conducting generator. In: IEEE power engineering society meeting 2004, Denver, CL. [38] Schiferl R...Development of ultra efficient electrical motor systems. In: DOE Annual Superconductivity Peer Review Meeting 2004, Wash- ington, DC; Schiferl R, Rockwell

The intervals method: a new approach to analyse finite element outputs using multivariate statistics

PubMed Central

De Esteban-Trivigno, Soledad; Püschel, Thomas A.; Fortuny, Josep

2017-01-01

Background In this paper, we propose a new method, named the intervals’ method, to analyse data from finite element models in a comparative multivariate framework. As a case study, several armadillo mandibles are analysed, showing that the proposed method is useful to distinguish and characterise biomechanical differences related to diet/ecomorphology. Methods The intervals’ method consists of generating a set of variables, each one defined by an interval of stress values. Each variable is expressed as a percentage of the area of the mandible occupied by those stress values. Afterwards these newly generated variables can be analysed using multivariate methods. Results Applying this novel method to the biological case study of whether armadillo mandibles differ according to dietary groups, we show that the intervals’ method is a powerful tool to characterize biomechanical performance and how this relates to different diets. This allows us to positively discriminate between specialist and generalist species. Discussion We show that the proposed approach is a useful methodology not affected by the characteristics of the finite element mesh. Additionally, the positive discriminating results obtained when analysing a difficult case study suggest that the proposed method could be a very useful tool for comparative studies in finite element analysis using multivariate statistical approaches. PMID:29043107

Computational neuroanatomy using brain deformations: From brain parcellation to multivariate pattern analysis and machine learning.

PubMed

Davatzikos, Christos

2016-10-01

The past 20 years have seen a mushrooming growth of the field of computational neuroanatomy. Much of this work has been enabled by the development and refinement of powerful, high-dimensional image warping methods, which have enabled detailed brain parcellation, voxel-based morphometric analyses, and multivariate pattern analyses using machine learning approaches. The evolution of these 3 types of analyses over the years has overcome many challenges. We present the evolution of our work in these 3 directions, which largely follows the evolution of this field. We discuss the progression from single-atlas, single-registration brain parcellation work to current ensemble-based parcellation; from relatively basic mass-univariate t-tests to optimized regional pattern analyses combining deformations and residuals; and from basic application of support vector machines to generative-discriminative formulations of multivariate pattern analyses, and to methods dealing with heterogeneity of neuroanatomical patterns. We conclude with discussion of some of the future directions and challenges. Copyright © 2016. Published by Elsevier B.V.

Computational neuroanatomy using brain deformations: From brain parcellation to multivariate pattern analysis and machine learning

PubMed Central

Davatzikos, Christos

2017-01-01

The past 20 years have seen a mushrooming growth of the field of computational neuroanatomy. Much of this work has been enabled by the development and refinement of powerful, high-dimensional image warping methods, which have enabled detailed brain parcellation, voxel-based morphometric analyses, and multivariate pattern analyses using machine learning approaches. The evolution of these 3 types of analyses over the years has overcome many challenges. We present the evolution of our work in these 3 directions, which largely follows the evolution of this field. We discuss the progression from single-atlas, single-registration brain parcellation work to current ensemble-based parcellation; from relatively basic mass-univariate t-tests to optimized regional pattern analyses combining deformations and residuals; and from basic application of support vector machines to generative-discriminative formulations of multivariate pattern analyses, and to methods dealing with heterogeneity of neuroanatomical patterns. We conclude with discussion of some of the future directions and challenges. PMID:27514582

Multi-country health surveys: are the analyses misleading?

PubMed

Masood, Mohd; Reidpath, Daniel D

2014-05-01

The aim of this paper was to review the types of approaches currently utilized in the analysis of multi-country survey data, specifically focusing on design and modeling issues with a focus on analyses of significant multi-country surveys published in 2010. A systematic search strategy was used to identify the 10 multi-country surveys and the articles published from them in 2010. The surveys were selected to reflect diverse topics and foci; and provide an insight into analytic approaches across research themes. The search identified 159 articles appropriate for full text review and data extraction. The analyses adopted in the multi-country surveys can be broadly classified as: univariate/bivariate analyses, and multivariate/multivariable analyses. Multivariate/multivariable analyses may be further divided into design- and model-based analyses. Of the 159 articles reviewed, 129 articles used model-based analysis, 30 articles used design-based analyses. Similar patterns could be seen in all the individual surveys. While there is general agreement among survey statisticians that complex surveys are most appropriately analyzed using design-based analyses, most researchers continued to use the more common model-based approaches. Recent developments in design-based multi-level analysis may be one approach to include all the survey design characteristics. This is a relatively new area, however, and there remains statistical, as well as applied analytic research required. An important limitation of this study relates to the selection of the surveys used and the choice of year for the analysis, i.e., year 2010 only. There is, however, no strong reason to believe that analytic strategies have changed radically in the past few years, and 2010 provides a credible snapshot of current practice.

Borrowing of strength and study weights in multivariate and network meta-analysis.

PubMed

Jackson, Dan; White, Ian R; Price, Malcolm; Copas, John; Riley, Richard D

2017-12-01

Multivariate and network meta-analysis have the potential for the estimated mean of one effect to borrow strength from the data on other effects of interest. The extent of this borrowing of strength is usually assessed informally. We present new mathematical definitions of 'borrowing of strength'. Our main proposal is based on a decomposition of the score statistic, which we show can be interpreted as comparing the precision of estimates from the multivariate and univariate models. Our definition of borrowing of strength therefore emulates the usual informal assessment. We also derive a method for calculating study weights, which we embed into the same framework as our borrowing of strength statistics, so that percentage study weights can accompany the results from multivariate and network meta-analyses as they do in conventional univariate meta-analyses. Our proposals are illustrated using three meta-analyses involving correlated effects for multiple outcomes, multiple risk factor associations and multiple treatments (network meta-analysis).

Borrowing of strength and study weights in multivariate and network meta-analysis

PubMed Central

Jackson, Dan; White, Ian R; Price, Malcolm; Copas, John; Riley, Richard D

2016-01-01

Multivariate and network meta-analysis have the potential for the estimated mean of one effect to borrow strength from the data on other effects of interest. The extent of this borrowing of strength is usually assessed informally. We present new mathematical definitions of ‘borrowing of strength’. Our main proposal is based on a decomposition of the score statistic, which we show can be interpreted as comparing the precision of estimates from the multivariate and univariate models. Our definition of borrowing of strength therefore emulates the usual informal assessment. We also derive a method for calculating study weights, which we embed into the same framework as our borrowing of strength statistics, so that percentage study weights can accompany the results from multivariate and network meta-analyses as they do in conventional univariate meta-analyses. Our proposals are illustrated using three meta-analyses involving correlated effects for multiple outcomes, multiple risk factor associations and multiple treatments (network meta-analysis). PMID:26546254

77 FR 9204 - Large Power Transformers From the Republic of Korea: Preliminary Determination of Sales at Less...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-16

...; (12) low voltage winding basic insulation level; (13) load loss at maximum MVA rating; (14) no-load loss; (15) cooling class designation; (16) overload requirement; (17) decibel rating; and (18... Transformers from Korea: Investigation No. 731-TA-1189 (Preliminary).'' On September 16, 2011, we selected...

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Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-04

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 14480-000] Alaska Electric... Comments, Motions To Intervene, and Competing Applications On January 11, 2013, Alaska Electric Light and... single 3.5-megavolt-ampere (MVA) transformer to adjust voltage to 23 kilovolts; and (7) appurtenant...

Determination of Flux rope axis for GS reconstruction

NASA Astrophysics Data System (ADS)

Tian, A.; Shi, Q.; Bai, S.; Zhang, S.

2016-12-01

It is important to give the axis direction and velocity of a magnetic flux ropes before employing Grad-Shafranov reconstruction. The ability of single-satellite based MVA (MVAB and CMVA) and multi-satellite based MDD methods in finding the invariant axis are tested by a model. The choice of principal axis given by MVA along the aimed direction is dependent on the distance of the path from the flux-rope axis. The MDD results are influenced by the ratio of Noise level/separation to the gradient of the structure. An accurate axial direction will be obtained when the ratio is less than 1. By a model, an example with failed HT method is displayed indicating the importance of the STD method in obtaining the velocity of such a structure. The applicability of trial and error method by Hu and Sonnerup(2012) was also used and discussed. Finally, all above methods were applied to a flux-rope observed by Cluster. It shows that the GS method can be easily carried out in the case of clearly known dimensionality and velocity.

Etiology and patterns of pediatric mandibular fractures in Portugal: a retrospective study of 10 years.

PubMed

Ferreira, Pedro Costa; Amarante, José Manuel; Silva, Alvaro Catarino; Pereira, José Miguel; Cardoso, Maria Augusta; Rodrigues, Jorge Manuel

2004-05-01

To determine the pattern of occurrence of mandibular fractures in the pediatric population in Portugal. This retrospective study reviews the records of patients 18 years of age or younger from the 10-year period 1993 to 2002. Age, gender, anatomic site, cause of the accident, weekly and monthly variation, location and type of fractures, presence and location of associated injuries, treatment methods, and complications were reviewed. During this 10-year period, 521 patients with 681 mandibular fractures were treated. Motor-vehicle accident (MVA) was the most common (53.9% patients) cause of fracture. Almost half of the patients (48.8%) were in the oldest age group (16 to 18 years old). The condyle of the mandible was involved in 31.0% of the fractures. Maxillomandibular (MMF) fixation was used in 534 (78.4%) fractures. Overall mortality in this series was 0.6% (3 patients); mortality was caused by multiple traumas, mainly head trauma. There is a need to reinforce legislation aimed to prevent MVA and the total enforcement of existing laws to reduce maxillofacial injuries among children and adolescents.

Study on Matching a 300 MVA Motor Generator with an Ohmic Heating Power Supply in HL-2M

NASA Astrophysics Data System (ADS)

Peng, Jianfei; Xuan, Weimin; Wang, Haibing; Li, Huajun; Wang, Yingqiao; Wang, Shujin

2013-03-01

A new 300 MVA/1350 MJ motor generator (MG) will be built to feed all of the poloidal field power supplies (PFPS) and auxiliary heating power supplies of the HL-2M tokamak. The MG has a vertical-shaft salient pole 6-phase synchronous generator and a coaxial 8500 kW induction motor. The Ohmic heating power supply (OHPS) consisting of 4-quadrant DC pulsed convertor is the one with the highest parameters among the PFPS. Therefore, the match between the generator and the OHPS is very important. The matching study with Matlab/Simulink is described in this paper. The simulation results show that the subtransient reactance of the generator is closely related to the inversion operation of the OHPS. By setting various subtransient reactance in the simulation generator model and considering the cost reduction, the optimized parameters are obtained as x″d = 0.405 p.u. at 100 Hz for the generator. The models built in the simulation can be used as an important tool for studying the dynamic characteristics and the control strategy of other HL-2M PFPSes.

Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.

PubMed

Tscharke, David C; Karupiah, Gunasegaran; Zhou, Jie; Palmore, Tara; Irvine, Kari R; Haeryfar, S M Mansour; Williams, Shanicka; Sidney, John; Sette, Alessandro; Bennink, Jack R; Yewdell, Jonathan W

2005-01-03

The large size of poxvirus genomes has stymied attempts to identify determinants recognized by CD8+ T cells and greatly impeded development of mouse smallpox vaccination models. Here, we use a vaccinia virus (VACV) expression library containing each of the predicted 258 open reading frames to identify five peptide determinants that account for approximately half of the VACV-specific CD8+ T cell response in C57BL/6 mice. We show that the primary immunodominance hierarchy is greatly affected by the route of VACV infection and the poxvirus strain used. Modified vaccinia virus ankara (MVA), a candidate replacement smallpox vaccine, failed to induce responses to two of the defined determinants. This could not be predicted by genomic comparison of viruses and is not due strictly to limited MVA replication in mice. Several determinants are immunogenic in cowpox and ectromelia (mousepox) virus infections, and immunization with the immunodominant determinant provided significant protection against lethal mousepox. These findings have important implications for understanding poxvirus immunity in animal models and bench-marking immune responses to poxvirus vaccines in humans.

Enhanced isoprene biosynthesis in Saccharomyces cerevisiae by engineering of the native acetyl-CoA and mevalonic acid pathways with a push-pull-restrain strategy.

PubMed

Lv, Xiaomei; Xie, Wenping; Lu, Wenqiang; Guo, Fei; Gu, Jiali; Yu, Hongwei; Ye, Lidan

2014-09-30

To explore the capacity of isoprene production in Saccharomyces cerevisiae, a rational push-pull-restrain strategy was proposed to engineer the mevalonic acid (MVA) and acetyl-CoA pathways. The strategy can be decomposed into the up-regulation of precursor supply in the acetyl-CoA module and the MVA pathway (push-strategy), increase of the isoprene branch flux (pull-strategy), and down-regulation of the competing pathway (restrain-strategy). Furthermore, to reduce the production cost arising from galactose addition and meanwhile maintain the high expression of Gal promoters, the galactose regulatory network was modulated by Gal80p deletion. Finally, the engineered strain YXM10-ispS-ispS could accumulate up to 37 mg/L isoprene (about 782-fold increase compared to the parental strain) under aerobic conditions with glycerol-sucrose as carbon source. In this way, a new potential platform for isoprene production was established via metabolic engineering of the yeast native pathways. Copyright © 2014 Elsevier B.V. All rights reserved.

Posttreatment Prostate-Specific Antigen 6 Months After Radiation With Androgen Deprivation Therapy Predicts for Distant Metastasis–Free Survival and Prostate Cancer–Specific Mortality

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

Naik, Mihir, E-mail: naikm@ccf.org; Reddy, Chandana A.; Stephans, Kevin L.

Objectives/Background: To determine whether a 6-month posttreatment prostate-specific antigen (PSA) value in patients with prostate cancer (PCa) treated with concurrent androgen deprivation therapy (ADT) and external beam radiation therapy (EBRT) serves as an early predictor for biochemical relapse free survival (bRFS), distant metastasis–free survival (DMFS), and prostate cancer–specific mortality (PCSM). Methods: A retrospective review of intermediate-risk and high-risk PCa patients treated with EBRT and concurrent ADT at a single institution between 1996 and 2012. All patients received high-dose radiation with either 78 Gy in 39 fractions or 70 Gy in 28 fractions. Kaplan-Meier analysis was used to estimate bRFS and DMFS, andmore » cumulative incidence was used to estimate PCSM. Results: 532 patients were identified. The median follow-up time was 7.5 years (range, 1-16.25 years). The median initial PSA (iPSA) was 13.0 ng/mL (range, 0.37-255 ng/mL), and the median duration of ADT was 6 months (range, 1-78 months). The median PSA 6 months after EBRT was 0.1 ng/mL (range, 0-19 ng/mL), and 310 patients (58.3%) had a 6-month PSA ≤0.1 ng/mL. Multivariable analysis (MVA) demonstrated that a 6-month post-EBRT PSA of >0.1 ng/mL was an independent predictor of worse bRFS (hazard ratio [HR] = 2.518; P<.0001), DMFS (HR=3.743; P<.0001), and PCSM (HR=5.435; P<.0001). On MVA, a Gleason score of 8 to 10 also correlated with worse DMFS and PCSM (P<.05). The duration of ADT (1-6 vs >6 months) was not predictive of any clinical endpoint. Conclusions: A 6-month posttreatment PSA >0.1 ng/mL in intermediate-risk and high-risk PCa patients treated with concurrent high-dose EBRT and ADT is associated with worse bRFS, DMFS, and PCSM. The duration of ADT was not predictive of any clinical endpoint. A 6-month PSA after definitive EBRT and ADT helps identify patients at higher risk of disease progression and may serve as a predictive tool to select patients for early salvage therapy on future clinical trials.« less

Sample size calculations for case-control studies

Cancer.gov

This R package can be used to calculate the required samples size for unconditional multivariate analyses of unmatched case-control studies. The sample sizes are for a scalar exposure effect, such as binary, ordinal or continuous exposures. The sample sizes can also be computed for scalar interaction effects. The analyses account for the effects of potential confounder variables that are also included in the multivariate logistic model.

Towards practical time-of-flight secondary ion mass spectrometry lignocellulolytic enzyme assays

PubMed Central

2013-01-01

Background Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) is a surface sensitive mass spectrometry technique with potential strengths as a method for detecting enzymatic activity on solid materials. In particular, ToF-SIMS has been applied to detect the enzymatic degradation of woody lignocellulose. Proof-of-principle experiments previously demonstrated the detection of both lignin-degrading and cellulose-degrading enzymes on solvent-extracted hardwood and softwood. However, these preliminary experiments suffered from low sample throughput and were restricted to samples which had been solvent-extracted in order to minimize the potential for mass interferences between low molecular weight extractive compounds and polymeric lignocellulose components. Results The present work introduces a new, higher-throughput method for processing powdered wood samples for ToF-SIMS, meanwhile exploring likely sources of sample contamination. Multivariate analysis (MVA) including Principal Component Analysis (PCA) and Multivariate Curve Resolution (MCR) was regularly used to check for sample contamination as well as to detect extractives and enzyme activity. New data also demonstrates successful ToF-SIMS analysis of unextracted samples, placing an emphasis on identifying the low-mass secondary ion peaks related to extractives, revealing how extractives change previously established peak ratios used to describe enzyme activity, and elucidating peak intensity patterns for better detection of cellulase activity in the presence of extractives. The sensitivity of ToF-SIMS to a range of cellulase doses is also shown, along with preliminary experiments augmenting the cellulase cocktail with other proteins. Conclusions These new procedures increase the throughput of sample preparation for ToF-SIMS analysis of lignocellulose and expand the applications of the method to include unextracted lignocellulose. These are important steps towards the practical use of ToF-SIMS as a tool to screen for changes in plant composition, whether the transformation of the lignocellulose is achieved through enzyme application, plant mutagenesis, or other treatments. PMID:24034438

Assessment of cellulolytic microorganisms in soils of Nevados Park, Colombia.

PubMed

Avellaneda-Torres, Lizeth Manuela; Pulido, Claudia Patricia Guevara; Rojas, Esperanza Torres

2014-01-01

A systematized survey was conducted to find soil-borne microbes that degrade cellulose in soils from unique ecosystems, such as the Superpáramo, Páramo, and the High Andean Forest in the Nevados National Natural Park (NNNP), Colombia. These high mountain ecosystems represent extreme environments, such as high levels of solar radiation, low atmospheric pressure, and extreme daily changes in temperature. Cellulolytic activity of the microorganisms was evaluated using qualitative tests, such as growth in selective media followed by staining with congo red and iodine, and quantitative tests to determine the activity of endoglucanase, β-glucosidase, exoglucanase, and total cellulase. Microorganisms were identified using molecular markers, such as the 16S rRNA gene for bacteria and the internal transcribed spacer region (ITS) of ribosomal DNA for fungi. Multivariate statistical analysis (MVA) was used to select microorganisms with high cellulolytic capacity. A total of 108 microorganisms were isolated from the soils and, in general, the enzymatic activities of fungi were higher than those of bacteria. Our results also found that none of the organisms studied were able to degrade all the components of the cellulose and it is therefore suggested that a combination of bacteria and/or fungi with various enzymatic activities be used to obtain high total cellulolytic activity. This study gives an overview of the potential microorganism that could be used for cellulose degradation in various biotechnological applications and for sustainable agricultural waste treatment.

Southwestern Regional Partnership For Carbon Sequestration (Phase 2) Pump Canyon CO2- ECBM/Sequestration Demonstration, San Juan Basin, New Mexico

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

Advanced Resources International

2010-01-31

Within the Southwest Regional Partnership on Carbon Sequestration (SWP), three demonstrations of geologic CO{sub 2} sequestration are being performed -- one in an oilfield (the SACROC Unit in the Permian basin of west Texas), one in a deep, unmineable coalbed (the Pump Canyon site in the San Juan basin of northern New Mexico), and one in a deep, saline reservoir (underlying the Aneth oilfield in the Paradox basin of southeast Utah). The Pump Canyon CO{sub 2}-enhanced coalbed methane (CO{sub 2}/ECBM) sequestration demonstration project plans to demonstrate the effectiveness of CO{sub 2} sequestration in deep, unmineable coal seams via a small-scalemore » geologic sequestration project. The site is located in San Juan County, northern New Mexico, just within the limits of the high-permeability fairway of prolific coalbed methane production. The study area for the SWP project consists of 31 coalbed methane production wells located in a nine section area. CO{sub 2} was injected continuously for a year and different monitoring, verification and accounting (MVA) techniques were implemented to track the CO{sub 2} movement inside and outside the reservoir. Some of the MVA methods include continuous measurement of injection volumes, pressures and temperatures within the injection well, coalbed methane production rates, pressures and gas compositions collected at the offset production wells, and tracers in the injected CO{sub 2}. In addition, time-lapse vertical seismic profiling (VSP), surface tiltmeter arrays, a series of shallow monitoring wells with a regular fluid sampling program, surface measurements of soil composition, CO{sub 2} fluxes, and tracers were used to help in tracking the injected CO{sub 2}. Finally, a detailed reservoir model was constructed to help reproduce and understand the behavior of the reservoir under production and injection operation. This report summarizes the different phases of the project, from permitting through site closure, and gives the results of the different MVA techniques.« less

Safety and immunogenicity of a modified vaccinia Ankara vaccine using three immunization schedules and two modes of delivery: A randomized clinical non-inferiority trial.

PubMed

Jackson, Lisa A; Frey, Sharon E; El Sahly, Hana M; Mulligan, Mark J; Winokur, Patricia L; Kotloff, Karen L; Campbell, James D; Atmar, Robert L; Graham, Irene; Anderson, Evan J; Anderson, Edwin L; Patel, Shital M; Fields, Colin; Keitel, Wendy; Rouphael, Nadine; Hill, Heather; Goll, Johannes B

2017-03-23

To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N). Healthy adults 18-40years of age were randomly assigned to receive MVA vaccine subcutaneously by S&N on Days 1 and 29 (standard), Days 1 and 15, or Days 1 and 22, or to receive the vaccine subcutaneously by JI on Days 1 and 29. Blood was collected at four time points after the second vaccination for plaque reduction neutralization test (PRNT) (primary endpoint) and ELISA (secondary endpoint) antibody assays. For each subject, the peak PRNT (or ELISA) titer was defined by the highest PRNT (or ELISA) titer among all available measurements post second vaccination. Non-inferiority of a non-standard arm compared to the standard arm was met if the upper limit of the 98.33% confidence interval of the difference in the mean log 2 peak titers between the standard and non-standard arm was less than 1. Non-inferiority of the PRNT antibody response was not established for any of the three non-standard study arms. Non-inferiority of the ELISA antibody response was established for the Day 1 and 22 compressed schedule and for administration by JI. Solicited local reactions, such as redness and swelling, tended to be more commonly reported with JI administration. Four post-vaccination hypersensitivity reactions were observed. Evaluations of the primary endpoint of PRNT antibody responses do not support alternative strategies of administering MVA vaccine by S&N on compressed schedules or administration by JI on the standard schedule. clinicaltrials.gov Identifier: NCT01827371. Copyright © 2017. Published by Elsevier Ltd.

Attenuated and Replication-Competent Vaccinia Virus Strains M65 and M101 with Distinct Biology and Immunogenicity as Potential Vaccine Candidates against Pathogens

PubMed Central

Sánchez-Sampedro, Lucas; Gómez, Carmen Elena; Mejías-Pérez, Ernesto; Pérez-Jiménez, Eva; Oliveros, Juan Carlos

2013-01-01

Replication-competent poxvirus vectors with an attenuation phenotype and with a high immunogenic capacity of the foreign expressed antigen are being pursued as novel vaccine vectors against different pathogens. In this investigation, we have examined the replication and immunogenic characteristics of two vaccinia virus (VACV) mutants, M65 and M101. These mutants were generated after 65 and 101 serial passages of persistently infected Friend erythroleukemia (FEL) cells. In cultured cells of different origins, the mutants are replication competent and have growth kinetics similar to or slightly reduced in comparison with those of the parental Western Reserve (WR) virus strain. In normal and immune-suppressed infected mice, the mutants showed different levels of attenuation and pathogenicity in comparison with WR and modified vaccinia Ankara (MVA) strains. Wide genome analysis after deep sequencing revealed selected genomic deletions and mutations in a number of viral open reading frames (ORFs). Mice immunized in a DNA prime/mutant boost regimen with viral vectors expressing the LACK (Leishmania homologue for receptors of activated C kinase) antigen of Leishmania infantum showed protection or a delay in the onset of cutaneous leishmaniasis. Protection was similar to that triggered by MVA-LACK. In immunized mice, both polyfunctional CD4+ and CD8+ T cells with an effector memory phenotype were activated by the two mutants, but the DNA-LACK/M65-LACK protocol preferentially induced CD4+ whereas DNA-LACK/M101-LACK preferentially induced CD8+ T cell responses. Altogether, our findings showed the adaptive changes of the WR genome during long-term virus-host cell interaction and how the replication competency of M65 and M101 mutants confers distinct biological properties and immunogenicity in mice compared to those of the MVA strain. These mutants could have applicability for understanding VACV biology and as potential vaccine vectors against pathogens and tumors. PMID:23596295

The Driving Behavior Survey as a Measure of Behavioral Stress Responses to MVA-related PTSD

PubMed Central

Baker, Aaron S.; Litwack, Scott D.; Clapp, Joshua D.; Beck, J. Gayle; Sloan, Denise M.

2014-01-01

Numerous treatments are available that address the core symptoms of posttraumatic stress disorder (PTSD). However, there are a number of related behavioral stress responses that are not assessed with PTSD measures, yet these behavioral stress responses affect quality of life. The goal of the current study was to investigate whether a recently developed measure of behavioral stress response, the Driving Behavior Survey (DBS), was sensitive to change associated with treatment among a group of participants diagnosed with PTSD. The DBS indexes anxious driving behavior, which is frequently observed among individuals with motor vehicle accident-related PTSD. Participants (n = 40) were racially-diverse adults (M age =40.78, 63% women) who met diagnostic criteria for motor vehicle accident-related PTSD. Hierarchical linear modeling analyses indicated that participants who were assigned to a brief, exposure-based intervention displayed significant reductions on the DBS subscales relative to participants assigned to the waitlist control condition (r = .41-.43). Moreover, meditational analyses indicated that the observed reductions on the DBS subscales were not better accounted for by reductions in PTSD. Taken together, these findings suggest that the DBS subscales are sensitive to changes associated with PTSD treatment and can be used to augment outcome measures in PTSD treatment trials PMID:24491201

The Driving Behavior Survey as a Measure of Behavioral Stress Responses to MVA-Related PTSD

PubMed Central

Baker, Aaron S.; Litwack, Scott D.; Clapp, Joshua D.; Beck, J. Gayle; Sloan, Denise M.

2014-01-01

Numerous treatments are available that address the core symptoms of posttraumatic stress disorder (PTSD). However, there are a number of related behavioral stress responses that are not assessed with PTSD measures, yet these behavioral stress responses affect quality of life. The goal of the current study was to investigate whether a recently developed measure of behavioral stress response, the Driving Behavior Survey (DBS), was sensitive to change associated with treatment among a group of participants diagnosed with PTSD. The DBS indexes anxious driving behavior, which is frequently observed among individuals with motor vehicle accident-related PTSD. Participants (n = 40) were racially diverse adults (M age = 40.78, 63% women) who met diagnostic criteria for motor vehicle accident-related PTSD. Hierarchical linear modeling analyses indicated that participants who were assigned to a brief, exposure-based intervention displayed significant reductions on the DBS subscales relative to participants assigned to the wait-list control condition (r = .41–.43). Moreover, mediational analyses indicated that the observed reductions on the DBS subscales were not better accounted for by reductions in PTSD. Taken together, these findings suggest that the DBS subscales are sensitive to changes associated with PTSD treatment and can be used to augment outcome assessment in PTSD treatment trials. PMID:24800313

Common reflection point migration and velocity analysis for anisotropic media

NASA Astrophysics Data System (ADS)

Oropeza, Ernesto V.

An efficient Kirchhoff-style prestack depth migration, called 'parsimonious' migration was developed a decade ago for isotropic 2D and 3D media. The common-reflection point (CRP) migration velocity analysis (MVA) was developed later for isotropic media. The isotropic parsimonious migration produces incorrect images when the media is actually anisotropic. Similarly, isotropic CRP MVA produces incorrect inversions when the medium is anisotropic. In this study both parsimonious depth migration and common-reflection point migration velocity analysis are extended for application to 2D tilted transversely isotropic (TTI) media and illustrated with synthetic P-wave data. While the framework of isotropic parsimonious migration may be retained, the extension to TTI media requires redevelopment of each of the numerical components, including calculation of the phase and group velocity for TTI media, development of a new two-point anisotropic ray tracer, and substitution of an initial-angle and anisotropic shooting ray-trace algorithm to replace the isotropic one. The 2D model parameterization consists of Thomsen's parameters (Vpo, epsilon, delta) and the tilt angle of the symmetry axis of the TI medium. The parsimonious anisotropic migration algorithm is successfully applied to synthetic data from a TTI version of the Marmousi-2 model. The quality of the image improves by weighting the impulse response by the calculation of the anisotropic Fresnel radius. The accuracy and speed of this migration makes it useful for anisotropic velocity model building. The common-reflection point migration velocity analysis for TTI media for P-waves includes (and inverts for) Vpo, epsilon, and delta. The orientation of the anisotropic symmetry axis have to be constrained. If it constrained orthogonal to the layer bottom (as it conventionally is), it is estimated at each CRP and updated at each iteration without intermediate picking. The extension to TTI media requires development of a new inversion procedure to include Vpo, epsilon, and delta in the perturbations. The TTI CRP MVA is applied to a single layer to demonstrate its feasibility. Errors in the estimation of the orientation of the symmetry axis larger that 5 degrees affect the inversion of epsilon and delta while Vpo is less sensitive to this parameter. The TTI CRP MVA is also applied to a version of the TTI BP model by layer stripping so one group of CRPs are used do to inversion top to bottom, constraining the model parameter after each previous group of CRPs converges. Vpo, delta and the orientation of the anisotropic symmetry axis (constrained orthogonal to the local reflector orientation) are successfully inverted. epsilon is less well constrained by the small acquisition aperture in the data .

Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques.

PubMed

Iyer, Smita S; Gangadhara, Sailaja; Victor, Blandine; Shen, Xiaoying; Chen, Xuemin; Nabi, Rafiq; Kasturi, Sudhir P; Sabula, Michael J; Labranche, Celia C; Reddy, Pradeep B J; Tomaras, Georgia D; Montefiori, David C; Moss, Bernard; Spearman, Paul; Pulendran, Bali; Kozlowski, Pamela A; Amara, Rama Rao

2016-10-01

The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations with DNA (D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the second MVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of seven DNA/MVA and VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control. The development of an effective HIV vaccine remains a global necessity for preventing HIV infection and reducing the burden of AIDS. While this goal represents a formidable challenge, the modest efficacy of the RV144 trial indicates that multicomponent vaccination regimens that elicit both cellular and humoral immune responses can prevent HIV infection in humans. However, whether protein immunizations synergize with DNA prime-viral vector boosts to enhance cellular and humoral immune responses remains poorly understood. We addressed this question in a nonhuman primate model, and our findings show benefit for sequential protein immunization combined with a potent adjuvant in boosting antibody titers induced by a preceding DNA/MVA immunization. This promising strategy can be further developed to enhance neutralizing antibody responses and boost CD8 T cells to provide robust protection and viral control. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Advances in high-resolution synchrotron micro-XANES for constraining the redox evolution of terrestrial and extraterrestrial magma

NASA Astrophysics Data System (ADS)

Lanzirotti, A.; Sutton, S. R.; Dyar, M. D.; McCanta, M. C.; Head, E.

2017-12-01

Quantifying the redox evolution of geological materials is of fundamental importance for understanding the evolution of the Earth and terrestrial planets. Microfocused, synchrotron X-ray Absorption Spectroscopy (XAS) provides direct, in-situ analyses of the valence state for elements that can be used as proxies for oxygen fugacity (Fe, V, Cr, Ti, S, Eu, and Ce). Such proxies span the entire fO2 range of solar system evolution, covering at least 16 log units. Recent technical improvements at the Advanced Photon Source 13-ID-E microspectroscopy beamline have improved the energy, spatial resolution and detection sensitivity for XAS. The application of multiple valence state oxybarometers to individual mineral grains is valuable as demonstrated in a study of Ti, V and Cr valence in olivine and pyroxene of the ungrouped achondrite NWA 7325 [1], results which yielded a very reduced fO2 estimate of IW-3 and suggested a likely origin of NWA 7325 in a parent body with similar redox conditions to the ureilite parent body. Simultaneously, we have made advances using multivariate prediction models to more precisely measure ever-smaller variations in elemental valence [2]. Applied to V XAS spectra in glasses, we have developed an MVA calibration model that directly relates the measured spectra to predicted fO2, improving the precision in calculating fO2 with more robust error analysis. These machine learning based algorithms also allow for XAS to be collected in an imaging modality to spatially map elemental redox states within samples. For example for imaging changes in Fe oxidation state in natural lunar picritic glasses [3] that may be related to magmatic degassing. This presentation highlights recent examples of this research at 13-ID-E, including application of Fe, S and V valence state oxybarometers in the analysis of terrestrial volcanic glasses and melt inclusions for looking at long term evolution of oxygen fugacity of magmas. [1] Sutton S. et al. (2017) GCA, 211, 115-132. [2] Dyar M. D et al. (2016) Amer. Mineral., 101, 744-748. [3] McCanta et al. (2017) Icarus, 285, 95-102.

Factory overload testing of a large power transformer

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

Douglas, D.H.; Lawrence, C.O.; Templeton, J.B.

1985-09-01

A factory overload test of up to 150% of the nameplate rating was run on a 224 MVA autotransformer. The results of this test were of great value and were used in identifying transformer overload limitations, in evaluating loading guide oil and winding equations, exponents and time constants, and in helping to perfect a factory overload test procedure.

MULTIVARIATE ANALYSES (CONONICAL CORRELATION AND PARTIAL LEAST SQUARE, PLS) TO MODEL AND ASSESS THE ASSOCIATION OF LANDSCAPE METRICS TO SURFACE WATER CHEMICAL AND BIOLOGICAL PROPERTIES USING SAVANNAH RIVER BASIN DATA.

EPA Science Inventory

Many multivariate methods are used in describing and predicting relation; each has its unique usage of categorical and non-categorical data. In multivariate analysis of variance (MANOVA), many response variables (y's) are related to many independent variables that are categorical...

Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant

ClinicalTrials.gov

2018-05-04

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Chronic Lymphocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Cytomegaloviral Infection; Hodgkin Lymphoma; Lymphadenopathy; Lymphoblastic Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma

Fruit color mutants in tomato reveal a function of the plastidial isopentenyl diphosphate isomerase (IDI1) in carotenoid biosynthesis

USDA-ARS?s Scientific Manuscript database

Isoprenoids are a large class of compounds that are present in all living organisms. They are derived from the 5C building blocks isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). In plants, IPP is synthesized in the cytoplasm from mevalonic acid via the “MVA pathway” a...

76 FR 59668 - Notice of Extension of Comment Period; International Transmission Company, d/b/a ITC Transmission

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-27

... transformer with two 700-MVA phase-shifting transformers connected in series at ITC's Bunce Creek Station in... installation of the new transformers, also known as phase angle regulators (PARs). On August 9, 2011, DOE... further notice so that the transformers can be placed into service and benefits from controlling the Lake...

75 FR 69425 - Qualified Hydro 30, LLC; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-12

... vertical Kaplan turbine-generator units with a combined capacity of 2.5 megawatts; (5) a new 3-MVA.../ferconline.asp ) under the ``eFiling'' link. For a simpler method of submitting text only comments, click on... this project, including a copy of the application can be viewed or printed on the ``eLibrary'' link of...

MGAS: a powerful tool for multivariate gene-based genome-wide association analysis.

PubMed

Van der Sluis, Sophie; Dolan, Conor V; Li, Jiang; Song, Youqiang; Sham, Pak; Posthuma, Danielle; Li, Miao-Xin

2015-04-01

Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

The role of high-density lipoprotein cholesterol in risk for posttraumatic stress disorder: taking a nutritional approach toward universal prevention.

PubMed

Hamazaki, K; Nishi, D; Yonemoto, N; Noguchi, H; Kim, Y; Matsuoka, Y

2014-09-01

Several cross-sectional studies, but no prospective studies, have reported an association between an abnormal lipid profile and posttraumatic stress disorder (PTSD). We hypothesized that an abnormal lipid profile might predict risk for developing PTSD. In this prospective study, we analyzed data from 237 antidepressant-naïve severely injured patients who participated in the Tachikawa Cohort of Motor Vehicle Accident Study. High-density lipoprotein cholesterol (HDL-C) levels at baseline were significantly lower in patients with PTSD than those without PTSD at 6 months after motor vehicle accident (MVA) and were inversely associated with risk for PTSD. In contrast, triglycerides (TG) at baseline were significantly higher in patients with PTSD than in those without PTSD at 6 months post-MVA and were positively associated with risk for PTSD. There was no clear association between low-density lipoprotein cholesterol or total cholesterol and risk for PTSD. In conclusion, low HDL-C and high TG may be risk factors for PTSD. Determining lipid profiles might help identify those at risk for PTSD after experiencing trauma. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Medical review of fitness to drive in older drivers: the Maryland experience.

PubMed

Soderstrom, Carl A; Joyce, John J

2008-08-01

Over the next several decades, both the number and percentage of older drivers will increase dramatically. Older age is inherently associated with medical conditions, particularly those involving cognition and vision, that can affect medical fitness to drive. Over a 60-year period, the Maryland Motor Vehicle Administration (MVA) in conjunction with its medical advisory board (MAB) has matured a comprehensive system to identify at-risk older drivers and to assess their medical fitness to drive. This paper describes the medical review process in general, and in particular for older drivers, that has evolved in the state of Maryland. The resources, philosophy and research underpinnings of its MAB review process are examined. Studies of functional screening measures in older drivers indicate that older drivers at risk of being at-fault for future crashes can be identified. The feasibility of using such screening measures for drivers referred to the MVA has been confirmed by practical use for a period of seven years. It is possible to create a medical review process with a goal of "safe mobility for life" that supports preservation of the driving privilege among many older drivers.

Mitral Valve Stenosis after Open Repair Surgery for Non-rheumatic Mitral Valve Regurgitation: A Review.

PubMed

Shabsigh, Muhammad; Lawrence, Cassidy; Rosero-Britton, Byron R; Kumar, Nicolas; Kimura, Satoshi; Durda, Michael Andrew; Essandoh, Michael

2016-01-01

Mitral stenosis (MS) after mitral valve (MV) repair is a slowly progressive condition, usually detected many years after the index MV surgery. It is defined as a mean transmitral pressure gradient (TMPG) >5 mmHg or a mitral valve area (MVA) <1.5 cm(2). Pannus formation around the mitral annulus or extending to the mitral leaflets is suggested as the main mechanism for developing delayed MS after MV repair. On the other hand, early stenosis is thought to be a direct result of an undersized annuloplasty ring. Furthermore, in MS following ischemic mitral regurgitation (MR) repair, subvalvular tethering is the hypothesized pathophysiology. MS after MV repair has an incidence of 9-54%. Several factors have been associated with a higher risk for developing MS after MV repair, including the use of flexible Duran annuloplasty rings versus rigid Carpentier-Edwards rings, complete annuloplasty rings versus partial bands, small versus large anterior leaflet opening angle, and anterior leaflet tip opening length. Intraoperative echocardiography can measure the anterior leaflet opening angle, the anterior leaflet tip opening dimension, the MVA and the mean TMPG, and may help identify patients at risk for developing MS after MV repair.

Mitral Valve Stenosis after Open Repair Surgery for Non-rheumatic Mitral Valve Regurgitation: A Review

PubMed Central

Shabsigh, Muhammad; Lawrence, Cassidy; Rosero-Britton, Byron R.; Kumar, Nicolas; Kimura, Satoshi; Durda, Michael Andrew; Essandoh, Michael

2016-01-01

Mitral stenosis (MS) after mitral valve (MV) repair is a slowly progressive condition, usually detected many years after the index MV surgery. It is defined as a mean transmitral pressure gradient (TMPG) >5 mmHg or a mitral valve area (MVA) <1.5 cm2. Pannus formation around the mitral annulus or extending to the mitral leaflets is suggested as the main mechanism for developing delayed MS after MV repair. On the other hand, early stenosis is thought to be a direct result of an undersized annuloplasty ring. Furthermore, in MS following ischemic mitral regurgitation (MR) repair, subvalvular tethering is the hypothesized pathophysiology. MS after MV repair has an incidence of 9–54%. Several factors have been associated with a higher risk for developing MS after MV repair, including the use of flexible Duran annuloplasty rings versus rigid Carpentier–Edwards rings, complete annuloplasty rings versus partial bands, small versus large anterior leaflet opening angle, and anterior leaflet tip opening length. Intraoperative echocardiography can measure the anterior leaflet opening angle, the anterior leaflet tip opening dimension, the MVA and the mean TMPG, and may help identify patients at risk for developing MS after MV repair. PMID:27148540

Technical and Economical Demands on 25K - 77K Refrigerators for Future HTS — Series Products in Power Engineering

NASA Astrophysics Data System (ADS)

Gromoll, B.

2004-06-01

For the future high temperature superconductivity, HTS, series products new refrigerators are essential. Demands are made on these which are only partly fulfilled by refrigerators available in the market today. This refers to cooling power, initial cost and in particular reliability. Without proper refrigeration techniques it will be almost impossible to bring HTS products to the market. Based on the experiences made by the construction and operation of HTS prototypes within our company, like the 400 kW motor, 1.2 MVA current limiter and 1 MVA traction-transformer provided with refrigerators which are available in the market today, criteria have been established to identify the future technical and economical requirements. These criteria apply to efficiency, maintainability, operation flexibility, feasibility of integration and performance/cost ratio. For the temperature range of 20 K to 77 K cooling with Gifford-McMahon, Pulse Tube, Stirling and Mixture-Cascade refrigerators are applicable. The development potential of these processes are compared for the different applications in future series products. Presented are the necessary steps towards reliable and economic refrigerators from the viewpoint of an equipment manufacturer. These are essential for a market entry in the year 2008.

Causal diagrams and multivariate analysis II: precision work.

PubMed

Jupiter, Daniel C

2014-01-01

In this Investigators' Corner, I continue my discussion of when and why we researchers should include variables in multivariate regression. My examination focuses on studies comparing treatment groups and situations for which we can either exclude variables from multivariate analyses or include them for reasons of precision. Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

A survey of variable selection methods in two Chinese epidemiology journals

PubMed Central

2010-01-01

Background Although much has been written on developing better procedures for variable selection, there is little research on how it is practiced in actual studies. This review surveys the variable selection methods reported in two high-ranking Chinese epidemiology journals. Methods Articles published in 2004, 2006, and 2008 in the Chinese Journal of Epidemiology and the Chinese Journal of Preventive Medicine were reviewed. Five categories of methods were identified whereby variables were selected using: A - bivariate analyses; B - multivariable analysis; e.g. stepwise or individual significance testing of model coefficients; C - first bivariate analyses, followed by multivariable analysis; D - bivariate analyses or multivariable analysis; and E - other criteria like prior knowledge or personal judgment. Results Among the 287 articles that reported using variable selection methods, 6%, 26%, 30%, 21%, and 17% were in categories A through E, respectively. One hundred sixty-three studies selected variables using bivariate analyses, 80% (130/163) via multiple significance testing at the 5% alpha-level. Of the 219 multivariable analyses, 97 (44%) used stepwise procedures, 89 (41%) tested individual regression coefficients, but 33 (15%) did not mention how variables were selected. Sixty percent (58/97) of the stepwise routines also did not specify the algorithm and/or significance levels. Conclusions The variable selection methods reported in the two journals were limited in variety, and details were often missing. Many studies still relied on problematic techniques like stepwise procedures and/or multiple testing of bivariate associations at the 0.05 alpha-level. These deficiencies should be rectified to safeguard the scientific validity of articles published in Chinese epidemiology journals. PMID:20920252

Retinoid production using metabolically engineered Escherichia coli with a two-phase culture system.

PubMed

Jang, Hui-Jeong; Yoon, Sang-Hwal; Ryu, Hee-Kyung; Kim, Jung-Hun; Wang, Chong-Long; Kim, Jae-Yean; Oh, Deok-Kun; Kim, Seon-Won

2011-07-29

Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of retinoids, is derived by β-carotene 15,15'-mono(di)oxygenase (BCM(D)O) from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, retinoid production using microbial metabolic engineering has not been reported. Here, we report retinoid production using engineered Escherichia coli that express exogenous BCM(D)O and the mevalonate (MVA) pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay. Among the BCM(D)O tested in E. coli, the synthetic retinoid synthesis protein (SR), based on bacteriorhodopsin-related protein-like homolog (Blh) of the uncultured marine bacteria 66A03, showed the highest β-carotene cleavage activity with no residual intracellular β-carotene. By introducing the exogenous MVA pathway, 8.7 mg/L of retinal was produced, which is 4-fold higher production than that of augmenting the MEP pathway (dxs overexpression). There was a large gap between retinal production and β-carotene consumption using the exogenous MVA pathway; therefore, the retinal derivatives were analyzed. The derivatives, except for retinoic acid, that formed were identified, and the levels of retinal, retinol, and retinyl acetate were measured. Amounts as high as 95 mg/L retinoids were obtained from engineered E. coli DH5α harboring the synthetic SR gene and the exogenous MVA pathway in addition to dxs overexpression, which were cultured at 29°C for 72 hours with 2YT medium containing 2.0% (w/v) glycerol as the main carbon source. However, a significant level of intracellular degradation of the retinoids was also observed in the culture. To prevent degradation of the intracellular retinoids through in situ extraction from the cells, a two-phase culture system with dodecane was used. The highest level of retinoid production (136 mg/L) was obtained after 72 hours with 5 mL of dodecane overlaid on a 5 mL culture. In this study, we successfully produced 136 mg/L retinoids, which were composed of 67 mg/L retinal, 54 mg/L retinol, and 15 mg/L retinyl acetate, using a two-phase culture system with dodecane, which produced 68-fold more retinoids than the initial level of production (2.2 mg/L). Our results demonstrate the potential use of E. coli as a promising microbial cell factory for retinoid production.

Complex Ancestries of Isoprenoid Synthesis in Dinoflagellates.

PubMed

Bentlage, Bastian; Rogers, Travis S; Bachvaroff, Tsvetan R; Delwiche, Charles F

2016-01-01

Isoprenoid metabolism occupies a central position in the anabolic metabolism of all living cells. In plastid-bearing organisms, two pathways may be present for de novo isoprenoid synthesis, the cytosolic mevalonate pathway (MVA) and nuclear-encoded, plastid-targeted nonmevalonate pathway (DOXP). Using transcriptomic data we find that dinoflagellates apparently make exclusive use of the DOXP pathway. Using phylogenetic analyses of all DOXP genes we inferred the evolutionary origins of DOXP genes in dinoflagellates. Plastid replacements led to a DOXP pathway of multiple evolutionary origins. Dinoflagellates commonly referred to as dinotoms due to their relatively recent acquisition of a diatom plastid, express two completely redundant DOXP pathways. Dinoflagellates with a tertiary plastid of haptophyte origin, by contrast, express a hybrid pathway of dual evolutionary origin. Here, changes in the targeting motif of signal/transit peptide likely allow for targeting the new plastid by the proteins of core isoprenoid metabolism proteins. Parasitic dinoflagellates of the Amoebophyra species complex appear to have lost the DOXP pathway, suggesting that they may rely on their host for sterol synthesis. © 2015 The Author(s) Journal of Eukaryotic Microbiology © 2015 International Society of Protistologists.

Structure-to-property relationships in fuel cell catalyst supports: Correlation of surface chemistry and morphology with oxidation resistance of carbon blacks

NASA Astrophysics Data System (ADS)

Artyushkova, Kateryna; Pylypenko, Svitlana; Dowlapalli, Madhu; Atanassov, Plamen

2012-09-01

Linking durability of carbon blacks, expressed as their oxidation resistance, used in PEMFCs as catalyst supports, with their chemistry and morphology is an important task towards designing carbon blacks with desired properties. Structure-to-property relationship between surface chemistry determined by X-ray photoelectron spectroscopy (XPS), morphological structure determined by digital image processing of scanning electron microscopy (SEM) images, physical properties, and electrochemical corrosion behavior determined in an air-breathing gas-diffusion electrode is studied for several un-altered and several modified carbon blacks. We are showing that surface chemistry, graphitic content and certain physical characteristics such as Brunauer-Emmett-Teller (BET) surface area and pore volume, determined by nitrogen adsorptions are not sufficient to explain high corrosion instability of types of carbon blacks. Inclusion of morphological characteristics, such as roughness, texture and shape parameters provide for more inclusive description and therefore more complete structure-to-property correlations of corrosion behavior of carbon blacks. This paper presents the first direct statistically-derived structure-to-property relationship, developed by multivariate analysis (MVA) that links chemical and physical structural properties of the carbon blacks to their critical properties as supports for PEMFC catalysts. We have found that balance between electrocatalytic activity and high resistance towards oxidation and corrosion is achieved by balance between amount of graphitic content and surface oxide coverage, smaller overall roughness and, finally, larger amount of big elongated and loose, and, hypothetically, more hydrophobic pores.

Assessment of cellulolytic microorganisms in soils of Nevados Park, Colombia

PubMed Central

Avellaneda-Torres, Lizeth Manuela; Pulido, Claudia Patricia Guevara; Rojas, Esperanza Torres

2014-01-01

A systematized survey was conducted to find soil-borne microbes that degrade cellulose in soils from unique ecosystems, such as the Superpáramo, Páramo, and the High Andean Forest in the Nevados National Natural Park (NNNP), Colombia. These high mountain ecosystems represent extreme environments, such as high levels of solar radiation, low atmospheric pressure, and extreme daily changes in temperature. Cellulolytic activity of the microorganisms was evaluated using qualitative tests, such as growth in selective media followed by staining with congo red and iodine, and quantitative tests to determine the activity of endoglucanase, β-glucosidase, exoglucanase, and total cellulase. Microorganisms were identified using molecular markers, such as the 16S rRNA gene for bacteria and the internal transcribed spacer region (ITS) of ribosomal DNA for fungi. Multivariate statistical analysis (MVA) was used to select microorganisms with high cellulolytic capacity. A total of 108 microorganisms were isolated from the soils and, in general, the enzymatic activities of fungi were higher than those of bacteria. Our results also found that none of the organisms studied were able to degrade all the components of the cellulose and it is therefore suggested that a combination of bacteria and/or fungi with various enzymatic activities be used to obtain high total cellulolytic activity. This study gives an overview of the potential microorganism that could be used for cellulose degradation in various biotechnological applications and for sustainable agricultural waste treatment. PMID:25763024

Self-Evaluative Appraisals of Coping Capability and Posttraumatic Distress following Motor Vehicle Accidents

ERIC Educational Resources Information Center

Benight, Charles C.; Cieslak, Roman; Molton, Ivan R.; Johnson, Lesley E.

2008-01-01

This study tested the importance of coping self-efficacy (CSE) perceptions and change in perceptions of CSE for recovery from motor vehicle accident (MVA) trauma. Data were collected 7 days following the accident (Time 1; n = 163), 1 month after the accident (Time 2; n = 91), and 3 months after the accident (Time 3; n = 70). Early changes in CSE…

In silico profiling of Escherichia coli and Saccharomyces cerevisiae as terpenoid factories

PubMed Central

2013-01-01

Background Heterologous microbial production of rare plant terpenoids of medicinal or industrial interest is attracting more and more attention but terpenoid yields are still low. Escherichia coli and Saccharomyces cerevisiae are the most widely used heterologous hosts; a direct comparison of both hosts based on experimental data is difficult though. Hence, the terpenoid pathways of E. coli (via 1-deoxy-D-xylulose 5-phosphate, DXP) and S. cerevisiae (via mevalonate, MVA), the impact of the respective hosts metabolism as well as the impact of different carbon sources were compared in silico by means of elementary mode analysis. The focus was set on the yield of isopentenyl diphosphate (IPP), the general terpenoid precursor, to identify new metabolic engineering strategies for an enhanced terpenoid yield. Results Starting from the respective precursor metabolites of the terpenoid pathways (pyruvate and glyceraldehyde-3-phosphate for the DXP pathway and acetyl-CoA for the MVA pathway) and considering only carbon stoichiometry, the two terpenoid pathways are identical with respect to carbon yield. However, with glucose as substrate, the MVA pathway has a lower potential to supply terpenoids in high yields than the DXP pathway if the formation of the required precursors is taken into account, due to the carbon loss in the formation of acetyl-CoA. This maximum yield is further reduced in both hosts when the required energy and reduction equivalents are considered. Moreover, the choice of carbon source (glucose, xylose, ethanol or glycerol) has an effect on terpenoid yield with non-fermentable carbon sources being more promising. Both hosts have deficiencies in energy and redox equivalents for high yield terpenoid production leading to new overexpression strategies (heterologous enzymes/pathways) for an enhanced terpenoid yield. Finally, several knockout strategies are identified using constrained minimal cut sets enforcing a coupling of growth to a terpenoid yield which is higher than any yield published in scientific literature so far. Conclusions This study provides for the first time a comprehensive and detailed in silico comparison of the most prominent heterologous hosts E. coli and S. cerevisiae as terpenoid factories giving an overview on several promising metabolic engineering strategies paving the way for an enhanced terpenoid yield. PMID:24059635

TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T Cell responses providing protection against Leishmania (Viannia).

PubMed

Jayakumar, Asha; Castilho, Tiago M; Park, Esther; Goldsmith-Pestana, Karen; Blackwell, Jenefer M; McMahon-Pratt, Diane

2011-06-01

Leishmania (Viannia) parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Further, vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective. Using a newly developed mouse model of chronic L. (Viannia) panamensis infection and the heterologous DNA prime - modified vaccinia virus Ankara (MVA) boost vaccination modality, we examined whether the conserved vaccine candidate antigen tryparedoxin peroxidase (TRYP) could provide protection against infection/disease. Heterologous prime - boost (DNA/MVA) vaccination utilizing TRYP antigen can provide protection against disease caused by L. (V.) panamensis. However, protection is dependent on modulating the innate immune response using the TLR1/2 agonist Pam3CSK4 during DNA priming. Prime-boost vaccination using DNA alone fails to protect. Prior to infection protectively vaccinated mice exhibit augmented CD4 and CD8 IFNγ and memory responses as well as decreased IL-10 and IL-13 responses. IL-13 and IL-10 have been shown to be independently critical for disease in this model. CD8 T cells have an essential role in mediating host defense, as CD8 depletion reversed protection in the vaccinated mice; vaccinated mice depleted of CD4 T cells remained protected. Hence, vaccine-induced protection is dependent upon TLR1/2 activation instructing the generation of antigen specific CD8 cells and restricting IL-13 and IL-10 responses. Given the general effectiveness of prime-boost vaccination, the recalcitrance of Leishmania (Viannia) to vaccine approaches effective against other species of Leishmania is again evident. However, prime-boost vaccination modality can with modulation induce protective responses, indicating that the delivery system is critical. Moreover, these results suggest that CD8 T cells should be targeted for the development of a vaccine against infection caused by Leishmania (Viannia) parasites. Further, TLR1/2 modulation may be useful in vaccines where CD8 T cell responses are critical.

Operational experience and performance characteristics of a valve-regulated lead-acid battery energy-storage system for providing the customer with critical load protection and energy-management benefits at a lead-recycling plant

NASA Astrophysics Data System (ADS)

Hunt, G. W.

The Power Control Division of GNB Technologies, commissioned on May 13, 1996 a new facility which houses a 5-MW battery energy-storage system (BESS) at GNB's Lead Recycling Centre in Vernon, CA. When the plant loses utility power (which typically happens two or three times a year), the BESS will provide up to 5 MW of power at 4160 VAC in support of all the plant loads. Since the critical loads are not isolated, it is necessary to carry the entire plant load (maximum of 5 MVA) for a short period immediately following an incident until non-critical loads have been automatically shed. Plant loading typically peaks at 3.5 MVA with critical loads of about 2.1 MVA. The BESS also provides the manufacturing plant with customer-side-of-the-meter energy management options to reduce its energy demand during peak periods of the day. The BESS has provided a reduction in monthly electric bills through daily peak-shaving. By design, the battery can provide up to 2.5 MWh of energy and still retain 2.5 MWh of capacity in reserve to handle the possibility of a power outage in protecting the critical loads for up to 1 h. By storing energy from the utility during off-peak hours of the night in the batteries when the cost is low (US4.5¢ per kWh), GNB can then discharge this energy during high demand periods of the day (US14.50 per kW). For example, by reducing its peak demand by 300 kW, the lead-recycling centre can save over US4000 per month in its electric bills. The BESS at Vernon represents a first large-scale use of valve-regulated lead-acid batteries in such a demanding application. This paper presents a summary of the operational experience and performance characteristics of the BESS over the past 2 years.

Sex Hormones and Sleep in Men and Women From the General Population: A Cross-Sectional Observational Study.

PubMed

Kische, Hanna; Ewert, Ralf; Fietze, Ingo; Gross, Stefan; Wallaschofski, Henri; Völzke, Henry; Dörr, Marcus; Nauck, Matthias; Obst, Anne; Stubbe, Beate; Penzel, Thomas; Haring, Robin

2016-11-01

Associations between sex hormones and sleep habits originate mainly from small and selected patient-based samples. We examined data from a population-based sample with various sleep characteristics and the major part of sex hormones measured by mass spectrometry. We used data from 204 men and 213 women of the cross-sectional Study of Health in Pomerania-TREND. Associations of total T (TT) and free T, androstenedione (ASD), estrone, estradiol (E2), dehydroepiandrosterone-sulphate, SHBG, and E2 to TT ratio with sleep measures (including total sleep time, sleep efficiency, wake after sleep onset, apnea-hypopnea index [AHI], Insomnia Severity Index, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index) were assessed by sex-specific multivariable regression models. In men, age-adjusted associations of TT (odds ratio 0.62; 95% confidence interval (CI) 0.46-0.83), free T, and SHBG with AHI were rendered nonsignificant after multivariable adjustment. In multivariable analyses, ASD was associated with Epworth Sleepiness Scale (β-coefficient per SD increase in ASD: -0.71; 95% CI: -1.18 to -0.25). In women, multivariable analyses showed positive associations of dehydroepiandrosterone-sulphate with wake after sleep onset (β-coefficient: .16; 95% CI 0.03-0.28) and of E2 and E2 to TT ratio with Epworth Sleepiness Scale. Additionally, free T and SHBG were associated with AHI in multivariable models among premenopausal women. The present cross-sectional, population-based study observed sex-specific associations of androgens, E2, and SHBG with sleep apnea and daytime sleepiness. However, multivariable-adjusted analyses confirmed the impact of body composition and health-related lifestyle on the association between sex hormones and sleep.

mvMapper: statistical and geographical data exploration and visualization of multivariate analysis of population structure

USDA-ARS?s Scientific Manuscript database

Characterizing population genetic structure across geographic space is a fundamental challenge in population genetics. Multivariate statistical analyses are powerful tools for summarizing genetic variability, but geographic information and accompanying metadata is not always easily integrated into t...

Multivariate analysis of prognostic factors for idiopathic sudden sensorineural hearing loss treated with adjuvant hyperbaric oxygen therapy.

PubMed

Xie, Shaobing; Qiang, Qingfen; Mei, Lingyun; He, Chufeng; Feng, Yong; Sun, Hong; Wu, Xuewen

2018-01-01

The objective of this study is to evaluate possible prognostic factors of idiopathic sudden sensorineural hearing loss (ISSNHL) treated with adjuvant hyperbaric oxygen therapy (HBOT) using univariate and multivariate analyses. From January 2008 to October 2016, records of 178 ISSNHL patients treated with auxiliary hyperbaric oxygen therapy were reviewed to assess hearing recovery and evaluate associated prognostic factors (gender, age, localization, initial hearing threshold, presence of tinnitus, vertigo, ear fullness, hypertension, diabetes, onset of HBOT, number of HBOT, and audiogram), by using univariate and multivariate analyses. The overall recovery rate was 37.1%, including complete recovery (19.7%) and partial recovery (17.4%). According to multivariate analysis, later onset of HBOT and higher initial hearing threshold were associated with a poor prognosis in ISSNHL patients treated with HBOT. HBOT is a safe and beneficial adjuvant therapy for ISSNHL patients. 20 sessions of HBOT is possibly enough to show its therapeutic effect. Earlier HBOT onset and lower initial hearing threshold is associated with favorable hearing recovery.

Cost-effectiveness of stereotactic radiosurgery with and without whole-brain radiotherapy for the treatment of newly diagnosed brain metastases.

PubMed

Hall, Matthew D; McGee, James L; McGee, Mackenzie C; Hall, Kevin A; Neils, David M; Klopfenstein, Jeffrey D; Elwood, Patrick W

2014-12-01

Stereotactic radiosurgery (SRS) alone is increasingly used in patients with newly diagnosed brain metastases. Stereotactic radiosurgery used together with whole-brain radiotherapy (WBRT) reduces intracranial failure rates, but this combination also causes greater neurocognitive toxicity and does not improve survival. Critics of SRS alone contend that deferring WBRT results in an increased need for salvage therapy and in higher costs. The authors compared the cost-effectiveness of treatment with SRS alone, SRS and WBRT (SRS+WBRT), and surgery followed by SRS (S+SRS) at the authors' institution. The authors retrospectively reviewed the medical records of 289 patients in whom brain metastases were newly diagnosed and who were treated between May 2001 and December 2007. Overall survival curves were plotted using the Kaplan-Meier method. Multivariate proportional hazards analysis (MVA) was used to identify factors associated with overall survival. Survival data were complete for 96.2% of patients, and comprehensive data on the resource use for imaging, hospitalizations, and salvage therapies were available from the medical records. Treatment costs included the cost of initial and all salvage therapies for brain metastases, hospitalizations, management of complications, and imaging. They were computed on the basis of the 2007 Medicare fee schedule from a payer perspective. Average treatment cost and average cost per month of median survival were compared. Sensitivity analysis was performed to examine the impact of variations in key cost variables. No significant differences in overall survival were observed among patients treated with SRS alone, SRS+WBRT, or S+SRS with respective median survival of 9.8, 7.4, and 10.6 months. The MVA detected a significant association of overall survival with female sex, Karnofsky Performance Scale (KPS) score, primary tumor control, absence of extracranial metastases, and number of brain metastases. Salvage therapy was required in 43% of SRS-alone and 26% of SRS+WBRT patients (p < 0.009). Despite an increased need for salvage therapy, the average cost per month of median survival was $2412 per month for SRS alone, $3220 per month for SRS+WBRT, and $4360 per month for S+SRS (p < 0.03). Compared with SRS+WBRT, SRS alone had an average incremental cost savings of $110 per patient. Sensitivity analysis confirmed that the average treatment cost of SRS alone remained less than or was comparable to SRS+WBRT over a wide range of costs and treatment efficacies. Despite an increased need for salvage therapy, patients with newly diagnosed brain metastases treated with SRS alone have similar overall survival and receive more cost-effective care than those treated with SRS+WBRT. Compared with SRS+WBRT, initial management with SRS alone does not result in a higher average cost.

Linkage Analysis of a Model Quantitative Trait in Humans: Finger Ridge Count Shows Significant Multivariate Linkage to 5q14.1

PubMed Central

Medland, Sarah E; Loesch, Danuta Z; Mdzewski, Bogdan; Zhu, Gu; Montgomery, Grant W; Martin, Nicholas G

2007-01-01

The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds [LOD] = 3.34, pointwise-empirical p-value = 0.00025) that was predominantly driven by linkage to the ring, index, and middle fingers. The strongest univariate linkage was to 1q42.2 (LOD = 2.04, point-wise p-value = 0.002, genome-wide p-value = 0.29). In summary, the combination of univariate and multivariate results was more informative than simple univariate analyses alone. Patterns of quantitative trait loci factor loadings consistent with developmental fields were observed, and the simple pleiotropic model underlying the absolute ridge count was not sufficient to characterize the interrelationships between the ridge counts of individual fingers. PMID:17907812

Contactless system of excitation current measurement in the windings with high inductance

NASA Astrophysics Data System (ADS)

Chubraeva, L.; Evseev, E.; Timofeev, S.

2018-02-01

The results of development, manufacturing and testing of a special contactless maintenance-free excitation current measurement system intended for the windings with high inductance, typical for superconductive alternators, are presented. The system was assembled on the brushless exciter is intended for 1 MVA wind-power generator with the winding, manufactured of high-temperature superconductors (HTSC). The alternator with brushless exciter were manufactured and successfully tested.

Isoprenoid biosynthesis in eukaryotic phototrophs: A spotlight on algae

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

Lohr M.; Schwender J.; Polle, J. E. W.

Isoprenoids are one of the largest groups of natural compounds and have a variety of important functions in the primary metabolism of land plants and algae. In recent years, our understanding of the numerous facets of isoprenoid metabolism in land plants has been rapidly increasing, while knowledge on the metabolic network of isoprenoids in algae still lags behind. Here, current views on the biochemistry and genetics of the core isoprenoid metabolism in land plants and in the major algal phyla are compared and some of the most pressing open questions are highlighted. Based on the different evolutionary histories of themore » various groups of eukaryotic phototrophs, we discuss the distribution and regulation of the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways in land plants and algae and the potential consequences of the loss of the MVA pathway in groups such as the green algae. For the prenyltransferases, serving as gatekeepers to the various branches of terpenoid biosynthesis in land plants and algae, we explore the minimal inventory necessary for the formation of primary isoprenoids and present a preliminary analysis of their occurrence and phylogeny in algae with primary and secondary plastids. The review concludes with some perspectives on genetic engineering of the isoprenoid metabolism in algae.« less

Three-dimensional echocardiographic assessment of the repaired mitral valve.

PubMed

Maslow, Andrew; Mahmood, Feroze; Poppas, Athena; Singh, Arun

2014-02-01

This study examined the geometric changes of the mitral valve (MV) after repair using conventional and three-dimensional echocardiography. Prospective evaluation of consecutive patients undergoing mitral valve repair. Tertiary care university hospital. Fifty consecutive patients scheduled for elective repair of the mitral valve for regurgitant disease. Intraoperative transesophageal echocardiography. Assessments of valve area (MVA) were performed using two-dimensional planimetry (2D-Plan), pressure half-time (PHT), and three-dimensional planimetry (3D-Plan). In addition, the direction of ventricular inflow was assessed from the three-dimensional imaging. Good correlations (r = 0.83) and agreement (-0.08 +/- 0.43 cm(2)) were seen between the MVA measured with 3D-Plan and PHT, and were better than either compared to 2D-Plan. MVAs were smaller after repair of functional disease repaired with an annuloplasty ring. After repair, ventricular inflow was directed toward the lateral ventricular wall. Subgroup analysis showed that the change in inflow angle was not different after repair of functional disease (168 to 171 degrees) as compared to those presenting with degenerative disease (168 to 148 degrees; p<0.0001). Three-dimensional imaging provides caregivers with a unique ability to assess changes in valve function after mitral valve repair. Copyright © 2014 Elsevier Inc. All rights reserved.

Generation of Recombinant Modified Vaccinia Virus Ankara Encoding VP2, NS1, and VP7 Proteins of Bluetongue Virus.

PubMed

Marín-López, Alejandro; Ortego, Javier

2016-01-01

Modified Vaccinia Virus Ankara (MVA) is employed widely as an experimental vaccine vector for its lack of replication in mammalian cells and high expression level of foreign/heterologous genes. Recombinant MVAs (rMVAs) are used as platforms for protein production as well as vectors to generate vaccines against a high number of infectious diseases and other pathologies. The portrait of the virus combines desirable elements such as high-level biological safety, the ability to activate appropriate innate immune mediators upon vaccination, and the capacity to deliver substantial amounts of heterologous antigens. Recombinant MVAs encoding proteins of bluetongue virus (BTV), an Orbivirus that infects domestic and wild ruminants transmitted by biting midges of the Culicoides species, are excellent vaccine candidates against this virus. In this chapter we describe the methods for the generation of rMVAs encoding VP2, NS1, and VP7 proteins of bluetongue virus as a model example for orbiviruses. The protocols included cover the cloning of VP2, NS1, and VP7 BTV-4 genes in a transfer plasmid, the construction of recombinant MVAs, the titration of virus working stocks and the protein expression analysis by immunofluorescence and radiolabeling of rMVA infected cells as well as virus purification.

Protein and modified vaccinia virus Ankara-based influenza virus nucleoprotein vaccines are differentially immunogenic in BALB/c mice.

PubMed

Altenburg, A F; Magnusson, S E; Bosman, F; Stertman, L; de Vries, R D; Rimmelzwaan, G F

2017-10-01

Because of the high variability of seasonal influenza viruses and the eminent threat of influenza viruses with pandemic potential, there is great interest in the development of vaccines that induce broadly protective immunity. Most probably, broadly protective influenza vaccines are based on conserved proteins, such as nucleoprotein (NP). NP is a vaccine target of interest as it has been shown to induce cross-reactive antibody and T cell responses. Here we tested and compared various NP-based vaccine preparations for their capacity to induce humoral and cellular immune responses to influenza virus NP. The immunogenicity of protein-based vaccine preparations with Matrix-M™ adjuvant as well as recombinant viral vaccine vector modified Vaccinia virus Ankara (MVA) expressing the influenza virus NP gene, with or without modifications that aim at optimization of CD8 + T cell responses, was addressed in BALB/c mice. Addition of Matrix-M™ adjuvant to NP wild-type protein-based vaccines significantly improved T cell responses. Furthermore, recombinant MVA expressing the influenza virus NP induced strong antibody and CD8 + T cell responses, which could not be improved further by modifications of NP to increase antigen processing and presentation. © 2017 British Society for Immunology.

Do X-ray-occult fractures play a role in chronic pain following a whiplash injury?

PubMed

Hertzum-Larsen, Rasmus; Petersen, Henrik; Kasch, Helge; Bendix, Tom

2014-08-01

Whiplash trauma in motor vehicle accidents (MVA) may involve various painful soft tissue damages, but weeks/months later a minority of victims still suffers from various long-lasting and disabling symptoms, whiplash-associated disorders (WAD). The etiology is currently unknown, but X-ray-occult fractures may be one cause in some cases. The purpose of this prospective study was to examine the association between occult fractures, as seen on bone single photon emission computed tomography (SPECT), with neck-, head- and arm pain. An inception cohort of 107 patients presenting with acute whiplash symptoms following an MVA was invited to have a cervical SPECT shortly post injury and again 6 months later. Associations between occult fractures and pain levels at baseline, 6 and 12 months of follow-up were analyzed. Eighty-eight patients had baseline SPECT performed at median 15 days (range 3-28) post injury, but only 49 patients accepted to have the follow-up SPECT at 6 months. Abnormal SPECT, defined as minimum one area of focal uptake, was seen in 32 patients at baseline, reflecting an occult fracture. Occult fractures were not associated with pain levels, neither at baseline nor at follow-up. Occult fractures do not seem to play a role for development of chronic pain after whiplash.

Functional capacity evaluation of work performance among individuals with pelvic injuries following motor vehicle accidents.

PubMed

Ratzon, Navah Z; Ari Shevil, Eynat Ben; Froom, Paul; Friedman, Sharon; Amit, Yehuda

2013-01-01

Pelvic injuries following motor vehicle accidents (MVA) cause disability and affect work capabilities. This study evaluated functional, self-report, and medical-based factors that could predict work capacity as was reflected in a functional capacity evaluation (FCE) among persons who sustained a pelvic injury. It was hypothesized that self-reported functional status and bio-demographic variables would predict work capacity. Sixty-one community-dwelling adults previously hospitalized following a MVA induced pelvic injury. FCE for work performance was conducted using the Physical Work Performance Evaluation (PWPE). Additional data was collected through a demographics questionnaire and the Functional Status Questionnaire. All participants underwent an orthopedic medical examination of the hip and lower extremities. Most participants self-reported that their work capacity post-injury were lower than their job required. PWPE scores indicated below-range functional performance. Regression models predicted 23% to 51% of PWPE subtests. Participants' self-report of functioning (instrumental activities of daily living and work) and bio-demographic variables (gender and age) were better predictors of PWPE scores than factors originating from the medical examination. Results support the inclusion of FCE, in addition to self-report of functioning and medical examination, to evaluate work capacity among individuals' post-pelvic injury and interventions and discharge planning.

Capacitive energy storage and recovery for synchrotron magnets

NASA Astrophysics Data System (ADS)

Koseki, K.

2014-06-01

Feasibility studies on capacitive energy storage and recovery in the main-ring synchrotron of the Japan Proton Accelerator Research Complex were conducted by circuit simulation. The estimated load fluctuation was 96 MVA in total for dipole magnets, which is likely to induce a serious disturbance in the main grid. It was found that the energy stored in the magnets after the excitation period can be recovered to the storage capacitor by controlling the voltage across the energy-storage capacitor using a pulse-width-modulation converter and reused in the next operational cycle. It was also found that the power fluctuation in the main grid can be reduced to 12 MVA. An experimental evaluation of an aluminum metalized film capacitor revealed that capacitance loss was induced by a fluctuating voltage applied to the storage capacitor when applying the proposed method. The capacitance loss was induced by corona discharge around the edges of segmented electrodes of a self-healing capacitor. The use of aluminum-zinc alloy was evaluated as a countermeasure to mitigate the effect induced by the corona discharge. For a zinc content of 8%, which was optimized experimentally, a capacitor with a sufficient life time expectancy of 20 years and a working potential gradient of 250 V/μm was developed.

A Multivariate Genome-Wide Association Analysis of 10 LDL Subfractions, and Their Response to Statin Treatment, in 1868 Caucasians

PubMed Central

Shim, Heejung; Chasman, Daniel I.; Smith, Joshua D.; Mora, Samia; Ridker, Paul M.; Nickerson, Deborah A.; Krauss, Ronald M.; Stephens, Matthew

2015-01-01

We conducted a genome-wide association analysis of 7 subfractions of low density lipoproteins (LDLs) and 3 subfractions of intermediate density lipoproteins (IDLs) measured by gradient gel electrophoresis, and their response to statin treatment, in 1868 individuals of European ancestry from the Pharmacogenomics and Risk of Cardiovascular Disease study. Our analyses identified four previously-implicated loci (SORT1, APOE, LPA, and CETP) as containing variants that are very strongly associated with lipoprotein subfractions (log10Bayes Factor > 15). Subsequent conditional analyses suggest that three of these (APOE, LPA and CETP) likely harbor multiple independently associated SNPs. Further, while different variants typically showed different characteristic patterns of association with combinations of subfractions, the two SNPs in CETP show strikingly similar patterns - both in our original data and in a replication cohort - consistent with a common underlying molecular mechanism. Notably, the CETP variants are very strongly associated with LDL subfractions, despite showing no association with total LDLs in our study, illustrating the potential value of the more detailed phenotypic measurements. In contrast with these strong subfraction associations, genetic association analysis of subfraction response to statins showed much weaker signals (none exceeding log10Bayes Factor of 6). However, two SNPs (in APOE and LPA) previously-reported to be associated with LDL statin response do show some modest evidence for association in our data, and the subfraction response proles at the LPA SNP are consistent with the LPA association, with response likely being due primarily to resistance of Lp(a) particles to statin therapy. An additional important feature of our analysis is that, unlike most previous analyses of multiple related phenotypes, we analyzed the subfractions jointly, rather than one at a time. Comparisons of our multivariate analyses with standard univariate analyses demonstrate that multivariate analyses can substantially increase power to detect associations. Software implementing our multivariate analysis methods is available at http://stephenslab.uchicago.edu/software.html. PMID:25898129

Multivariate evaluation of the effectiveness of treatment efficacy of cypermethrin against sea lice (Lepeophtheirus salmonis) in Atlantic salmon (Salmo salar)

PubMed Central

2013-01-01

Background The sea louse Lepeophtheirus salmonis is the most important ectoparasite of farmed Atlantic salmon (Salmo salar) in Norwegian aquaculture. Control of sea lice is primarily dependent on the use of delousing chemotherapeutants, which are both expensive and toxic to other wildlife. The method most commonly used for monitoring treatment effectiveness relies on measuring the percentage reduction in the mobile stages of Lepeophtheirus salmonis only. However, this does not account for changes in the other sea lice stages and may result in misleading or incomplete interpretation regarding the effectiveness of treatment. With the aim of improving the evaluation of delousing treatments, we explored multivariate analyses of bath treatments using the topical pyrethroid, cypermethrin, in salmon pens at five Norwegian production sites. Results Conventional univariate analysis indicated reductions of over 90% in mobile stages at all sites. In contrast, multivariate analyses indicated differing treatment effectiveness between sites (p-value < 0.01) based on changes in the proportion and abundance of the chalimus and PAAM (pre-adult and adult males) stages. Low water temperatures and shortened intervals between sampling after treatment may account for the differences in the composition of chalimus and PAAM stage groups following treatment. Using multivariate analysis, such factors could be separated from those which were attributable to inadequate treatment or chemotherapeutant failure. Conclusions Multivariate analyses for evaluation of treatment effectiveness against multiple life cycle stages of L. salmonis yield additional information beyond that derivable from univariate methods. This can aid in the identification of causes of apparent treatment failure in salmon aquaculture. PMID:24354936

Effects of Flavor and Texture on the Sensory Perception of Gouda-Type Cheese Varieties during Ripening Using Multivariate Analysis.

PubMed

Shiota, Makoto; Iwasawa, Ai; Suzuki-Iwashima, Ai; Iida, Fumiko

2015-12-01

The impact of flavor composition, texture, and other factors on desirability of different commercial sources of Gouda-type cheese using multivariate analyses on the basis of sensory and instrumental analyses were investigated. Volatile aroma compounds were measured using headspace solid-phase microextraction gas chromatography/mass spectrometry (GC/MS) and steam distillation extraction (SDE)-GC/MS, and fatty acid composition, low-molecular-weight compounds, including amino acids, and organic acids, as well pH, texture, and color were measured to determine their relationship with sensory perception. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed to discriminate between 2 different ripening periods in 7 sample sets, revealing that ethanol, ethyl acetate, hexanoic acid, and octanoic acid increased with increasing sensory attribute scores for sweetness, fruity, and sulfurous. A partial least squares (PLS) regression model was constructed to predict the desirability of cheese using these parameters. We showed that texture and buttery flavors are important factors affecting the desirability of Gouda-type cheeses for Japanese consumers using these multivariate analyses. © 2015 Institute of Food Technologists®

Extending Inferential Group Analysis in Type 2 Diabetic Patients with Multivariate GLM Implemented in SPM8.

PubMed

Ferreira, Fábio S; Pereira, João M S; Duarte, João V; Castelo-Branco, Miguel

2017-01-01

Although voxel based morphometry studies are still the standard for analyzing brain structure, their dependence on massive univariate inferential methods is a limiting factor. A better understanding of brain pathologies can be achieved by applying inferential multivariate methods, which allow the study of multiple dependent variables, e.g. different imaging modalities of the same subject. Given the widespread use of SPM software in the brain imaging community, the main aim of this work is the implementation of massive multivariate inferential analysis as a toolbox in this software package. applied to the use of T1 and T2 structural data from diabetic patients and controls. This implementation was compared with the traditional ANCOVA in SPM and a similar multivariate GLM toolbox (MRM). We implemented the new toolbox and tested it by investigating brain alterations on a cohort of twenty-eight type 2 diabetes patients and twenty-six matched healthy controls, using information from both T1 and T2 weighted structural MRI scans, both separately - using standard univariate VBM - and simultaneously, with multivariate analyses. Univariate VBM replicated predominantly bilateral changes in basal ganglia and insular regions in type 2 diabetes patients. On the other hand, multivariate analyses replicated key findings of univariate results, while also revealing the thalami as additional foci of pathology. While the presented algorithm must be further optimized, the proposed toolbox is the first implementation of multivariate statistics in SPM8 as a user-friendly toolbox, which shows great potential and is ready to be validated in other clinical cohorts and modalities.

Extending Inferential Group Analysis in Type 2 Diabetic Patients with Multivariate GLM Implemented in SPM8

PubMed Central

Ferreira, Fábio S.; Pereira, João M.S.; Duarte, João V.; Castelo-Branco, Miguel

2017-01-01

Background: Although voxel based morphometry studies are still the standard for analyzing brain structure, their dependence on massive univariate inferential methods is a limiting factor. A better understanding of brain pathologies can be achieved by applying inferential multivariate methods, which allow the study of multiple dependent variables, e.g. different imaging modalities of the same subject. Objective: Given the widespread use of SPM software in the brain imaging community, the main aim of this work is the implementation of massive multivariate inferential analysis as a toolbox in this software package. applied to the use of T1 and T2 structural data from diabetic patients and controls. This implementation was compared with the traditional ANCOVA in SPM and a similar multivariate GLM toolbox (MRM). Method: We implemented the new toolbox and tested it by investigating brain alterations on a cohort of twenty-eight type 2 diabetes patients and twenty-six matched healthy controls, using information from both T1 and T2 weighted structural MRI scans, both separately – using standard univariate VBM - and simultaneously, with multivariate analyses. Results: Univariate VBM replicated predominantly bilateral changes in basal ganglia and insular regions in type 2 diabetes patients. On the other hand, multivariate analyses replicated key findings of univariate results, while also revealing the thalami as additional foci of pathology. Conclusion: While the presented algorithm must be further optimized, the proposed toolbox is the first implementation of multivariate statistics in SPM8 as a user-friendly toolbox, which shows great potential and is ready to be validated in other clinical cohorts and modalities. PMID:28761571

Multivariate geomorphic analysis of forest streams: Implications for assessment of land use impacts on channel condition

Treesearch

Richard. D. Wood-Smith; John M. Buffington

1996-01-01

Multivariate statistical analyses of geomorphic variables from 23 forest stream reaches in southeast Alaska result in successful discrimination between pristine streams and those disturbed by land management, specifically timber harvesting and associated road building. Results of discriminant function analysis indicate that a three-variable model discriminates 10...

Application of multivariate statistical techniques in microbial ecology.

PubMed

Paliy, O; Shankar, V

2016-03-01

Recent advances in high-throughput methods of molecular analyses have led to an explosion of studies generating large-scale ecological data sets. In particular, noticeable effect has been attained in the field of microbial ecology, where new experimental approaches provided in-depth assessments of the composition, functions and dynamic changes of complex microbial communities. Because even a single high-throughput experiment produces large amount of data, powerful statistical techniques of multivariate analysis are well suited to analyse and interpret these data sets. Many different multivariate techniques are available, and often it is not clear which method should be applied to a particular data set. In this review, we describe and compare the most widely used multivariate statistical techniques including exploratory, interpretive and discriminatory procedures. We consider several important limitations and assumptions of these methods, and we present examples of how these approaches have been utilized in recent studies to provide insight into the ecology of the microbial world. Finally, we offer suggestions for the selection of appropriate methods based on the research question and data set structure. © 2016 John Wiley & Sons Ltd.

NONPARAMETRIC MANOVA APPROACHES FOR NON-NORMAL MULTIVARIATE OUTCOMES WITH MISSING VALUES

PubMed Central

He, Fanyin; Mazumdar, Sati; Tang, Gong; Bhatia, Triptish; Anderson, Stewart J.; Dew, Mary Amanda; Krafty, Robert; Nimgaonkar, Vishwajit; Deshpande, Smita; Hall, Martica; Reynolds, Charles F.

2017-01-01

Between-group comparisons often entail many correlated response variables. The multivariate linear model, with its assumption of multivariate normality, is the accepted standard tool for these tests. When this assumption is violated, the nonparametric multivariate Kruskal-Wallis (MKW) test is frequently used. However, this test requires complete cases with no missing values in response variables. Deletion of cases with missing values likely leads to inefficient statistical inference. Here we extend the MKW test to retain information from partially-observed cases. Results of simulated studies and analysis of real data show that the proposed method provides adequate coverage and superior power to complete-case analyses. PMID:29416225

Graphite Web: web tool for gene set analysis exploiting pathway topology

PubMed Central

Sales, Gabriele; Calura, Enrica; Martini, Paolo; Romualdi, Chiara

2013-01-01

Graphite web is a novel web tool for pathway analyses and network visualization for gene expression data of both microarray and RNA-seq experiments. Several pathway analyses have been proposed either in the univariate or in the global and multivariate context to tackle the complexity and the interpretation of expression results. These methods can be further divided into ‘topological’ and ‘non-topological’ methods according to their ability to gain power from pathway topology. Biological pathways are, in fact, not only gene lists but can be represented through a network where genes and connections are, respectively, nodes and edges. To this day, the most used approaches are non-topological and univariate although they miss the relationship among genes. On the contrary, topological and multivariate approaches are more powerful, but difficult to be used by researchers without bioinformatic skills. Here we present Graphite web, the first public web server for pathway analysis on gene expression data that combines topological and multivariate pathway analyses with an efficient system of interactive network visualizations for easy results interpretation. Specifically, Graphite web implements five different gene set analyses on three model organisms and two pathway databases. Graphite Web is freely available at http://graphiteweb.bio.unipd.it/. PMID:23666626

Quantifying Impacts of Urban Growth Potential on Army Training Capabilities

DTIC Science & Technology

2017-09-12

Capacity” ERDC/CERL TR-17-34 ii Abstract Building on previous studies of urban growth and population effects on U.S. military installations and...combat team studies . CAA has developed an iterative process that builds on Military Value Anal- ysis (MVA) models that include a set of attributes that...Methods and tools were developed to support a nationwide analysis. This study focused on installations operating training areas that were high

Reduced Power Laer Designation Systems

DTIC Science & Technology

2008-06-20

200KD, Ri = = 60Kfl, and R 2 = R4 = 2K yields an overall transimpedance gain of 200K x 30 x 30 = 180MV/A. Figure 3. Three stage photodiode amplifier ...transistor circuit for bootstrap buffering of the input stage, comparing the noise performance of the candidate amplifier designs, selecting the two...transistor bootstrap design as the circuit of choice, and comparing the performance of this circuit against that of a basic transconductance amplifier

Interpretation of Data from Uphole Refraction Surveys

DTIC Science & Technology

1980-06-01

Seismic refraction Seismic refraction method Seismic surveys Subsurface exploration ""-. 20, AI0SrRACT -(CmtuamU 00MvaO eL If naaaaamr and Identlfyby...by the presence of subsurface cavities and large cavities are identifiable, the sensitivity of the method is marginal for practical use in cavity...detection. Some cavities large enough to be of engineering signifi- cance (e.g., a tunnel of h-m diameter) may be practically undetectable by this method

Dosimetric Predictors of Hypothyroidism After Radical Intensity-modulated Radiation Therapy for Non-metastatic Nasopharyngeal Carcinoma.

PubMed

Lee, V; Chan, Sum-Yin; Choi, Cheuk-Wai; Kwong, D; Lam, Ka-On; Tong, Chi-Chung; Sze, Chun-Kin; Ng, S; Leung, To-Wai; Lee, A

2016-08-01

To investigate dosimetric predictors of hypothyroidism after radical intensity-modulated radiation therapy (IMRT) for non-metastatic nasopharyngeal carcinoma (NPC). Patients with non-metastatic NPC treated with radical IMRT from 2008 to 2013 were reviewed. Serum thyroid function tests before and after IMRT were regularly monitored. Univariable and multivariable analyses were carried out for predictors of biochemical and clinical hypothyroidism. In total, 149 patients were recruited. After a median follow-up duration of 3.1 years, 33 (22.1%) and 21 (14.1%) patients developed biochemical and clinical hypothyroidism, respectively. Eight (24.2%) patients who had biochemical hypothyroidism developed clinical hypothyroidism later. Univariable and multivariable analyses revealed that the volume of the thyroid (P=0.002, multivariable), VS60 (the absolute thyroid volume spared from 60 Gy or less) (P<0.001, multivariable) and VS45 (P<0.001, multivariable) of the thyroid were significant predictors of biochemical hypothyroidism. The freedom from biochemical hypothyroidism was longer for those whose VS60 ≥ 10 cm(3) (mean 90.9 versus 62.6 months; P<0.001) and VS45 ≥ 5 cm(3) (mean 91.9 versus 65.2 months; P=0.001). Similarly multivariable analyses revealed that VS60 (P=0.001) and VS45 (P=0.003) were significant predictors of clinical hypothyroidism. The freedom from clinical hypothyroidism was longer for those whose VS60 ≥ 10 cm(3) (91.5 versus 73.3 months; P=0.002) and VS45 ≥ 5 cm(3) (91.5 versus 75.9 months; P=0.007). VS60 and VS45 of the thyroid should be considered important dose constraints against hypothyroidism without compromising target coverage during IMRT optimisation for NPC. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Differentiation of Toxocara canis and Toxocara cati based on PCR-RFLP analyses of rDNA-ITS and mitochondrial cox1 and nad1 regions.

PubMed

Mikaeili, Fattaneh; Mathis, Alexander; Deplazes, Peter; Mirhendi, Hossein; Barazesh, Afshin; Ebrahimi, Sepideh; Kia, Eshrat Beigom

2017-09-26

The definitive genetic identification of Toxocara species is currently based on PCR/sequencing. The objectives of the present study were to design and conduct an in silico polymerase chain reaction-restriction fragment length polymorphism method for identification of Toxocara species. In silico analyses using the DNASIS and NEBcutter softwares were performed with rDNA internal transcribed spacers, and mitochondrial cox1 and nad1 sequences obtained in our previous studies along with relevant sequences deposited in GenBank. Consequently, RFLP profiles were designed and all isolates of T. canis and T. cati collected from dogs and cats in different geographical areas of Iran were investigated with the RFLP method using some of the identified suitable enzymes. The findings of in silico analyses predicted that on the cox1 gene only the MboII enzyme is appropriate for PCR-RFLP to reliably distinguish the two species. No suitable enzyme for PCR-RFLP on the nad1 gene was identified that yields the same pattern for all isolates of a species. DNASIS software showed that there are 241 suitable restriction enzymes for the differentiation of T. canis from T. cati based on ITS sequences. RsaI, MvaI and SalI enzymes were selected to evaluate the reliability of the in silico PCR-RFLP. The sizes of restriction fragments obtained by PCR-RFLP of all samples consistently matched the expected RFLP patterns. The ITS sequences are usually conserved and the PCR-RFLP approach targeting the ITS sequence is recommended for the molecular differentiation of Toxocara species and can provide a reliable tool for identification purposes particularly at the larval and egg stages.

Hydrothermal contamination of public supply wells in Napa and Sonoma Valleys, California

USGS Publications Warehouse

Forrest, Matthew J.; Kulongoski, Justin T.; Edwards, Matthew S.; Farrar, Christopher D.; Belitz, Kenneth; Norris, Richard D.

2013-01-01

Groundwater chemistry and isotope data from 44 public supply wells in the Napa and Sonoma Valleys, California were determined to investigate mixing of relatively shallow groundwater with deeper hydrothermal fluids. Multivariate analyses including Cluster Analyses, Multidimensional Scaling (MDS), Principal Components Analyses (PCA), Analysis of Similarities (ANOSIM), and Similarity Percentage Analyses (SIMPER) were used to elucidate constituent distribution patterns, determine which constituents are significantly associated with these hydrothermal systems, and investigate hydrothermal contamination of local groundwater used for drinking water. Multivariate statistical analyses were essential to this study because traditional methods, such as mixing tests involving single species (e.g. Cl or SiO2) were incapable of quantifying component proportions due to mixing of multiple water types. Based on these analyses, water samples collected from the wells were broadly classified as fresh groundwater, saline waters, hydrothermal fluids, or mixed hydrothermal fluids/meteoric water wells. The Multivariate Mixing and Mass-balance (M3) model was applied in order to determine the proportion of hydrothermal fluids, saline water, and fresh groundwater in each sample. Major ions, isotopes, and physical parameters of the waters were used to characterize the hydrothermal fluids as Na–Cl type, with significant enrichment in the trace elements As, B, F and Li. Five of the wells from this study were classified as hydrothermal, 28 as fresh groundwater, two as saline water, and nine as mixed hydrothermal fluids/meteoric water wells. The M3 mixing-model results indicated that the nine mixed wells contained between 14% and 30% hydrothermal fluids. Further, the chemical analyses show that several of these mixed-water wells have concentrations of As, F and B that exceed drinking-water standards or notification levels due to contamination by hydrothermal fluids.

A Multivariate Genetic Analysis of Specific Phobia, Separation Anxiety and Social Phobia in Early Childhood

ERIC Educational Resources Information Center

Eley, Thalia C.; Rijsdijk, Fruhling V.; Perrin, Sean; O'Connor, Thomas G.; Bolton, Derek

2008-01-01

Background: Comorbidity amongst anxiety disorders is very common in children as in adults and leads to considerable distress and impairment, yet is poorly understood. Multivariate genetic analyses can shed light on the origins of this comorbidity by revealing whether genetic or environmental risks for one disorder also influence another. We…

Decomposing biodiversity data using the Latent Dirichlet Allocation model, a probabilistic multivariate statistical method

Treesearch

Denis Valle; Benjamin Baiser; Christopher W. Woodall; Robin Chazdon; Jerome Chave

2014-01-01

We propose a novel multivariate method to analyse biodiversity data based on the Latent Dirichlet Allocation (LDA) model. LDA, a probabilistic model, reduces assemblages to sets of distinct component communities. It produces easily interpretable results, can represent abrupt and gradual changes in composition, accommodates missing data and allows for coherent estimates...

Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults

PubMed Central

Grunenberg, Nicole A.; Sanchez, Brittany J.; Seaton, Kelly E.; Ferrari, Guido; Moody, M. Anthony; Frahm, Nicole; Montefiori, David C.; Hay, Christine M.; Goepfert, Paul A.; Baden, Lindsey R.; Robinson, Harriet L.; Yu, Xuesong; Gilbert, Peter B.; McElrath, M. Juliana; Huang, Yunda; Tomaras, Georgia D.

2017-01-01

Background A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. Methods Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination. Results All regimens were well tolerated and safe. Full dose DgDgM_M and DgDgMM_M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one-year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF. Conclusion This DNA/MVA prime-boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation. Trial registration ClinicalTrials.gov NCT01571960 PMID:28727817

Applying monitoring, verification, and accounting techniques to a real-world, enhanced oil recovery operational CO2 leak

USGS Publications Warehouse

Wimmer, B.T.; Krapac, I.G.; Locke, R.; Iranmanesh, A.

2011-01-01

The use of carbon dioxide (CO2) for enhanced oil recovery (EOR) is being tested for oil fields in the Illinois Basin, USA. While this technology has shown promise for improving oil production, it has raised some issues about the safety of CO2 injection and storage. The Midwest Geological Sequestration Consortium (MGSC) organized a Monitoring, Verification, and Accounting (MVA) team to develop and deploy monitoring programs at three EOR sites in Illinois, Indiana, and Kentucky, USA. MVA goals include establishing baseline conditions to evaluate potential impacts from CO2 injection, demonstrating that project activities are protective of human health and the environment, and providing an accurate accounting of stored CO2. This paper focuses on the use of MVA techniques in monitoring a small CO2 leak from a supply line at an EOR facility under real-world conditions. The ability of shallow monitoring techniques to detect and quantify a CO2 leak under real-world conditions has been largely unproven. In July of 2009, a leak in the pipe supplying pressurized CO2 to an injection well was observed at an MGSC EOR site located in west-central Kentucky. Carbon dioxide was escaping from the supply pipe located approximately 1 m underground. The leak was discovered visually by site personnel and injection was halted immediately. At its largest extent, the hole created by the leak was approximately 1.9 m long by 1.7 m wide and 0.7 m deep in the land surface. This circumstance provided an excellent opportunity to evaluate the performance of several monitoring techniques including soil CO2 flux measurements, portable infrared gas analysis, thermal infrared imagery, and aerial hyperspectral imagery. Valuable experience was gained during this effort. Lessons learned included determining 1) hyperspectral imagery was not effective in detecting this relatively small, short-term CO2 leak, 2) even though injection was halted, the leak remained dynamic and presented a safety risk concern during monitoring activities and, 3) the atmospheric and soil monitoring techniques used were relatively cost-effective, easily and rapidly deployable, and required minimal manpower to set up and maintain for short-term assessments. However, characterization of CO2 distribution near the land surface resulting from a dynamic leak with widely variable concentrations and fluxes was challenging. ?? 2011 Published by Elsevier Ltd.

Optimized, Budget-constrained Monitoring Well Placement Using DREAM

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

Yonkofski, Catherine M. R.; Davidson, Casie L.; Rodriguez, Luke R.

Defining the ideal suite of monitoring technologies to be deployed at a carbon capture and storage (CCS) site presents a challenge to project developers, financers, insurers, regulators and other stakeholders. The monitoring, verification, and accounting (MVA) toolkit offers a suite of technologies to monitor an extensive range of parameters across a wide span of spatial and temporal resolutions, each with their own degree of sensitivity to changes in the parameter being monitored. Understanding how best to optimize MVA budgets to minimize the time to leak detection could help to address issues around project risks, and in turn help support broadmore » CCS deployment. This paper presents a case study demonstrating an application of the Designs for Risk Evaluation and Management (DREAM) tool using an ensemble of CO 2 leakage scenarios taken from a previous study on leakage impacts to groundwater. Impacts were assessed and monitored as a function of pH, total dissolved solids (TDS), and trace metal concentrations of arsenic (As), cadmium (Cd), chromium (Cr), and lead (Pb). Using output from the previous study, DREAM was used to optimize monitoring system designs based on variable sampling locations and parameters. The algorithm requires the user to define a finite budget to limit the number of monitoring wells and technologies deployed, and then iterates well placement and sensor type and location until it converges on the configuration with the lowest time to first detection of the leak averaged across all scenarios. To facilitate an understanding of the optimal number of sampling wells, DREAM was used to assess the marginal utility of additional sampling locations. Based on assumptions about monitoring costs and replacement costs of degraded water, the incremental cost of each additional sampling well can be compared against its marginal value in terms of avoided aquifer degradation. Applying this method, DREAM identified the most cost-effective ensemble with 14 monitoring locations. Here, while this preliminary study applied relatively simplistic cost and technology assumptions, it provides an exciting proof-of-concept for the application of DREAM to questions of cost-optimized MVA system design that are informed not only by site-specific costs and technology options, but also by reservoir simulation results developed during site characterization and operation.« less

Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults.

PubMed

Buchbinder, Susan P; Grunenberg, Nicole A; Sanchez, Brittany J; Seaton, Kelly E; Ferrari, Guido; Moody, M Anthony; Frahm, Nicole; Montefiori, David C; Hay, Christine M; Goepfert, Paul A; Baden, Lindsey R; Robinson, Harriet L; Yu, Xuesong; Gilbert, Peter B; McElrath, M Juliana; Huang, Yunda; Tomaras, Georgia D

2017-01-01

A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination. All regimens were well tolerated and safe. Full dose DgDgM_M and DgDgMM_M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one-year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF. This DNA/MVA prime-boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation. ClinicalTrials.gov NCT01571960.

Optimized, Budget-constrained Monitoring Well Placement Using DREAM

DOE PAGES

Yonkofski, Catherine M. R.; Davidson, Casie L.; Rodriguez, Luke R.; ...

2017-08-18

Defining the ideal suite of monitoring technologies to be deployed at a carbon capture and storage (CCS) site presents a challenge to project developers, financers, insurers, regulators and other stakeholders. The monitoring, verification, and accounting (MVA) toolkit offers a suite of technologies to monitor an extensive range of parameters across a wide span of spatial and temporal resolutions, each with their own degree of sensitivity to changes in the parameter being monitored. Understanding how best to optimize MVA budgets to minimize the time to leak detection could help to address issues around project risks, and in turn help support broadmore » CCS deployment. This paper presents a case study demonstrating an application of the Designs for Risk Evaluation and Management (DREAM) tool using an ensemble of CO 2 leakage scenarios taken from a previous study on leakage impacts to groundwater. Impacts were assessed and monitored as a function of pH, total dissolved solids (TDS), and trace metal concentrations of arsenic (As), cadmium (Cd), chromium (Cr), and lead (Pb). Using output from the previous study, DREAM was used to optimize monitoring system designs based on variable sampling locations and parameters. The algorithm requires the user to define a finite budget to limit the number of monitoring wells and technologies deployed, and then iterates well placement and sensor type and location until it converges on the configuration with the lowest time to first detection of the leak averaged across all scenarios. To facilitate an understanding of the optimal number of sampling wells, DREAM was used to assess the marginal utility of additional sampling locations. Based on assumptions about monitoring costs and replacement costs of degraded water, the incremental cost of each additional sampling well can be compared against its marginal value in terms of avoided aquifer degradation. Applying this method, DREAM identified the most cost-effective ensemble with 14 monitoring locations. Here, while this preliminary study applied relatively simplistic cost and technology assumptions, it provides an exciting proof-of-concept for the application of DREAM to questions of cost-optimized MVA system design that are informed not only by site-specific costs and technology options, but also by reservoir simulation results developed during site characterization and operation.« less

Traditional food consumption and nutritional status of Dalit mothers in rural Andhra Pradesh, South India.

PubMed

Schmid, M A; Egeland, G M; Salomeyesudas, B; Satheesh, P V; Kuhnlein, H V

2006-11-01

To describe prevalence of malnutrition and their correlates of nutrient and traditional food consumption in rural Dalit mothers. In a cross-sectional study, we used socio-cultural questionnaires, anthropometric measurements and clinical eye examinations during the rainy season in 2003. Food frequency questionnaires and 24-h recalls were conducted during both summer and rainy seasons. Dalit mothers with young children were recruited from 37 villages in the Medak District of rural Andhra Pradesh, India. Dalit mothers (n = 220) participated. The prevalence of chronic energy-deficient (CED) mothers (body mass index <18.5 kg/m2) was 58%. Illiterate women and active women were more likely to have CED than those literate and non-active (relative risks (RR) = 1.6 and 1.4, respectively, P < or = 0.05), but literacy and activity level were not significant in multivariable analyses including sanitation and number of children < or =5 years of age. Increasing levels of fat intake, as a percent of total energy, was significantly associated with lower risk of CED (RR of the lowest 25th percentile compared to those in the 75th percentile or above was 1.6, P < or = 0.05), findings that remained significant in multivariable analyses. Consumption of pulses (g/day) was also inversely related to CED in univariate and multivariable analyses. Carbohydrate intake, as a percent of total energy, was inversely related to percent energy from fat (r = -0.96, P < or = 0.01), and, although positively related to CED in univariate analyses, carbohydrate consumption was not significant in multivariable analyses. Mothers' age in years and income was positively related to vitamin A deficiency. These results confirm that CED and vitamin A malnutrition among Dalit women are predominant problems in this area. Increased consumption of local traditional Dalit food (particularly sorghum, pulses, vegetables and animal source food) should be incorporated as an important component of intervention strategies to improve nutritional status.

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

Grigg, Reid; McPherson, Brian; Lee, Rober

The Southwest Regional Partnership on Carbon Sequestration (SWP) one of seven regional partnerships sponsored by the U.S. Department of Energy (USDOE) carried out five field pilot tests in its Phase II Carbon Sequestration Demonstration effort, to validate the most promising sequestration technologies and infrastructure concepts, including three geologic pilot tests and two terrestrial pilot programs. This field testing demonstrated the efficacy of proposed sequestration technologies to reduce or offset greenhouse gas emissions in the region. Risk mitigation, optimization of monitoring, verification, and accounting (MVA) protocols, and effective outreach and communication were additional critical goals of these field validation tests. Themore » program included geologic pilot tests located in Utah, New Mexico, Texas, and a region-wide terrestrial analysis. Each geologic sequestration test site was intended to include injection of a minimum of ~75,000 tons/year CO{sub 2}, with minimum injection duration of one year. These pilots represent medium- scale validation tests in sinks that host capacity for possible larger-scale sequestration operations in the future. These validation tests also demonstrated a broad variety of carbon sink targets and multiple value-added benefits, including testing of enhanced oil recovery and sequestration, enhanced coalbed methane production and a geologic sequestration test combined with a local terrestrial sequestration pilot. A regional terrestrial sequestration demonstration was also carried out, with a focus on improved terrestrial MVA methods and reporting approaches specific for the Southwest region.« less

The SUD1 gene encodes a putative E3 ubiquitin ligase and is a positive regulator of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity in Arabidopsis.

PubMed

Doblas, Verónica G; Amorim-Silva, Vítor; Posé, David; Rosado, Abel; Esteban, Alicia; Arró, Montserrat; Azevedo, Herlander; Bombarely, Aureliano; Borsani, Omar; Valpuesta, Victoriano; Ferrer, Albert; Tavares, Rui M; Botella, Miguel A

2013-02-01

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme catalyzes the major rate-limiting step of the mevalonic acid (MVA) pathway from which sterols and other isoprenoids are synthesized. In contrast with our extensive knowledge of the regulation of HMGR in yeast and animals, little is known about this process in plants. To identify regulatory components of the MVA pathway in plants, we performed a genetic screen for second-site suppressor mutations of the Arabidopsis thaliana highly drought-sensitive drought hypersensitive2 (dry2) mutant that shows decreased squalene epoxidase activity. We show that mutations in SUPPRESSOR OF DRY2 DEFECTS1 (SUD1) gene recover most developmental defects in dry2 through changes in HMGR activity. SUD1 encodes a putative E3 ubiquitin ligase that shows sequence and structural similarity to yeast Degradation of α factor (Doα10) and human TEB4, components of the endoplasmic reticulum-associated degradation C (ERAD-C) pathway. While in yeast and animals, the alternative ERAD-L/ERAD-M pathway regulates HMGR activity by controlling protein stability, SUD1 regulates HMGR activity without apparent changes in protein content. These results highlight similarities, as well as important mechanistic differences, among the components involved in HMGR regulation in plants, yeast, and animals.

A two-dose heterologous prime-boost vaccine regimen eliciting sustained immune responses to Ebola Zaire could support a preventive strategy for future outbreaks

PubMed Central

Shukarev, Georgi; Callendret, Benoit; Luhn, Kerstin; Douoguih, Macaya

2017-01-01

ABSTRACT The consequences of the 2013–16 Ebola Zaire virus disease epidemic in West Africa were grave. The economies, healthcare systems and communities of Guinea, Sierra Leone and Liberia were devastated by over 18 months of active Ebola virus transmission, followed by sporadic resurgences potentially related to sexual transmission by survivors with viral persistence in body fluids following recovery. The need to develop and implement strategies to prevent and mitigate future outbreaks is now beyond dispute. The potential for unpredictable outbreaks of indeterminate duration, and control challenges posed by the possibility of sporadic re-emergence, mean that implementation of an effective vaccination program for outbreak containment necessitates a vaccine providing durable immunity. Heterologous prime-boost vaccine regimens deliver the same or similar antigens through different vaccine types, the first to prime and the second to boost the immune system. Ad26.ZEBOV/MVA-BN-Filo is an investigational Ebola Zaire vaccine regimen that uses this heterologous prime-boost approach. Preliminary Phase 1 data suggest that Ad26.ZEBOV/MVA-BN-Filo confers durable immunity for at least 240 d and is well-tolerated with a good safety profile. This regimen may therefore be suitable for prophylactic use in a regional or targeted population vaccination strategy, and could potentially aid prevention and control of future Ebola outbreaks. PMID:27925844

Development of cooling system for 66/6.9kV-20MVA REBCO superconducting transformers with Ne turbo-Brayton refrigerator and subcooled liquid nitrogen

NASA Astrophysics Data System (ADS)

Iwakuma, M.; Adachi, K.; Yun, K.; Yoshida, K.; Sato, S.; Suzuki, Y.; Umeno, T.; Konno, M.; Hayashi, H.; Eguchi, T.; Izumi, T.; Shiohara, Y.

2015-12-01

We developed a turbo-Brayton refrigerator with Ne gas as a working fluid for a 3 ϕ- 66/6.9kV-2MVA superconducting transformer with coated conductors which was bath-cooled with subcooled LN2. The two-stage compressor and expansion turbine had non-contact magnetic bearings for a long maintenance interval. In the future, we intend to directly install a heat exchanger into the Glass-Fiber-Reinforced-Plastics cryostat of a transformer and make a heat exchange between the working fluid gas and subcooled LN2. In this paper we investigate the behaviour of subcooled LN2 in a test cryostat, in which heater coils were arranged side by side with a flat plate finned-tube heat exchanger. Here a He turbo-Brayton refrigerator was used as a substitute for a Ne turbo-Brayton one. The pressure at the surface of LN2 in the cryostat was one atmosphere. Just under the LN2 surface, a stationary layer of LN2 was created over the depth of 20 cm and temperature dropped from 77 K to 65 K with depth while, in the lower level than that, a natural convection flow of LN2 was formed and temperature was almost uniform over 1 m depth. The boundary plane between the stationary layer and the natural convection region was visible.

The SUD1 Gene Encodes a Putative E3 Ubiquitin Ligase and Is a Positive Regulator of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity in Arabidopsis[C][W

PubMed Central

Doblas, Verónica G.; Amorim-Silva, Vítor; Posé, David; Rosado, Abel; Esteban, Alicia; Arró, Montserrat; Azevedo, Herlander; Bombarely, Aureliano; Borsani, Omar; Valpuesta, Victoriano; Ferrer, Albert; Tavares, Rui M.; Botella, Miguel A.

2013-01-01

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme catalyzes the major rate-limiting step of the mevalonic acid (MVA) pathway from which sterols and other isoprenoids are synthesized. In contrast with our extensive knowledge of the regulation of HMGR in yeast and animals, little is known about this process in plants. To identify regulatory components of the MVA pathway in plants, we performed a genetic screen for second-site suppressor mutations of the Arabidopsis thaliana highly drought-sensitive drought hypersensitive2 (dry2) mutant that shows decreased squalene epoxidase activity. We show that mutations in SUPPRESSOR OF DRY2 DEFECTS1 (SUD1) gene recover most developmental defects in dry2 through changes in HMGR activity. SUD1 encodes a putative E3 ubiquitin ligase that shows sequence and structural similarity to yeast Degradation of α factor (Doα10) and human TEB4, components of the endoplasmic reticulum–associated degradation C (ERAD-C) pathway. While in yeast and animals, the alternative ERAD-L/ERAD-M pathway regulates HMGR activity by controlling protein stability, SUD1 regulates HMGR activity without apparent changes in protein content. These results highlight similarities, as well as important mechanistic differences, among the components involved in HMGR regulation in plants, yeast, and animals. PMID:23404890

Comparative Assessment of Transmission-Blocking Vaccine Candidates against Plasmodium falciparum

PubMed Central

Kapulu, M. C.; Da, D. F.; Miura, K.; Li, Y; Blagborough, A. M.; Churcher, T. S.; Nikolaeva, D.; Williams, A. R.; Goodman, A. L.; Sangare, I.; Turner, A. V.; Cottingham, M. G.; Nicosia, A.; Straschil, U.; Tsuboi, T.; Gilbert, S. C.; Long, Carole A.; Sinden, R. E.; Draper, S. J.; Hill, A. V. S.; Cohuet, A.; Biswas, S.

2015-01-01

Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform. PMID:26063320

Muscle recruitment patterns of the subscapularis, serratus anterior and other shoulder girdle muscles during isokinetic internal and external rotations.

PubMed

Gaudet, Sylvain; Tremblay, Jonathan; Begon, Mickael

2018-05-01

The aims of this study were to investigate the differences in peak muscle activity and recruitment patterns during high- and low-velocity, concentric and eccentric, internal and external isokinetic shoulder rotations. Electromyographic activity of the rotator cuff and eight superficial muscles of the shoulder girdle was recorded on 25 healthy adults during isokinetic internal and external shoulder rotation at 60°/s and 240°/s. Peak muscle activity, electromyographic envelopes and peak isokinetic moments were analyzed using three-factor ANOVA and statistical parametric mapping. The subscapularis and serratus anterior showed moderate to high peak activity levels during each conditions, while the middle and posterior deltoids, upper, middle and lower trapezius, infraspinatus and supraspinatus showed higher peak activity levels during external rotations (+36.5% of maximum voluntary activation (MVA)). The pectoralis major and latissimus dorsi were more active during internal rotations (+40% of MVA). Only middle trapezius and pectoralis major electromyographic activity decreased with increasing velocity. Peak muscle activity was similar or lower during eccentric contractions, although the peak isokinetic moment increased by 35% on average. The subscapularis and serratus anterior appear to be important stabilizers of the glenohumeral joint and scapula. Isokinetic eccentric training at high velocities may allow for faster recruitment of the shoulder girdle muscles, which could improve joint stability during shoulder internal and external rotations.

Diffraction effects incorporated design of a parallax barrier for a high-density multi-view autostereoscopic 3D display.

PubMed

Yoon, Ki-Hyuk; Ju, Heongkyu; Kwon, Hyunkyung; Park, Inkyu; Kim, Sung-Kyu

2016-02-22

We present optical characteristics of view image provided by a high-density multi-view autostereoscopic 3D display (HD-MVA3D) with a parallax barrier (PB). Diffraction effects that become of great importance in such a display system that uses a PB, are considered in an one-dimensional model of the 3D display, in which the numerical simulation of light from display panel pixels through PB slits to viewing zone is performed. The simulation results are then compared to the corresponding experimental measurements with discussion. We demonstrate that, as a main parameter for view image quality evaluation, the Fresnel number can be used to determine the PB slit aperture for the best performance of the display system. It is revealed that a set of the display parameters, which gives the Fresnel number of ∼ 0.7 offers maximized brightness of the view images while that corresponding to the Fresnel number of 0.4 ∼ 0.5 offers minimized image crosstalk. The compromise between the brightness and crosstalk enables optimization of the relative magnitude of the brightness to the crosstalk and lead to the choice of display parameter set for the HD-MVA3D with a PB, which satisfies the condition where the Fresnel number lies between 0.4 and 0.7.

Palladium alpha-lipoic acid complex formulation enhances activities of Krebs cycle dehydrogenases and respiratory complexes I-IV in the heart of aged rats.

PubMed

Sudheesh, N P; Ajith, T A; Janardhanan, K K; Krishnan, C V

2009-08-01

Age-related decline in the capacity to withstand stress, such as ischemia and reperfusion, results in congestive heart failure. Though the mechanisms underlying cardiac decay are not clear, age dependent somatic damages to mitochondrial DNA (mtDNA), loss of mitochondrial function, and a resultant increase in oxidative stress in heart muscle cells may be responsible for the increased risk for cardiovascular diseases. The effect of a safe nutritional supplement, POLY-MVA, containing the active ingredient palladium alpha-lipoic acid complex, was evaluated on the activities of the Krebs cycle enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, II, III, and IV in heart mitochondria of aged male albino rats of Wistar strain. Administration of 0.05 ml/kg of POLY-MVA (which is equivalent to 0.38 mg complexed alpha-lipoic acid/kg, p.o), once daily for 30 days, was significantly (p<0.05) effective to enhance the Krebs cycle dehydrogenases, and mitochondrial electron transport chain complexes. The unique electronic and redox properties of palladium alpha-lipoic acid complex appear to be a key to this physiological effectiveness. The results strongly suggest that this formulation might be effective to protect the aging associated risk of cardiovascular and neurodegenerative diseases.

Costs of postabortion care in public sector health facilities in Malawi: a cross-sectional survey.

PubMed

Benson, Janie; Gebreselassie, Hailemichael; Mañibo, Maribel Amor; Raisanen, Keris; Johnston, Heidi Bart; Mhango, Chisale; Levandowski, Brooke A

2015-12-17

Health systems could obtain substantial cost savings by providing safe abortion care rather than providing expensive treatment for complications of unsafely performed abortions. This study estimates current health system costs of treating unsafe abortion complications and compares these findings with newly-projected costs for providing safe abortion in Malawi. We conducted in-depth surveys of medications, supplies, and time spent by clinical personnel dedicated to postabortion care (PAC) for three treatment categories (simple, severe non-surgical, and severe surgical complications) and three uterine evacuation (UE) procedure types (manual vacuum aspiration (MVA), dilation and curettage (D&C) and misoprostol-alone) at 15 purposively-selected public health facilities. Per-case treatment costs were calculated and applied to national, annual PAC caseload data. The median cost per D&C case ($63) was 29% higher than MVA treatment ($49). Costs to treat severe non-surgical complications ($63) were almost five times higher than those of a simple PAC case ($13). Severe surgical complications were especially costly to treat at $128. PAC treatment in public facilities cost an estimated $314,000 annually. Transition to safe, legal abortion would yield an estimated cost reduction of 20%-30%. The method of UE and severity of complications have a large impact on overall costs. With a liberalized abortion law and implementation of induced abortion services with WHO-recommended UE methods, current PAC costs to the health system could markedly decrease.

Production of taxadiene by engineering of mevalonate pathway in Escherichia coli and endophytic fungus Alternaria alternata TPF6.

PubMed

Bian, Guangkai; Yuan, Yujie; Tao, Hui; Shi, Xiaofei; Zhong, Xiaofang; Han, Yichao; Fu, Shuai; Fang, Chengxiang; Deng, Zixin; Liu, Tiangang

2017-04-01

Taxol (paclitaxel) is a diterpenoid compound with significant and extensive applications in the treatment of cancer. The production of Taxol and relevant intermediates by engineered microbes is an attractive alternative to the semichemical synthesis of Taxol. In this study, based on a previously developed platform, the authors first established taxadiene production in mutant E. coli T2 and T4 by engineering of the mevalonate (MVA) pathway. The authors then developed an Agrobacterium tumefaciens-mediated transformation (ATMT) method and verified the strength of heterologous promoters in Alternaria alternata TPF6. The authors next transformed the taxadiene-producing platform into A. alternata TPF6, and the MVA pathway was engineered, with introduction of the plant taxadiene-forming gene. Notably, by co-overexpression of isopentenyl diphosphate isomerase (Idi), a truncated version of 3-hydroxy-3-methylglutaryl-CoA reductase (tHMG1), and taxadiene synthase (TS), the authors could detect 61.9 ± 6.3 μg/L taxadiene in the engineered strain GB127. This is the first demonstration of taxadiene production in filamentous fungi, and the approach presented in this study provides a new method for microbial production of Taxol. The well-established ATMT method and the known promoter strengths facilitated further engineering of taxaenes in this fungus. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A two-dose heterologous prime-boost vaccine regimen eliciting sustained immune responses to Ebola Zaire could support a preventive strategy for future outbreaks.

PubMed

Shukarev, Georgi; Callendret, Benoit; Luhn, Kerstin; Douoguih, Macaya

2017-02-01

The consequences of the 2013-16 Ebola Zaire virus disease epidemic in West Africa were grave. The economies, healthcare systems and communities of Guinea, Sierra Leone and Liberia were devastated by over 18 months of active Ebola virus transmission, followed by sporadic resurgences potentially related to sexual transmission by survivors with viral persistence in body fluids following recovery. The need to develop and implement strategies to prevent and mitigate future outbreaks is now beyond dispute. The potential for unpredictable outbreaks of indeterminate duration, and control challenges posed by the possibility of sporadic re-emergence, mean that implementation of an effective vaccination program for outbreak containment necessitates a vaccine providing durable immunity. Heterologous prime-boost vaccine regimens deliver the same or similar antigens through different vaccine types, the first to prime and the second to boost the immune system. Ad26.ZEBOV/MVA-BN-Filo is an investigational Ebola Zaire vaccine regimen that uses this heterologous prime-boost approach. Preliminary Phase 1 data suggest that Ad26.ZEBOV/MVA-BN-Filo confers durable immunity for at least 240 d and is well-tolerated with a good safety profile. This regimen may therefore be suitable for prophylactic use in a regional or targeted population vaccination strategy, and could potentially aid prevention and control of future Ebola outbreaks.

Relationship Between Central and Peripheral Atherosclerosis and Left Ventricular Dysfunction in a Community Population

PubMed Central

Tsao, Connie W.; Gona, Philimon; Salton, Carol; Murabito, Joanne M.; Oyama, Noriko; Danias, Peter G.; O’Donnell, Christopher J.; Manning, Warren J.; Yeon, Susan B.

2011-01-01

We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and PAD in a community cohort. 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65±9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional LV systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at Examination 7. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p<0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p<0.001) and volume of aortic plaque were associated with decreased ABI (p<0.001). After multivariable adjustment, ABI≤0.9 or prior revascularization was associated with a three-fold odds of aortic plaque (p=0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p<0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment suggesting shared mechanisms beyond those captured by traditional risk factors. PMID:21708875

A framework for multivariate data-based at-site flood frequency analysis: Essentiality of the conjugal application of parametric and nonparametric approaches

NASA Astrophysics Data System (ADS)

Vittal, H.; Singh, Jitendra; Kumar, Pankaj; Karmakar, Subhankar

2015-06-01

In watershed management, flood frequency analysis (FFA) is performed to quantify the risk of flooding at different spatial locations and also to provide guidelines for determining the design periods of flood control structures. The traditional FFA was extensively performed by considering univariate scenario for both at-site and regional estimation of return periods. However, due to inherent mutual dependence of the flood variables or characteristics [i.e., peak flow (P), flood volume (V) and flood duration (D), which are random in nature], analysis has been further extended to multivariate scenario, with some restrictive assumptions. To overcome the assumption of same family of marginal density function for all flood variables, the concept of copula has been introduced. Although, the advancement from univariate to multivariate analyses drew formidable attention to the FFA research community, the basic limitation was that the analyses were performed with the implementation of only parametric family of distributions. The aim of the current study is to emphasize the importance of nonparametric approaches in the field of multivariate FFA; however, the nonparametric distribution may not always be a good-fit and capable of replacing well-implemented multivariate parametric and multivariate copula-based applications. Nevertheless, the potential of obtaining best-fit using nonparametric distributions might be improved because such distributions reproduce the sample's characteristics, resulting in more accurate estimations of the multivariate return period. Hence, the current study shows the importance of conjugating multivariate nonparametric approach with multivariate parametric and copula-based approaches, thereby results in a comprehensive framework for complete at-site FFA. Although the proposed framework is designed for at-site FFA, this approach can also be applied to regional FFA because regional estimations ideally include at-site estimations. The framework is based on the following steps: (i) comprehensive trend analysis to assess nonstationarity in the observed data; (ii) selection of the best-fit univariate marginal distribution with a comprehensive set of parametric and nonparametric distributions for the flood variables; (iii) multivariate frequency analyses with parametric, copula-based and nonparametric approaches; and (iv) estimation of joint and various conditional return periods. The proposed framework for frequency analysis is demonstrated using 110 years of observed data from Allegheny River at Salamanca, New York, USA. The results show that for both univariate and multivariate cases, the nonparametric Gaussian kernel provides the best estimate. Further, we perform FFA for twenty major rivers over continental USA, which shows for seven rivers, all the flood variables followed nonparametric Gaussian kernel; whereas for other rivers, parametric distributions provide the best-fit either for one or two flood variables. Thus the summary of results shows that the nonparametric method cannot substitute the parametric and copula-based approaches, but should be considered during any at-site FFA to provide the broadest choices for best estimation of the flood return periods.

Statins inhibit blastocyst formation by preventing geranylgeranylation

PubMed Central

Alarcon, Vernadeth B.; Marikawa, Yusuke

2016-01-01

STUDY HYPOTHESIS Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the mevalonate pathway and prescription drugs that treat hypercholesterolemia, compromise preimplantation mouse development via modulation of HIPPO signaling. STUDY FINDING HMG-CoA reductase activity is required for trophectoderm specification, namely blastocyst cavity formation and Yes-associated protein (YAP) nuclear localization, through the production of isoprenoid geranylgeranyl pyrophosphate (GGPP) and the action of geranylgeranyl transferase. WHAT IS KNOWN ALREADY Previous studies have shown that treatment of mouse embryos with mevastatin prevents blastocyst formation, but how HMG-CoA reductase is involved in preimplantation development is unknown. HIPPO signaling regulates specification of the trophectoderm lineage of the mouse blastocyst by controlling the nuclear localization of YAP. In human cell lines, the mevalonate pathway regulates YAP to mediate self-renewal and survival through geranylgeranylation of RHO proteins. These studies suggest that in preimplantation development, statins may act through HIPPO pathway to interfere with trophectoderm specification and thereby inhibit blastocyst formation. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Eight-cell stage (E2.5) mouse embryos were treated in hanging drop culture with chemical agents, namely statins (lovastatin, atorvastatin, cerivastatin and pravastatin), mevalonic acid (MVA), cholesterol, squalene, farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), geranylgeranyltransferase inhibitor GGTI-298, RHO inhibitor I, and squalene synthase inhibitor YM-53601, up to the late blastocyst stage (E4.5). Efficiency of blastocyst formation was assessed based on gross morphology and the measurement of the cavity size using an image analysis software. Effects on cell lineages and HIPPO signaling were analyzed using immunohistochemistry with confocal microscopy based on the expression patterns of the lineage-specific markers and the nuclear accumulation of YAP. Effects on cell lineages were also examined by quantitative RT–PCR based on the transcript levels of the lineage-specific marker genes. Data were analyzed using one-way ANOVA and two-sample t-test. MAIN RESULTS AND THE ROLE OF CHANCE All four statins examined inhibited blastocyst formation. The adverse impact of statins was rescued by supplementation of MVA (P < 0.01) or GGPP (P < 0.01) but not squalene nor cholesterol. Blastocyst formation was also prevented by GGTI-298 (P < 0.01). These results indicate that HMG-CoA reductase activity is required for blastocyst formation mainly through the production of GGPP but not cholesterol. Inhibition of RHO proteins, known targets of geranylgeranylation, impaired blastocyst formation, which was not reversed by GGPP supplementation. Nuclear localization of YAP was diminished by statin treatment but fully restored by supplementation of MVA (P < 0.01) or GGPP (P < 0.01). This suggests that HIPPO signaling is regulated by GGPP-dependent mechanisms, possibly geranylgeranylation of RHO, to enable trophectoderm formation. YM-53601 prevented blastocyst formation (P < 0.01), but its adverse impact was not rescued by supplementation of squalene or cholesterol, suggesting that squalene synthesis inhibition was not the cause of blastocyst defects. LIMITATIONS, REASONS FOR CAUTION Analyses were conducted on embryos cultured ex vivo, but they enable the determination of specific concentrations that impair embryo development which can be compared with drug concentrations in the reproductive tract when testing in vivo impact of statins through animal experimentations. Also, analyses were conducted in only one species, the mouse. Epidemiological studies on the effects of various types of statins on the fertility of women are necessary. WIDER IMPLICATIONS OF THE FINDINGS Our study reveals how the mevalonate pathway is required for blastocyst formation and intersects with HIPPO pathway to provide a mechanistic basis for the embryotoxic effect of statins. This bears relevance for women who are taking statins while trying to conceive, since statins have potential to prevent the conceptus from reaching the blastocyst stage and to cause early conceptus demise. LARGE SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This study was supported by grants from the George F. Straub Trust of the Hawaii Community Foundation (13ADVC-60315 to V.B.A.) and the National Institutes of Health, USA (P20GM103457 to V.B.A.). The authors have no conflict of interest to declare. PMID:26908642

Multivariate pattern analysis of MEG and EEG: A comparison of representational structure in time and space.

PubMed

Cichy, Radoslaw Martin; Pantazis, Dimitrios

2017-09-01

Multivariate pattern analysis of magnetoencephalography (MEG) and electroencephalography (EEG) data can reveal the rapid neural dynamics underlying cognition. However, MEG and EEG have systematic differences in sampling neural activity. This poses the question to which degree such measurement differences consistently bias the results of multivariate analysis applied to MEG and EEG activation patterns. To investigate, we conducted a concurrent MEG/EEG study while participants viewed images of everyday objects. We applied multivariate classification analyses to MEG and EEG data, and compared the resulting time courses to each other, and to fMRI data for an independent evaluation in space. We found that both MEG and EEG revealed the millisecond spatio-temporal dynamics of visual processing with largely equivalent results. Beyond yielding convergent results, we found that MEG and EEG also captured partly unique aspects of visual representations. Those unique components emerged earlier in time for MEG than for EEG. Identifying the sources of those unique components with fMRI, we found the locus for both MEG and EEG in high-level visual cortex, and in addition for MEG in low-level visual cortex. Together, our results show that multivariate analyses of MEG and EEG data offer a convergent and complimentary view on neural processing, and motivate the wider adoption of these methods in both MEG and EEG research. Copyright © 2017 Elsevier Inc. All rights reserved.

Changes in Landscape Greenness and Climatic Factors over ...

EPA Pesticide Factsheets

Monitoring and quantifying changes in vegetation cover over large areas using remote sensing can be achieved using the Normalized Difference Vegetation Index (NDVI), an indicator of greenness. However, distinguishing gradual shifts in NDVI (e.g. climate change) versus direct and rapid changes (e.g., fire, land development) is challenging as changes can be confounded by time-dependent patterns, and variation associated with climatic factors. In the present study we leveraged a method, that we previously developed for a pilot study, to address these confounding factors by evaluating NDVI change using autoregression techniques that compare results from univariate (NDVI vs. time) and multivariate analyses (NDVI vs. time and climatic factors) for ~7,660,636 1-km2 pixels comprising the 48 contiguous states of the USA, over a 25-year period (1989−2013). NDVI changed significantly for 48% of the nation over the 25-year in the univariate analyses where most significant trends (85%) indicated an increase in greenness over time. By including climatic factors in the multivariate analyses of NDVI over time, the detection of significant NDVI trends increased to 53% (an increase of 5%). Comparisons of univariate and multivariate analyses for each pixel showed that less than 4% of the pixels had a significant NDVI trend attributable to gradual climatic changes while the remainder of pixels with a significant NDVI trend indicated that changes were due to direct factors. Whi

A system to build distributed multivariate models and manage disparate data sharing policies: implementation in the scalable national network for effectiveness research.

PubMed

Meeker, Daniella; Jiang, Xiaoqian; Matheny, Michael E; Farcas, Claudiu; D'Arcy, Michel; Pearlman, Laura; Nookala, Lavanya; Day, Michele E; Kim, Katherine K; Kim, Hyeoneui; Boxwala, Aziz; El-Kareh, Robert; Kuo, Grace M; Resnic, Frederic S; Kesselman, Carl; Ohno-Machado, Lucila

2015-11-01

Centralized and federated models for sharing data in research networks currently exist. To build multivariate data analysis for centralized networks, transfer of patient-level data to a central computation resource is necessary. The authors implemented distributed multivariate models for federated networks in which patient-level data is kept at each site and data exchange policies are managed in a study-centric manner. The objective was to implement infrastructure that supports the functionality of some existing research networks (e.g., cohort discovery, workflow management, and estimation of multivariate analytic models on centralized data) while adding additional important new features, such as algorithms for distributed iterative multivariate models, a graphical interface for multivariate model specification, synchronous and asynchronous response to network queries, investigator-initiated studies, and study-based control of staff, protocols, and data sharing policies. Based on the requirements gathered from statisticians, administrators, and investigators from multiple institutions, the authors developed infrastructure and tools to support multisite comparative effectiveness studies using web services for multivariate statistical estimation in the SCANNER federated network. The authors implemented massively parallel (map-reduce) computation methods and a new policy management system to enable each study initiated by network participants to define the ways in which data may be processed, managed, queried, and shared. The authors illustrated the use of these systems among institutions with highly different policies and operating under different state laws. Federated research networks need not limit distributed query functionality to count queries, cohort discovery, or independently estimated analytic models. Multivariate analyses can be efficiently and securely conducted without patient-level data transport, allowing institutions with strict local data storage requirements to participate in sophisticated analyses based on federated research networks. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Panic disorder and agoraphobia: A direct comparison of their multivariate comorbidity patterns.

PubMed

Greene, Ashley L; Eaton, Nicholas R

2016-01-15

Scientific debate has long surrounded whether agoraphobia is a severe consequence of panic disorder or a frequently comorbid diagnosis. Multivariate comorbidity investigations typically treat these diagnoses as fungible in structural models, assuming both are manifestations of the fear-subfactor in the internalizing-externalizing model. No studies have directly compared these disorders' multivariate associations, which could clarify their conceptualization in classification and comorbidity research. In a nationally representative sample (N=43,093), we examined the multivariate comorbidity of panic disorder (1) without agoraphobia, (2) with agoraphobia, and (3) regardless of agoraphobia; and (4) agoraphobia without panic. We conducted exploratory and confirmatory factor analyses of these and 10 other lifetime DSM-IV diagnoses in a nationally representative sample (N=43,093). Differing bivariate and multivariate relations were found. Panic disorder without agoraphobia was largely a distress disorder, related to emotional disorders. Agoraphobia without panic was largely a fear disorder, related to phobias. When considered jointly, concomitant agoraphobia and panic was a fear disorder, and when panic was assessed without regard to agoraphobia (some individuals had agoraphobia while others did not) it was a mixed distress and fear disorder. Diagnoses were obtained from comprehensively trained lay interviewers, not clinicians and analyses used DSM-IV diagnoses (rather than DSM-5). These findings support the conceptualization of agoraphobia as a distinct diagnostic entity and the independent classification of both disorders in DSM-5, suggesting future multivariate comorbidity studies should not assume various panic/agoraphobia diagnoses are invariably fear disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Modeling the Drift Towards Sex Role Deviance.

ERIC Educational Resources Information Center

James, Jennifer; Vitaliano, Peter Paul

The interrelationships of deviant life experiences and current status, i.e., prostitution versus non-prostitution, were investigated by the application of multivariate analyses. Variables were studied involving early home life, pregnancy history, sexual history, and criminal involvement. Based on the analyses, three models were developed that…

A multivariate time series approach to modeling and forecasting demand in the emergency department.

PubMed

Jones, Spencer S; Evans, R Scott; Allen, Todd L; Thomas, Alun; Haug, Peter J; Welch, Shari J; Snow, Gregory L

2009-02-01

The goals of this investigation were to study the temporal relationships between the demands for key resources in the emergency department (ED) and the inpatient hospital, and to develop multivariate forecasting models. Hourly data were collected from three diverse hospitals for the year 2006. Descriptive analysis and model fitting were carried out using graphical and multivariate time series methods. Multivariate models were compared to a univariate benchmark model in terms of their ability to provide out-of-sample forecasts of ED census and the demands for diagnostic resources. Descriptive analyses revealed little temporal interaction between the demand for inpatient resources and the demand for ED resources at the facilities considered. Multivariate models provided more accurate forecasts of ED census and of the demands for diagnostic resources. Our results suggest that multivariate time series models can be used to reliably forecast ED patient census; however, forecasts of the demands for diagnostic resources were not sufficiently reliable to be useful in the clinical setting.

Synergism in work site adoption of employee assistance programs and health promotion activities.

PubMed

Blum, T C; Roman, P M; Patrick, L

1990-05-01

As workplaces increasingly adopt proactive programs directed toward employee health issues, the interrelation between different programs becomes an important issue. Of interest here is the "synergy" in patterns of program adoption between employee assistance programs (EAPs) and health promotion activities (HPAs). We utilize the 1985 National Survey of Worksite Health Promotion Activities (N = 1358) for analyses of the dual presence of EAPs and HPAs, and in multivariate analyses we consider factors affecting such dual presence. The data suggest that synergy occurs, with EAP adoption appearing to influence HPA adoption to a greater extent than the reverse. In multivariate analyses, synergy is confirmed by the finding that, among a variety of relevant organizational characteristics, EAP presence and HPA presence are the best predictors of each other's presence. The analyses also indicate that there is minimal commonality in program ingredients across organizations reporting the presence of HPAs. Implications of the data for the future development of these two programming strategies are discussed.

Immediate versus delayed intramedullary nailing for open fractures of the tibial shaft: a multivariate analysis of factors affecting deep infection and fracture healing.

PubMed

Yokoyama, Kazuhiko; Itoman, Moritoshi; Uchino, Masataka; Fukushima, Kensuke; Nitta, Hiroshi; Kojima, Yoshiaki

2008-10-01

The purpose of this study was to evaluate contributing factors affecting deep infection and fracture healing of open tibia fractures treated with locked intramedullary nailing (IMN) by multivariate analysis. We examined 99 open tibial fractures (98 patients) treated with immediate or delayed locked IMN in static fashion from 1991 to 2002. Multivariate analyses following univariate analyses were derived to determine predictors of deep infection, nonunion, and healing time to union. The following predictive variables of deep infection were selected for analysis: age, sex, Gustilo type, fracture grade by AO type, fracture location, timing or method of IMN, reamed or unreamed nailing, debridement time (< or =6 h or >6 h), method of soft-tissue management, skin closure time (< or =1 week or >1 week), existence of polytrauma (ISS< 18 or ISS> or =18), existence of floating knee injury, and existence of superficial/pin site infection. The predictive variables of nonunion selected for analysis was the same as those for deep infection, with the addition of deep infection for exchange of pin site infection. The predictive variables of union time selected for analysis was the same as those for nonunion, excluding of location, debridement time, and existence of floating knee and superficial infection. Six (6.1%; type II Gustilo n=1, type IIIB Gustilo n=5) of the 99 open tibial fractures developed deep infections. Multivariate analysis revealed that timing or method of IMN, debridement time, method of soft-tissue management, and existence of superficial or pin site infection significantly correlated with the occurrence of deep infection (P< 0.0001). In the immediate nailing group alone, the deep infection rate in type IIIB + IIIC was significantly higher than those in type I + II and IIIA (P = 0.016). Nonunion occurred in 17 fractures (20.3%, 17/84). Multivariate analysis revealed that Gustilo type, skin closure time, and existence of deep infection significantly correlated with occurrence of nonunion (P < 0.05). Gustilo type and existence of deep infection were significantly correlated with healing time to union on multivariate analysis (r(2) = 0.263, P = 0.0001). Multivariate analyses for open tibial fractures treated with IMN showed that IMN after EF (especially in existence of pin site infection) was at high risk of deep infection, and that debridement within 6 h and appropriate soft-tissue managements were also important factor in preventing deep infections. These analyses postulated that both the Gustilo type and the existence of deep infection is related with fracture healing in open fractures treated with IMN. In addition, immediate IMN for type IIIB and IIIC is potentially risky, and canal reaming did not increase the risk of complication for open tibial fractures treated with IMN.

Multivariate geometry as an approach to algal community analysis

USGS Publications Warehouse

Allen, T.F.H.; Skagen, S.

1973-01-01

Multivariate analyses are put in the context of more usual approaches to phycological investigations. The intuitive common-sense involved in methods of ordination, classification and discrimination are emphasised by simple geometric accounts which avoid jargon and matrix algebra. Warnings are given that artifacts result from technique abuses by the naive or over-enthusiastic. An analysis of a simple periphyton data set is presented as an example of the approach. Suggestions are made as to situations in phycological investigations, where the techniques could be appropriate. The discipline is reprimanded for its neglect of the multivariate approach.

Multivariate Quantitative Chemical Analysis

NASA Technical Reports Server (NTRS)

Kinchen, David G.; Capezza, Mary

1995-01-01

Technique of multivariate quantitative chemical analysis devised for use in determining relative proportions of two components mixed and sprayed together onto object to form thermally insulating foam. Potentially adaptable to other materials, especially in process-monitoring applications in which necessary to know and control critical properties of products via quantitative chemical analyses of products. In addition to chemical composition, also used to determine such physical properties as densities and strengths.

Causal diagrams and multivariate analysis III: confound it!

PubMed

Jupiter, Daniel C

2015-01-01

This commentary concludes my series concerning inclusion of variables in multivariate analyses. We take up the issues of confounding and effect modification and summarize the work we have thus far done. Finally, we provide a rough algorithm to help guide us through the maze of possibilities that we have outlined. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

The relationship between physical appearance concerns, disgust, and anti-fat prejudice.

PubMed

O'Brien, Kerry S; Daníelsdóttir, Sigrún; Ólafsson, Ragnar P; Hansdóttir, Ingunn; Fridjónsdóttir, Thorarna G; Jónsdóttir, Halla

2013-09-01

This study examined relationships between physical appearance concerns (fear of fat, body image disturbance; BIDQ), disgust, and anti-fat prejudice (dislike, blame), and tested whether disgust mediates relationships between physical appearance concerns and anti-fat prejudice. Participants (N=1649; age=28 years) provided demographic data and completed measures of anti-fat prejudice, tendency to feel disgust, and physical appearance concerns. Univariate, multivariate, and mediation analyses were conducted. Univariate and multivariate associations were found between fear of fat, BIDQ, disgust, and anti-fat prejudice for women. For women only, mediation analyses showed that disgust partially mediated relationships between physical appearance concerns and dislike of fat people. For men, univariate and multivariate relationships were found between fear of fat, and dislike and blame of fat people, but disgust was not related to anti-fat prejudice. Newer constructs centering on physical appearance concerns and disgust appear promising candidates for understanding anti-fat prejudice. Copyright © 2013 Elsevier Ltd. All rights reserved.

Partial Least Square Analyses of Landscape and Surface Water Biota Associations in the Savannah River Basin

EPA Science Inventory

Ecologists are often faced with problem of small sample size, correlated and large number of predictors, and high noise-to-signal relationships. This necessitates excluding important variables from the model when applying standard multiple or multivariate regression analyses. In ...

Matrix metalloproteinase-2 gene variants and abdominal aortic aneurysm.

PubMed

Smallwood, L; Warrington, N; Allcock, R; van Bockxmeer, F; Palmer, L J; Iacopetta, B; Golledge, J; Norman, P E

2009-08-01

To investigate associations between two polymorphisms of the matrix metalloproteinase-2 gene (MMP2) and the incidence and progression of abdominal aortic aneurysm (AAA). Cases and controls were recruited from a trial of screening for AAAs. The association between two variants of MMP2 (-1360C>T, and +649C>T) in men with AAA (n=678) and in controls (n=659) was examined using multivariate analyses. The association with AAA expansion (n=638) was also assessed. In multivariate analyses with adjustments for multiple testing, no association between either SNP and AAA presence or expansion was detected. MMP2 -1360C>T and +649C>T variants are not risk factors for AAA.

Relationship between central and peripheral atherosclerosis and left ventricular dysfunction in a community population.

PubMed

Tsao, Connie W; Gona, Philimon; Salton, Carol; Murabito, Joanne M; Oyama, Noriko; Danias, Peter G; O'Donnell, Christopher J; Manning, Warren J; Yeon, Susan B

2011-08-01

We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and peripheral artery disease (PAD) in a community cohort. A total of 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65 ± 9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional left ventricular systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at the most contemporaneous examination visit. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p < 0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p < 0.001) and volume of aortic plaque were associated with decreased ABI (p < 0.001). After multivariable adjustment, an ABI ≤ 0.9 or prior revascularization was associated with a threefold odds of aortic plaque (p = 0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p < 0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment, suggesting shared mechanisms beyond those captured by traditional risk factors.

Is the prognostic significance of O6-methylguanine- DNA methyltransferase promoter methylation equally important in glioblastomas of patients from different continents? A systematic review with meta-analysis.

PubMed

Meng, Wei; Jiang, Yangyang; Ma, Jie

2017-01-01

O6-methylguanine-DNA methyltransferase (MGMT) is an independent predictor of therapeutic response and potential prognosis in patients with glioblastoma multiforme (GBM). However, its significance of clinical prognosis in different continents still needs to be explored. To explore the effects of MGMT promoter methylation on both progression-free survival (PFS) and overall survival (OS) among GBM patients from different continents, a systematic review of published studies was conducted. A total of 5103 patients from 53 studies were involved in the systematic review and the total percentage of MGMT promoter methylation was 45.53%. Of these studies, 16 studies performed univariate analyses and 17 performed multivariate analyses of MGMT promoter methylation on PFS. The pooled hazard ratio (HR) estimated for PFS was 0.55 (95% CI 0.50, 0.60) by univariate analysis and 0.43 (95% CI 0.38, 0.48) by multivariate analysis. The effect of MGMT promoter methylation on OS was explored in 30 studies by univariate analysis and in 30 studies by multivariate analysis. The combined HR was 0.48 (95% CI 0.44, 0.52) and 0.42 (95% CI 0.38, 0.45), respectively. In each subgroup divided by areas, the prognostic significance still remained highly significant. The proportion of methylation in each group was in inverse proportion to the corresponding HR in the univariate and multivariate analyses of PFS. However, from the perspective of OS, compared with data from Europe and the US, higher methylation rates in Asia did not bring better returns.

Network meta-analysis of multiple outcome measures accounting for borrowing of information across outcomes.

PubMed

Achana, Felix A; Cooper, Nicola J; Bujkiewicz, Sylwia; Hubbard, Stephanie J; Kendrick, Denise; Jones, David R; Sutton, Alex J

2014-07-21

Network meta-analysis (NMA) enables simultaneous comparison of multiple treatments while preserving randomisation. When summarising evidence to inform an economic evaluation, it is important that the analysis accurately reflects the dependency structure within the data, as correlations between outcomes may have implication for estimating the net benefit associated with treatment. A multivariate NMA offers a framework for evaluating multiple treatments across multiple outcome measures while accounting for the correlation structure between outcomes. The standard NMA model is extended to multiple outcome settings in two stages. In the first stage, information is borrowed across outcomes as well across studies through modelling the within-study and between-study correlation structure. In the second stage, we make use of the additional assumption that intervention effects are exchangeable between outcomes to predict effect estimates for all outcomes, including effect estimates on outcomes where evidence is either sparse or the treatment had not been considered by any one of the studies included in the analysis. We apply the methods to binary outcome data from a systematic review evaluating the effectiveness of nine home safety interventions on uptake of three poisoning prevention practices (safe storage of medicines, safe storage of other household products, and possession of poison centre control telephone number) in households with children. Analyses are conducted in WinBUGS using Markov Chain Monte Carlo (MCMC) simulations. Univariate and the first stage multivariate models produced broadly similar point estimates of intervention effects but the uncertainty around the multivariate estimates varied depending on the prior distribution specified for the between-study covariance structure. The second stage multivariate analyses produced more precise effect estimates while enabling intervention effects to be predicted for all outcomes, including intervention effects on outcomes not directly considered by the studies included in the analysis. Accounting for the dependency between outcomes in a multivariate meta-analysis may or may not improve the precision of effect estimates from a network meta-analysis compared to analysing each outcome separately.

Transition from a multiport technique to a single-port technique for lung cancer surgery: is lymph node dissection inferior using the single-port technique?†.

PubMed

Liu, Chia-Chuan; Shih, Chih-Shiun; Pennarun, Nicolas; Cheng, Chih-Tao

2016-01-01

The feasibility and radicalism of lymph node dissection for lung cancer surgery by a single-port technique has frequently been challenged. We performed a retrospective cohort study to investigate this issue. Two chest surgeons initiated multiple-port thoracoscopic surgery in a 180-bed cancer centre in 2005 and shifted to a single-port technique gradually after 2010. Data, including demographic and clinical information, from 389 patients receiving multiport thoracoscopic lobectomy or segmentectomy and 149 consecutive patients undergoing either single-port lobectomy or segmentectomy for primary non-small-cell lung cancer were retrieved and entered for statistical analysis by multivariable linear regression models and Box-Cox transformed multivariable analysis. The mean number of total dissected lymph nodes in the lobectomy group was 28.5 ± 11.7 for the single-port group versus 25.2 ± 11.3 for the multiport group; the mean number of total dissected lymph nodes in the segmentectomy group was 19.5 ± 10.8 for the single-port group versus 17.9 ± 10.3 for the multiport group. In linear multivariable and after Box-Cox transformed multivariable analyses, the single-port approach was still associated with a higher total number of dissected lymph nodes. The total number of dissected lymph nodes for primary lung cancer surgery by single-port video-assisted thoracoscopic surgery (VATS) was higher than by multiport VATS in univariable, multivariable linear regression and Box-Cox transformed multivariable analyses. This study confirmed that highly effective lymph node dissection could be achieved through single-port VATS in our setting. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Analysing the magnetopause internal structure: new possibilities offered by MMS

NASA Astrophysics Data System (ADS)

Belmont, G.; Rezeau, L.; Manuzzo, R.; Aunai, N.; Dargent, J.

2017-12-01

We explore the structure of the magnetopause using a crossing observed by the MMS spacecraft on October 16th, 2015. Several methods (MVA, BV, CVA) are first applied to compute the normal to the magnetopause considered as a whole. The different results obtained are not identical and we show that the whole boundary is not stationary and not planar, so that basic assumptions of these methods are not well satisfied. We then analyse more finely the internal structure for investigating the departures from planarity. Using the basic mathematical definition of what is a one-dimensional physical problem, we introduce a new method, called LNA (Local Normal Analysis) for determining the varying normal, and we compare the results so obtained with those coming from the MDD tool developed by [Shi et al., 2005]. This method gives the dimensionality of the magnetic variations from multi-point measurements and allows estimating the direction of the local normal using the magnetic field. On the other hand, LNA is a single-spacecraft method which gives the local normal from the magnetic field and particle data. This study shows that the magnetopause does include approximate one-dimensional sub-structures but also two and three dimensional intervals. It also shows that the dimensionality of the magnetic variations can differ from the variations of the other fields so that, at some places, the magnetic field can have a 1D structure although all the plasma variations do not verify the properties of a global one-dimensional problem. Finally a generalisation and a systematic application of the MDD method to the physical quantities of interest is shown.

De novo assembly and transcriptome analysis of the rubber tree (Hevea brasiliensis) and SNP markers development for rubber biosynthesis pathways.

PubMed

Mantello, Camila Campos; Cardoso-Silva, Claudio Benicio; da Silva, Carla Cristina; de Souza, Livia Moura; Scaloppi Junior, Erivaldo José; de Souza Gonçalves, Paulo; Vicentini, Renato; de Souza, Anete Pereira

2014-01-01

Hevea brasiliensis (Willd. Ex Adr. Juss.) Muell.-Arg. is the primary source of natural rubber that is native to the Amazon rainforest. The singular properties of natural rubber make it superior to and competitive with synthetic rubber for use in several applications. Here, we performed RNA sequencing (RNA-seq) of H. brasiliensis bark on the Illumina GAIIx platform, which generated 179,326,804 raw reads on the Illumina GAIIx platform. A total of 50,384 contigs that were over 400 bp in size were obtained and subjected to further analyses. A similarity search against the non-redundant (nr) protein database returned 32,018 (63%) positive BLASTx hits. The transcriptome analysis was annotated using the clusters of orthologous groups (COG), gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Pfam databases. A search for putative molecular marker was performed to identify simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs). In total, 17,927 SSRs and 404,114 SNPs were detected. Finally, we selected sequences that were identified as belonging to the mevalonate (MVA) and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways, which are involved in rubber biosynthesis, to validate the SNP markers. A total of 78 SNPs were validated in 36 genotypes of H. brasiliensis. This new dataset represents a powerful information source for rubber tree bark genes and will be an important tool for the development of microsatellites and SNP markers for use in future genetic analyses such as genetic linkage mapping, quantitative trait loci identification, investigations of linkage disequilibrium and marker-assisted selection.

Multivariate analysis of volatile compounds detected by headspace solid-phase microextraction/gas chromatography: A tool for sensory classification of cork stoppers.

PubMed

Prat, Chantal; Besalú, Emili; Bañeras, Lluís; Anticó, Enriqueta

2011-06-15

The volatile fraction of aqueous cork macerates of tainted and non-tainted agglomerate cork stoppers was analysed by headspace solid-phase microextraction (HS-SPME)/gas chromatography. Twenty compounds containing terpenoids, aliphatic alcohols, lignin-related compounds and others were selected and analysed in individual corks. Cork stoppers were previously classified in six different classes according to sensory descriptions including, 2,4,6-trichloroanisole taint and other frequent, non-characteristic odours found in cork. A multivariate analysis of the chromatographic data of 20 selected chemical compounds using linear discriminant analysis models helped in the differentiation of the a priori made groups. The discriminant model selected five compounds as the best combination. Selected compounds appear in the model in the following order; 2,4,6 TCA, fenchyl alcohol, 1-octen-3-ol, benzyl alcohol and benzothiazole. Unfortunately, not all six a priori differentiated sensory classes were clearly discriminated in the model, probably indicating that no measurable differences exist in the chromatographic data for some categories. The predictive analyses of a refined model in which two sensory classes were fused together resulted in a good classification. Prediction rates of control (non-tainted), TCA, musty-earthy-vegetative, vegetative and chemical descriptions were 100%, 100%, 85%, 67.3% and 100%, respectively, when the modified model was used. The multivariate analysis of chromatographic data will help in the classification of stoppers and provide a perfect complement to sensory analyses. Copyright © 2010 Elsevier Ltd. All rights reserved.

Individual, Psychosocial, and Social Correlates of Unprotected Anal Intercourse in a New Generation of Young Men Who Have Sex With Men in New York City

PubMed Central

Kapadia, Farzana; Siconolfi, Daniel E.; Moeller, Robert W.; Figueroa, Rafael Perez; Barton, Staci C.; Blachman-Forshay, Jaclyn

2013-01-01

Objectives. We examined associations of individual, psychosocial, and social factors with unprotected anal intercourse (UAI) among young men who have sex with men in New York City. Methods. Using baseline assessment data from 592 young men who have sex with men participating in an ongoing prospective cohort study, we conducted multivariable logistic regression analyses to examine the associations between covariates and likelihood of recently engaging in UAI with same-sex partners. Results. Nineteen percent reported recent UAI with a same-sex partner. In multivariable models, being in a current relationship with another man (adjusted odds ratio [AOR] = 4.87), an arrest history (AOR = 2.01), greater residential instability (AOR = 1.75), and unstable housing or homelessness (AOR = 3.10) was associated with recent UAI. Although high levels of gay community affinity and low internalized homophobia were associated with engaging in UAI in bivariate analyses, these associations did not persist in multivariable analyses. Conclusions. Associations of psychosocial and socially produced conditions with UAI among a new generation of young men who have sex with men warrant that HIV prevention programs and policies address structural factors that predispose sexual risk behaviors. PMID:23488487

A Call for Conducting Multivariate Mixed Analyses

ERIC Educational Resources Information Center

Onwuegbuzie, Anthony J.

2016-01-01

Several authors have written methodological works that provide an introductory- and/or intermediate-level guide to conducting mixed analyses. Although these works have been useful for beginning and emergent mixed researchers, with very few exceptions, works are lacking that describe and illustrate advanced-level mixed analysis approaches. Thus,…

Distribution of putative xenogeneic silencers in prokaryote genomes.

PubMed

Perez-Rueda, Ernesto; Ibarra, J Antonio

2015-10-01

Gene silencing is an important function as it keeps newly acquired foreign DNA repressed, thereby avoiding possible deleterious effects in the host organism. Known transcriptional regulators associated with this process are called xenogeneic silencers (XS) and belong to either the H-NS, Lsr2, MvaT or Rok families. In the work described here we looked for XS-like regulators and their distribution in prokaryotic organisms was evaluated. Our analysis showed that putative XS regulators similar to H-NS, Lsr2, MvaT or Rok are present only in bacteria (31.7%). This does not exclude the existence of alternative XS in the rest of the organisms analyzed. Additionally, of the four XS groups evaluated in this work, those from the H-NS family have diversified more than the other groups. In order to compare the distribution of these putative XS regulators we also searched for other nucleoid-associated proteins (NAPs) not included in this group such as Fis, EbfC/YbaB, HU/IHF and Alba. Results showed that NAPs from the Fis, EbfC/YbaB, HU/IHF and Alba families are widely (94%) distributed among prokaryotes. These NAPs were found in multiple combinations with or without XS-like proteins. In regard with XS regulators, results showed that only XS proteins from one family were found in those organisms containing them. This suggests specificity for this type of regulators and their corresponding genomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Double triplex real-time PCR assay for simultaneous detection of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, and Staphylococcus haemolyticus and determination of their methicillin resistance directly from positive blood culture bottles.

PubMed

Kilic, Abdullah; Basustaoglu, A Celal

2011-12-01

We developed and validated here a double triplex real-time PCR assay to simultaneously detect and identify Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus haemolyticus and their methicillin resistance in a single reaction directly from Gram-positive cocci-in-clusters (GPCs)-positive blood culture bottles. From August 15, 2009 through February 15, 2010, 238 GPC-positive samples were collected and identified by conventional methods as 11 methicillin-resistant S. aureus (MRSA), 28 methicillin-susceptible S. aureus (MSSA), 176 MR coagulase-negative staphylococci (MRCoNS), 21 MSCoNS and two Enterococcus faecalis. The double triplex real-time PCR assay was targeted and detected tuf, nuc and mecA genes in the first tube and atlE, gap and mvaA genes in the second tube which could be run simultaneously. The detection limit of the assay was found at 10(3) CFU/ml for the atleE gene, 10(4) CFU/ml for the mva gene and 10(5) CFU/ml for gap, nuc, mecA and tuf genes based on seeding experiments. All Staphylococcus species except two S. epidermidis were correctly identified by the assay. The double triplex real-time PCR assay quickly and accurately detects S. aureus, S. epidermidis, S. hominis and S. haemolyticus and their methicillin resistance in a single reaction directly from positive blood culture bottles within 83 min. Copyright © 2011 Institut Pasteur. All rights reserved.

Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis.

PubMed

Williams, Ann; Hatch, Graham J; Clark, Simon O; Gooch, Karen E; Hatch, Kim A; Hall, Graham A; Huygen, Kris; Ottenhoff, Tom H M; Franken, Kees L M C; Andersen, Peter; Doherty, T Mark; Kaufmann, Stefan H E; Grode, Leander; Seiler, Peter; Martin, Carlos; Gicquel, Brigitte; Cole, Stewart T; Brodin, Priscille; Pym, Alexander S; Dalemans, Wilfried; Cohen, Joe; Lobet, Yves; Goonetilleke, Nilu; McShane, Helen; Hill, Adrian; Parish, Tanya; Smith, Debbie; Stoker, Neil G; Lowrie, Douglas B; Källenius, Gunilla; Svenson, Stefan; Pawlowski, Andrzej; Blake, Karen; Marsh, Philip D

2005-01-01

The TB Vaccine Cluster project funded by the EU Fifth Framework programme aims to provide novel vaccines against tuberculosis that are suitable for evaluation in humans. This paper describes the studies of the protective efficacy of vaccines in a guinea pig aerosol-infection model of primary tuberculosis. The objective was to conduct comparative evaluations of vaccines that had previously demonstrated efficacy in other animal models. Groups of 6 guinea pigs were immunized with vaccines provided by the relevant EU Vaccine Cluster partners. Survival over 17 or 26 weeks was used as the principal measure of vaccine efficacy following aerosol challenge with H37Rv. Counts of mycobacteria in lungs and spleens, and histopathological changes in the lungs, were also used to provide evidence of protection. A total of 24 vaccines were evaluated in 4 experiments each of a different design. A heterologous prime-boost strategy of DNA and MVA, each expressing Ag85A and a fusion protein of ESAT-6 and Ag85B in adjuvant, protected the guinea pigs to the same extent as BCG. Genetically modified BCG vaccines and boosted BCG strategies also protected guinea pigs to the same extent as BCG but not statistically significantly better. A relatively high aerosol-challenge dose and evaluation over a protracted time post-challenge allowed superior protection over BCG to be demonstrated by BCG boosted with MVA and fowl pox vectors expressing Ag85A.

Cortical folding in post-traumatic stress disorder after motor vehicle accidents: Regional differences in gyrification.

PubMed

Chu, Chun; Xie, Bing; Qiu, Mingguo; Liu, Kaijun; Tan, Liwen; Wu, Yi; Chen, Wei; Zhang, Shaoxiang

2017-04-01

Structural and functional magnetic resonance imaging (MRI) studies have revealed evidence of brain abnormalities in post-traumatic stress disorder (PTSD) patients. Cortical complexity and local gyrification index (lGI) reflect potential biological processes associated with normal or abnormal cognitive functioning. In the current study, lGI was used to explore cortical folding in PTSD patients involved in motor vehicle accidents (MVA). MRI brain scans were acquired from 18 PTSD patients who had suffered MVA at least 6 months previously and 18 healthy control subjects. All MRI images were obtained on a 3-T Siemens MRI machine and the cortical folding was analyzed using the workflow provided by software FreeSurfer. A general FreeSurfer's general linear model was used in the group analysis. In addition, correlation analysis was performed between the average of lGI extracted from the significantly different areas and the data for the clinical scale. The PTSD patients had significantly greater Clinician-Administered PTSD Scale scores than the control group. The patients showed significantly reduced lGI in the left lateral orbitofrontal cortex, consistent with findings of previous volumetric studies on PTSD. But there were no significant correlations in the left lateral orbitofrontal cortex between Clinician-Administered PTSD Scale scores and lGI. We suggest that abnormal gyrification in PTSD patients can be an important indicator of neurodevelopment deficits and may indeed be a biological marker for PTSD. © 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.

School-Based Obesity Prevention Intervention in Chilean Children: Effective in Controlling, but not Reducing Obesity

PubMed Central

Kain, Juliana; Concha, Fernando; Moreno, Lorena; Leyton, Bárbara

2014-01-01

Objective. To evaluate the effectiveness of a 12-month multicomponent obesity prevention intervention. Setting. 9 elementary schools in Santiago, Chile. Subjects. 6–8 y old low-income children (N = 1474). Design. Randomized controlled study; 5 intervention/4 control schools. We trained teachers to deliver nutrition contents and improve the quality of PE classes. We determined % healthy snacks brought from home, children's nutrition knowledge, nutritional status, duration of PE classes, and % time in moderate/vigorous activity (MVA). Effectiveness was determined by comparing Δ BMI Z between intervention and control children using PROCMIXED. Results. % obesity increased in boys from both types of schools and in girls from control schools, while decreasing in girls from intervention schools (all nonsignificant). % class time in MVA declined (24.5–16.2) while remaining unchanged (24.8–23.7%) in classes conducted by untrained and trained teachers, respectively. In boys, BMI Z declined (1.33–1.24) and increased (1.22–1.35) in intervention and control schools, respectively. In girls, BMI Z remained unchanged in intervention schools, while increasing significantly in control schools (0.91–1.06, P = 0.024). Interaction group ∗ time was significant for boys (P < 0.0001) and girls (P = 0.004). Conclusions. This intervention was effective in controlling obesity, but not preventing it. Even though impact was small, results showed that when no intervention is implemented, obesity increases. PMID:24872892

Functionally Convergent B Cell Receptor Sequences in Transgenic Rats Expressing a Human B Cell Repertoire in Response to Tetanus Toxoid and Measles Antigens.

PubMed

Bürckert, Jean-Philippe; Dubois, Axel R S X; Faison, William J; Farinelle, Sophie; Charpentier, Emilie; Sinner, Regina; Wienecke-Baldacchino, Anke; Muller, Claude P

2017-01-01

The identification and tracking of antigen-specific immunoglobulin (Ig) sequences within total Ig repertoires is central to high-throughput sequencing (HTS) studies of infections or vaccinations. In this context, public Ig sequences shared by different individuals exposed to the same antigen could be valuable markers for tracing back infections, measuring vaccine immunogenicity, and perhaps ultimately allow the reconstruction of the immunological history of an individual. Here, we immunized groups of transgenic rats expressing human Ig against tetanus toxoid (TT), Modified Vaccinia virus Ankara (MVA), measles virus hemagglutinin and fusion proteins expressed on MVA, and the environmental carcinogen benzo[a]pyrene, coupled to TT. We showed that these antigens impose a selective pressure causing the Ig heavy chain (IgH) repertoires of the rats to converge toward the expression of antibodies with highly similar IgH CDR3 amino acid sequences. We present a computational approach, similar to differential gene expression analysis, that selects for clusters of CDR3s with 80% similarity, significantly overrepresented within the different groups of immunized rats. These IgH clusters represent antigen-induced IgH signatures exhibiting stereotypic amino acid patterns including previously described TT- and measles-specific IgH sequences. Our data suggest that with the presented methodology, transgenic Ig rats can be utilized as a model to identify antigen-induced, human IgH signatures to a variety of different antigens.

Genome-wide comparison of genes involved in the biosynthesis, metabolism, and signaling of juvenile hormone between silkworm and other insects

PubMed Central

Cheng, Daojun; Meng, Meng; Peng, Jian; Qian, Wenliang; Kang, Lixia; Xia, Qingyou

2014-01-01

Juvenile hormone (JH) contributes to the regulation of larval molting and metamorphosis in insects. Herein, we comprehensively identified 55 genes involved in JH biosynthesis, metabolism and signaling in the silkworm (Bombyx mori) as well as 35 in Drosophila melanogaster, 35 in Anopheles gambiae, 36 in Apis mellifera, 47 in Tribolium castaneum, and 44 in Danaus plexippus. Comparative analysis showed that each gene involved in the early steps of the mevalonate (MVA) pathway, in the neuropeptide regulation of JH biosynthesis, or in JH signaling is a single copy in B. mori and other surveyed insects, indicating that these JH-related pathways or steps are likely conserved in all surveyed insects. However, each gene participating in the isoprenoid branch of JH biosynthesis and JH metabolism, together with the FPPS genes for catalyzing the final step of the MVA pathway of JH biosynthesis, exhibited an obvious duplication in Lepidoptera, including B. mori and D. plexippus. Microarray and real-time RT-PCR analysis revealed that different copies of several JH-related genes presented expression changes that correlated with the dynamics of JH titer during larval growth and metamorphosis. Taken together, the findings suggest that duplication-derived copy variation of JH-related genes might be evolutionarily associated with the variation of JH types between Lepidoptera and other insect orders. In conclusion, our results provide useful clues for further functional analysis of JH-related genes in B. mori and other insects. PMID:25071411

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B

PubMed Central

Noguera-Julian, Marc; Bellido, Rocío; Puertas, Maria C.; Carrillo, Jorge; Rodriguez, C.; Perez-Alvarez, Núria; Cobarsí, Patricia; Gomez, Carmen E.; Esteban, Mariano; Jímenez, Jose Luis; García, Felipe; Blanco, Julià; Martinez-Picado, Javier; Paredes, Roger

2017-01-01

The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches. PMID:28953921

Multiscale field-aligned current analyzer

NASA Astrophysics Data System (ADS)

Bunescu, C.; Marghitu, O.; Constantinescu, D.; Narita, Y.; Vogt, J.; Blǎgǎu, A.

2015-11-01

The magnetosphere-ionosphere coupling is achieved, essentially, by a superposition of quasi-stationary and time-dependent field-aligned currents (FACs), over a broad range of spatial and temporal scales. The planarity of the FAC structures observed by satellite data and the orientation of the planar FAC sheets can be investigated by the well-established minimum variance analysis (MVA) of the magnetic perturbation. However, such investigations are often constrained to a predefined time window, i.e., to a specific scale of the FAC. The multiscale field-aligned current analyzer, introduced here, relies on performing MVA continuously and over a range of scales by varying the width of the analyzing window, appropriate for the complexity of the magnetic field signatures above the auroral oval. The proposed technique provides multiscale information on the planarity and orientation of the observed FACs. A new approach, based on the derivative of the largest eigenvalue of the magnetic variance matrix with respect to the length of the analysis window, makes possible the inference of the current structures' location (center) and scale (thickness). The capabilities of the FAC analyzer are explored analytically for the magnetic field profile of the Harris sheet and tested on synthetic FAC structures with uniform current density and infinite or finite geometry in the cross-section plane of the FAC. The method is illustrated with data observed by the Cluster spacecraft on crossing the nightside auroral region, and the results are cross checked with the optical observations from the Time History of Events and Macroscale Interactions during Substorms ground network.

Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial.

PubMed

Overton, Edgar Turner; Stapleton, Jack; Frank, Ian; Hassler, Shawn; Goepfert, Paul A; Barker, David; Wagner, Eva; von Krempelhuber, Alfred; Virgin, Garth; Meyer, Thomas Peter; Müller, Jutta; Bädeker, Nicole; Grünert, Robert; Young, Philip; Rösch, Siegfried; Maclennan, Jane; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

2015-04-01

Background.  First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods.  An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results.  Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions.  Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.