Chromosomally mediated intrinsic resistance to penicillin of penicillinase producing strains of Neisseria gonorrhoeae isolated in Sydney: guide to treatment with Augmentin.

PubMed Central

Tapsall, J W; Phillips, E A; Morris, L M

1987-01-01

Single dose Augmentin treatment fails to cure an appreciable proportion of patients infected with penicillinase producing Neisseria gonorrhoeae (PPNG) strains in parts of the world where high levels of chromosomally mediated intrinsic resistance are also present in gonococci. The levels of intrinsic resistance to penicillin of 31 PPNG strains isolated in Sydney were assessed by obtaining beta lactamase negative variants of these strains and measuring the minimum inhibitory concentration of penicillin by agar plate dilution techniques. The levels of intrinsic resistance found in these imported PPNG strains were higher than those recorded for local isolates of non-PPNG strains, which indicates that caution should be exercised in the use of single dose Augmentin treatment of infections with PPNG strains in Sydney. PMID:3119461

Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus.

PubMed

Murillo, O; Doménech, A; Garcia, A; Tubau, F; Cabellos, C; Gudiol, F; Ariza, J

2006-12-01

Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic- and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: -1.24, -2.26, -2.1, -1.56, -1.47, -1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P = 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r = 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.

Fungemia Due to Fusarium sacchari in an Immunosuppressed Patient

PubMed Central

Guarro, Josep; Nucci, Marcio; Akiti, Tiyomi; Gené, Josepa; Barreiro, M. Da Gloria C.; Gonçalves, Renato T.

2000-01-01

The fungus Fusarium sacchari was isolated repeatedly from the blood of an immunosuppressed host. The infection was treated successfully with a small dose of amphotericin B. The strain was resistant to this antifungal in vitro. MICs and minimum fungicidal concentrations of six antifungals for the clinical isolate are provided. To our knowledge, this is the first report involving this fungus in a case of fungemia. PMID:10618130

The anthelmintic effect of aqueous methanol extract of Combretum molle (R. Br. x. G. Don) (Combretaceae) in lambs experimentally infected with Haemonchus contortus.

PubMed

Simon, M K; Ajanusi, O J; Abubakar, M S; Idris, A L; Suleiman, M M

2012-06-08

The aqueous methanol extract from the stem-bark of Combretum molle was evaluated for anthelmintic activity in lambs infected with Haemonchus contortus using faecal egg count (FEC) reduction assay. The extract showed a dose-dependent reduction in FEC in infected animals. At doses of 500, 1000 and 2000 mg kg(-1), the extract caused FEC reduction of 63%, 69.25% and 96.23%, respectively. Similarly, the standard anthelmintic (albendazole) at a dose of 200 mg kg(-1) produced FEC reduction of 99.24%. FEC reduction produced by the extract at doses of 500 and 1000 mg kg(-1) is below the minimum standard of 90% FEC recommended by the World Association for the Advancement of Veterinary Parasitology (WAAVP). However, there was no significant (P>0.05) difference between the means of groups treated with 1000 mg kg(-1) and 2000 mg kg(-1) compared to that of albendazole. In this study, C. molle has shown a promising anthelmintic activity against experimental haemonchosis. Nonetheless, further studies to evaluate its detailed toxicity are required for the plant extract to be developed into a useful anthelmintic drug. There is also the need to evaluate other parts of the plant (root, leaves, fruits, etc.) for the same effect. Copyright © 2012 Elsevier B.V. All rights reserved.

Investigation of pregnancy-associated malaria by microscopy, rapid diagnostic test and PCR in Bandundu, the Democratic Republic of Congo.

PubMed

Ruh, Emrah; Bateko, Jean Paul; Imir, Turgut; Taylan-Ozkan, Aysegul

2018-01-01

The study was conducted to investigate malaria prevalence among a group of women in the Democratic Republic of Congo (DRC) who received intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). A total of 250 women from Bandundu city who received two doses of IPTp-SP were enrolled in the survey. Blood samples were collected at the time of delivery and malaria prevalence was determined using microscopy, rapid diagnostic test (RDT), and nested polymerase chain reaction (PCR). Malaria infection was detected in 81 (32.4%), 93 (37.2%), and 92 (36.8%) samples by microscopy, RDT, and PCR, respectively. Among 92 samples, P. falciparum mono-infection (n=87; 94.5%), P. falciparum+P. vivax (n=2; 2.2%) and P. falciparum+P. malariae (n=1; 1.1%) mixed infections, and P. vivax mono-infection (n=2; 2.2%) were detected. Prevalence of malaria was not affected by age and number of pregnancies (p>0.05). Microscopy and RDT, either alone (κ=0.29; p<0.001) or in combination (κ=0.33; p<0.001) showed a fair agreement with PCR. Our findings indicate that two doses of IPTp-SP did not protect the women against malaria in the DRC, and support the World Health Organization (WHO) guidelines that ensure a minimum of three doses of SP in pregnancy.

Metam sodium reduces viability and infectivity of Eimeria oocysts.

PubMed

Fetterer, R H; Jenkins, M C; Miska, K B; Cain, G D

2010-06-01

Metam sodium (MS, sodium N-methyldithiocarbamate) is a widely used soil pesticide. Fumigation or chemical sterilization of poultry litter containing infectious oocysts could be an effective strategy to block the transmission of avian coccidia. In the current study, the effect of MS on the viability and infectivity of ocysts was investigated. The development of isolated, unsporulated oocysts of both Eimeria tenella and Eimeria maxima was inhibited, in a dose-related manner (IC(50) 8 to 14 microg/ml), by exposure to aqueous MS. Most treated oocysts failed to develop beyond early stages of sporulation. To determine the effect of MS on infectivity, isolated oocysts of E. tenella , Eimeria acervulina , and E. maxima were exposed for 24 hr to aqueous concentrations of MS ranging from 0 to 1,000 microg/ml. Treated oocysts were inoculated into chickens, and parameters of coccidiosis infection were compared to chickens inoculated with equal numbers of untreated oocysts. In a dose-related manner, MS significantly reduced the infectivity of oocysts with maximum effect observed at a dose of 300 microg/ml. When a mixture of oocysts containing 3 coccidian species was exposed to 300 microg/ml MS, from 0 to 24 hr, infectivity of oocysts was significantly reduced after a minimum of 12 hr of exposure. Treatment of aqueous slurries of litter samples obtained from commercial poultry houses, with 300 microg/ml MS for 24 hr, prevented the sporulation of eimerian oocysts in the litter samples relative to untreated control samples. The results indicate that MS could be used to reduce coccidial contamination of poultry litter.

In vitro activity and rodent efficacy of clinafloxacin for bovine and swine respiratory disease.

PubMed

Sweeney, Michael T; Quesnell, Rebecca; Tiwari, Raksha; Lemay, Mary; Watts, Jeffrey L

2013-01-01

Clinafloxacin is a broad-spectrum fluoroquinolone that was originally developed and subsequently abandoned in the late 1990s as a human health antibiotic for respiratory diseases. The purpose of this study was to investigate the activity of clinafloxacin as a possible treatment for respiratory disease in cattle and pigs. Minimum inhibitory concentration (MIC) values were determined using Clinical and Laboratory Standards Institute recommended procedures with recent strains from the Zoetis culture collection. Rodent efficacy was determined in CD-1 mice infected systemically or intranasally with bovine Mannheimia haemolytica or Pasteurella multocida, or swine Actinobacillus pleuropneumoniae, and administered clinafloxacin for determination of ED50 (efficacious dose-50%) values. The MIC90 values for clinafloxacin against bovine P. multocida, M. haemolytica, Histophilus somni, and M. bovis were 0.125, 0.5, 0.125, and 1 μg/ml, respectively, and the MIC90 values against swine P. multocida, A. pleuropneumoniae, S. suis, and M. hyopneumoniae were í0.03, í0.03, 0.125, and í0.008 μg/ml, respectively. Efficacy in mouse models showed average ED50 values of 0.019 mg/kg/dose in the bovine M. haemolytica systemic infection model, 0.55 mg/kg in the bovine P. multocida intranasal lung challenge model, 0.08 mg/kg/dose in the bovine P. multocida systemic infection model, and 0.7 mg/kg/dose in the swine A. pleuropneumoniae systemic infection model. Clinafloxacin shows good in vitro activity and efficacy in mouse models and may be a novel treatment alternative for the treatment of respiratory disease in cattle and pigs.

Oronasal and intramuscular vaccination of swine with a modified live porcine parvovirus vaccine: multiplication and transmission of the vaccine virus.

PubMed

Paul, P S; Mengeling, W L

1984-12-01

An attenuated strain NADL-2 of porcine parvovirus (PPV) has been used at the 54th cell culture passage as a modified live-virus (MLV) vaccine. The present study was conducted to determine the minimum immunizing dose of MLV, the extent of MLV multiplication in swine tissues, and its transmission from swine administered MLV oronasally or intramuscularly. Immune response to MLV was dose dependent and swine responded to as little as 10(2) median cell-culture infective doses (CCID50). A 10(5) CCID50 of MLV, the largest dose given, induced the best immune response and was used in subsequent experiments. Route of MLV administration also was found to be important. The MLV replicated in tissues of swine after IM inoculation; however, viral antigen in tissues was less, as measured by immunofluorescence, and serum hemagglutination-inhibition titers for PPV were lower in MLV-inoculated swine than we have previously observed in virulent PPV-inoculated swine. In contrast, oronasal inoculation with MLV did not consistently result in infection of pigs; only 5 of 23 swine had virologic and/or serologic evidence of infection. Virus transmission studies indicated that MLV is shed in feces, but shedding occurs later than that in virulent-PPV-inoculated swine and is inconsistent. Delayed transmission of MLV was observed in contact pigs, which were seronegative at 2 weeks, but became seropositive at 4 weeks--indicating that perhaps a virus population capable of infecting pigs by oronasal route was selected by passage through the pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

PubMed Central

Fernandes, Prabhavathi

2016-01-01

Fusidic acid is an oral antistaphylococcal antibiotic that has been used in Europe for more than 40 years to treat skin infections as well as chronic bone and joint infections. It is a steroidal antibiotic and the only marketed member of the fusidane class. Fusidic acid inhibits protein synthesis by binding EF-G-GDP, which results in the inhibition of both peptide translocation and ribosome disassembly. It has a novel structure and novel mode of action and, therefore, there is little cross-resistance with other known antibiotics. Many mutations can occur in the FusA gene that codes for EF-G, and some of these mutations can result in high-level resistance (minimum inhibitory concentration [MIC] > 64 mg/L), whereas others result in biologically unfit staphylococci that require compensatory mutations to survive. Low-level resistance (<8 mg/L) is more common and is mediated by fusB, fusC, and fusD genes that code for small proteins that protect EF-G-GDP from binding fusidic acid. The genes for these proteins are spread by plasmids and can be selected mostly by topical antibiotic use. Reports of resistance have led to combination use of fusidic acid with rifampin, which is superseded by the development of a new dosing regimen for fusidic acid that can be used in monotherapy. It consists of a front-loading dose to decrease the potential for resistance development followed by a maintenance dose. This dosing regimen is now being used in clinical trials in the United States for skin and refractory bone and joint infections. PMID:26729758

Quantitative risk assessment of E. coli in street-vended cassava-based delicacies in the Philippines

NASA Astrophysics Data System (ADS)

Mesias, I. C. P.

2018-01-01

In the Philippines, rootcrop-based food products are gaining popularity in street food trade. However, a number of street-vended food products in the country are reported to be contaminated with E. coli posing possible risk among consumers. In this study, information on quantitative risk assessment of E. coli in street-vended cassava-based delicacies was generated. The assessment started with the prevalence and concentration of E. coli at post production in packages of the cassava-based delicacies. Combase growth predictor was used to trace the microbial population of E. coli in each step of the food chain. The @Risk software package, version 6 (Palisade USA) was used to run the simulations. Scenarios in the post-production to consumption pathway were simulated. The effect was then assessed in relation to exposure to the defined infective dose. In the worst case scenario, a minimum and most likely concentration of 6.3 and 7.8 log CFU of E. coli per serving respectively were observed. The simulation revealed that lowering the temperature in the chain considerably decreased the E. coli concentration prior to consumption and subsequently decreased the percentage of exposure to the infective dose. Exposure to infective dose however was increased with longer lag time from postproduction to consumption.

The Impact of AUC-Based Monitoring on Pharmacist-Directed Vancomycin Dose Adjustments in Complicated Methicillin-Resistant Staphylococcus aureus Infection.

PubMed

Stoessel, Andrew M; Hale, Cory M; Seabury, Robert W; Miller, Christopher D; Steele, Jeffrey M

2018-01-01

This study aimed to assess the impact of area under the curve (AUC)-based vancomycin monitoring on pharmacist-initiated dose adjustments after transitioning from a trough-only to an AUC-based monitoring method at our institution. A retrospective cohort study of patients treated with vancomycin for complicated methicillin-resistant Staphylococcus aureus (MRSA) infection between November 2013 and December 2016 was conducted. The frequency of pharmacist-initiated dose adjustments was assessed for patients monitored via trough-only and AUC-based approaches for trough ranges: 10 to 14.9 mg/L and 15 to 20 mg/L. Fifty patients were included: 36 in the trough-based monitoring and 14 in the AUC-based-monitoring group. The vancomycin dose was increased in 71.4% of patients when troughs were 10 to 14.9 mg/L when a trough-only approach was used and in only 25% of patients when using AUC estimation ( P = .048). In the AUC group, the dose was increased only when AUC/minimum inhibitory concentration (MIC) <400; unchanged regimens had an estimated AUC/MIC ≥400. The AUC-based monitoring did not significantly increase the frequency of dose reductions when trough concentrations were 15 to 20 mg/L (AUC: 33.3% vs trough: 4.6%; P = .107). The AUC-based monitoring resulted in fewer patients with dose adjustments when trough levels were 10 to 14.9 mg/L. The AUC-based monitoring has the potential to reduce unnecessary vancomycin exposure and warrants further investigation.

A spore counting method and cell culture model for chlorine disinfection studies of Encephalitozoon syn. Septata intestinalis.

PubMed

Wolk, D M; Johnson, C H; Rice, E W; Marshall, M M; Grahn, K F; Plummer, C B; Sterling, C R

2000-04-01

The microsporidia have recently been recognized as a group of pathogens that have potential for waterborne transmission; however, little is known about the effects of routine disinfection on microsporidian spore viability. In this study, in vitro growth of Encephalitozoon syn. Septata intestinalis, a microsporidium found in the human gut, was used as a model to assess the effect of chlorine on the infectivity and viability of microsporidian spores. Spore inoculum concentrations were determined by using spectrophotometric measurements (percent transmittance at 625 nm) and by traditional hemacytometer counting. To determine quantitative dose-response data for spore infectivity, we optimized a rabbit kidney cell culture system in 24-well plates, which facilitated calculation of a 50% tissue culture infective dose (TCID(50)) and a minimal infective dose (MID) for E. intestinalis. The TCID(50) is a quantitative measure of infectivity and growth and is the number of organisms that must be present to infect 50% of the cell culture wells tested. The MID is as a measure of a system's permissiveness to infection and a measure of spore infectivity. A standardized MID and a standardized TCID(50) have not been reported previously for any microsporidian species. Both types of doses are reported in this paper, and the values were used to evaluate the effects of chlorine disinfection on the in vitro growth of microsporidia. Spores were treated with chlorine at concentrations of 0, 1, 2, 5, and 10 mg/liter. The exposure times ranged from 0 to 80 min at 25 degrees C and pH 7. MID data for E. intestinalis were compared before and after chlorine disinfection. A 3-log reduction (99.9% inhibition) in the E. intestinalis MID was observed at a chlorine concentration of 2 mg/liter after a minimum exposure time of 16 min. The log(10) reduction results based on percent transmittance-derived spore counts were equivalent to the results based on hemacytometer-derived spore counts. Our data suggest that chlorine treatment may be an effective water treatment for E. intestinalis and that spectrophotometric methods may be substituted for labor-intensive hemacytometer methods when spores are counted in laboratory-based chlorine disinfection studies.

Environmental Persistence Influences Infection Dynamics for a Butterfly Pathogen

PubMed Central

Altizer, Sonia; Williams, Mary-Kate; Hall, Richard J.

2017-01-01

Many pathogens, including those infecting insects, are transmitted via dormant stages shed into the environment, where they must persist until encountering a susceptible host. Understanding how abiotic conditions influence environmental persistence and how these factors influence pathogen spread are crucial for predicting patterns of infection risk. Here, we explored the consequences of environmental transmission for infection dynamics of a debilitating protozoan parasite (Ophryocystis elektroscirrha) that infects monarch butterflies (Danaus plexippus). We first conducted an experiment to observe the persistence of protozoan spores exposed to natural conditions. Experimental results showed that, contrary to our expectations, pathogen doses maintained high infectivity even after 16 days in the environment, although pathogens did yield infections with lower parasite loads after environmental exposure. Because pathogen longevity exceeded the time span of our experiment, we developed a mechanistic model to better explore environmental persistence for this host-pathogen system. Model analysis showed that, in general, longer spore persistence led to higher infection prevalence and slightly smaller monarch population sizes. The model indicated that typical parasite doses shed onto milkweed plants must remain viable for a minimum of 3 weeks for prevalence to increase during the summer-breeding season, and for 11 weeks or longer to match levels of infection commonly reported from the wild, assuming moderate values for parasite shedding rate. Our findings showed that transmission stages of this butterfly pathogen are long-lived and indicated that this is a necessary condition for the protozoan to persist in local monarch populations. This study provides a modeling framework for future work examining the dynamics of an ecologically important pathogen in an iconic insect. PMID:28099501

Evaluation of the dependence of the exposure dose on the attenuation correction in brain PET/CT scans using 18F-FDG

NASA Astrophysics Data System (ADS)

Choi, Eun-Jin; Jeong, Moon-Taeg; Jang, Seong-Joo; Choi, Nam-Gil; Han, Jae-Bok; Yang, Nam-Hee; Dong, Kyung-Rae; Chung, Woon-Kwan; Lee, Yun-Jong; Ryu, Young-Hwan; Choi, Sung-Hyun; Seong, Kyeong-Jeong

2014-01-01

This study examined whether scanning could be performed with minimum dose and minimum exposure to the patient after an attenuation correction. A Hoffman 3D Brain Phantom was used in BIO_40 and D_690 PET/CT scanners, and the CT dose for the equipment was classified as a low dose (minimum dose), medium dose (general dose for scanning) and high dose (dose with use of contrast medium) before obtaining the image at a fixed kilo-voltage-peak (kVp) and milliampere (mA) that were adjusted gradually in 17-20 stages. A PET image was then obtained to perform an attenuation correction based on an attenuation map before analyzing the dose difference. Depending on tube current in the range of 33-190 milliampere-second (mAs) when BIO_40 was used, a significant difference in the effective dose was observed between the minimum and the maximum mAs (p < 0.05). According to a Scheffe post-hoc test, the ratio of the minimum to the maximum of the effective dose was increased by approximately 5.26-fold. Depending on the change in the tube current in the range of 10-200 mA when D_690 was used, a significant difference in the effective dose was observed between the minimum and the maximum of mA (p < 0.05). The Scheffe posthoc test revealed a 20.5-fold difference. In conclusion, because effective exposure dose increases with increasing operating current, it is possible to reduce the exposure limit in a brain scan can be reduced if the CT dose can be minimized for a transmission scan.

Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals.

PubMed

Luna, T; Santos, S B; Nascimento, M; Porto, M A F; Muniz, A L; Carvalho, E M; Jesus, A R

2011-11-01

Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.

Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles.

PubMed

Warfield, Kelly L; Dye, John M; Wells, Jay B; Unfer, Robert C; Holtsberg, Frederick W; Shulenin, Sergey; Vu, Hong; Swenson, Dana L; Bavari, Sina; Aman, M Javad

2015-01-01

Filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. Several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (VLPs) have shown efficacy in nonhuman primates. Previous studies have shown protection of cynomolgus macaques against homologous infection for Ebola virus (EBOV) and Marburg virus (MARV) following a three-dose vaccine regimen of EBOV or MARV VLPs, as well as heterologous protection against Ravn Virus (RAVV) following vaccination with MARV VLPs. The objectives of the current studies were to determine the minimum number of vaccine doses required for protection (using EBOV as the test system) and then demonstrate protection against Sudan virus (SUDV) and Taï Forest virus (TAFV). Using the EBOV nonhuman primate model, we show that one or two doses of VLP vaccine can confer protection from lethal infection. VLPs containing the SUDV glycoprotein, nucleoprotein and VP40 matrix protein provide complete protection against lethal SUDV infection in macaques. Finally, we demonstrate protective efficacy mediated by EBOV, but not SUDV, VLPs against TAFV; this is the first demonstration of complete cross-filovirus protection using a single component heterologous vaccine within the Ebolavirus genus. Along with our previous results, this observation provides strong evidence that it will be possible to develop and administer a broad-spectrum VLP-based vaccine that will protect against multiple filoviruses by combining only three EBOV, SUDV and MARV components.

Homologous and Heterologous Protection of Nonhuman Primates by Ebola and Sudan Virus-Like Particles

PubMed Central

Warfield, Kelly L.; Dye, John M.; Wells, Jay B.; Unfer, Robert C.; Holtsberg, Frederick W.; Shulenin, Sergey; Vu, Hong; Swenson, Dana L.; Bavari, Sina; Aman, M. Javad

2015-01-01

Filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. Several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (VLPs) have shown efficacy in nonhuman primates. Previous studies have shown protection of cynomolgus macaques against homologous infection for Ebola virus (EBOV) and Marburg virus (MARV) following a three-dose vaccine regimen of EBOV or MARV VLPs, as well as heterologous protection against Ravn Virus (RAVV) following vaccination with MARV VLPs. The objectives of the current studies were to determine the minimum number of vaccine doses required for protection (using EBOV as the test system) and then demonstrate protection against Sudan virus (SUDV) and Taï Forest virus (TAFV). Using the EBOV nonhuman primate model, we show that one or two doses of VLP vaccine can confer protection from lethal infection. VLPs containing the SUDV glycoprotein, nucleoprotein and VP40 matrix protein provide complete protection against lethal SUDV infection in macaques. Finally, we demonstrate protective efficacy mediated by EBOV, but not SUDV, VLPs against TAFV; this is the first demonstration of complete cross-filovirus protection using a single component heterologous vaccine within the Ebolavirus genus. Along with our previous results, this observation provides strong evidence that it will be possible to develop and administer a broad-spectrum VLP-based vaccine that will protect against multiple filoviruses by combining only three EBOV, SUDV and MARV components. PMID:25793502

DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

PubMed

Roberts, Jason A; Paul, Sanjoy K; Akova, Murat; Bassetti, Matteo; De Waele, Jan J; Dimopoulos, George; Kaukonen, Kirsi-Maija; Koulenti, Despoina; Martin, Claude; Montravers, Philippe; Rello, Jordi; Rhodes, Andrew; Starr, Therese; Wallis, Steven C; Lipman, Jeffrey

2014-04-01

Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides.

PubMed

Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

2005-07-01

We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

PubMed Central

Zeng, Dongping; Sun, Meizhen; Lin, Zhoumeng; Li, Miao; Gehring, Ronette; Zeng, Zhenling

2018-01-01

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle. PMID:29867911

A randomized trial to determine the optimal dosage of multivitamin supplements to reduce adverse pregnancy outcomes among HIV-infected women in Tanzania.

PubMed

Kawai, Kosuke; Kupka, Roland; Mugusi, Ferdinand; Aboud, Said; Okuma, James; Villamor, Eduardo; Spiegelman, Donna; Fawzi, Wafaie W

2010-02-01

We previously reported that supplementation with multivitamins (vitamin B complex, vitamin C, and vitamin E) at multiples of the Recommended Dietary Allowance (RDA) significantly decreased the risk of adverse pregnancy outcomes among HIV-infected women. The minimum dosage of multivitamins necessary for optimal benefits is unknown. We investigated the efficacy of multivitamin supplements at single compared with multiple RDAs on decreasing the risk of adverse pregnancy outcomes among HIV-infected women. We conducted a double-blind, randomized controlled trial among 1129 HIV-infected pregnant women in Tanzania. Eligible women between 12 and 27 gestational weeks were randomly assigned to receive daily oral supplements of either single or multiple RDA multivitamins from enrollment until 6 wk after delivery. Multivitamins at multiple and single doses of the RDA had similar effects on the risk of low birth weight (11.6% and 10.2%, respectively; P = 0.75). We found no difference between the 2 groups in the risk of preterm birth (19.3% and 18.4%, respectively; P = 0.73) or small-for-gestational-age (14.8% and 12.0%, respectively; P = 0.18). The mean birth weights were similar in the multiple RDA (3045 + or - 549 g) and single RDA multivitamins group (3052 + or - 534 g; P = 0.83). There were no significant differences between the 2 groups in the risk of fetal death (P = 0.99) or early infant death (P = 0.19). Multivitamin supplements at a single dose of the RDA may be as efficacious as multiple doses of the RDA in decreasing the risk of adverse pregnancy outcomes among HIV-infected women. This trial was registered at clinicaltrials.gov as NCT00197678.

The management of multidrug-resistant Enterobacteriaceae.

PubMed

Bassetti, Matteo; Peghin, Maddalena; Pecori, Davide

2016-12-01

Multidrug-resistant (MDR) Enterobacteriaceae are often related to the production of extended-spectrum b-lactamases (ESBLs) and carbapenemase-producing Enterobacteriaceae (CRE), and represent an increasing global threat. Recommendations for the therapeutic management of MDR-related infections, however, are mainly derived from retrospective and nonrandomized prospective studies. The aim of this review is to discuss the challenges in the treatment of patients with infections because of MDR Enterobacteriaceae and provide an expert opinion while awaiting for more definitive data. To avoid the selection of carbapenemase-producing Enterobacteriaceae, carbapenem-sparing strategies should be considered. B-lactams/b-lactamase inhibitors, mainly piperacillin-tazobactam, minimum inhibitory concentration (MIC) 16/4mg/ml or less represents the best alternative to carbapenems for the treatment of ESBL-producing strains. Overall, combination therapy may be preferred over monotherapy for CRE. The combination of a carbapenem-containing regimen with colistin or high-dose tigecycline or aminoglycoside can be administered at high-dose prolonged infusion with therapeutic drug monitoring for the treatment of CRE with MIC for meropenem 8-16 mg/l or less. For MIC higher than 8-16 mg/l, the use of meropenem should be avoided and various combination therapies based on the in-vitro susceptibility of antimicrobials (e.g., colistin, high-dose tigecycline, fosfomycin, and aminoglycosides) should be selected. Carbapenem-sparing strategies should be used, when feasible, for ESBL infections. The majority of available nonrandomized studies highlight that combination for CRE seem to offer some therapeutic advantage over monotherapy. Strict infection control measures toward MDR Gram-negative pathogens remain necessary while awaiting for new treatment options.

Infectivity of Theileria parva sporozoites following cryopreservation in four suspension media and multiple refreezing: evaluation by in vitro titration.

PubMed

Mbao, V; Berkvens, D; Dolan, T; Speybroeck, N; Brandt, J; Dorny, P; Van den Bossche, P; Marcotty, T

2006-09-01

Theileria parva sporozoite stabilates are used for immunizing cattle against East Coast fever and in in vitro sporozoite neutralization assays. In this study, we attempted to identify a cheaper freezing medium and quantified the infectivity loss of sporozoites due to refreezing of stabilates, using an in vitro technique. Pools of stabilates prepared using Minimum Essential Medium (MEM), Roswell Park Memorial Institute (RPMI 1640), foetal calf serum (FCS) and phosphate-buffered saline (PBS) were compared. All were supplemented with bovine serum albumin except the FCS. RPMI 1640 was as effective as MEM in maintaining sporozoite infectivity while the infectivity in PBS and FCS reached only 59% and 67%, respectively. In a second experiment, a stabiiate based on MEM was subjected to several freeze-thaw cycles including various holding times on ice between thawing and refreezing. Refrozen stabilate gave an average sporozoite infectivity loss of 35% per cycle. The results indicate that RPMI can be used as a cheaper freezing medium for T. parva stabilates and that refrozen stabilate doses need to be adjusted for the 35% loss of infectivity.

Limited transmission of emergent H7N9 influenza A virus in a simulated live animal market: Do chickens pose the principal transmission threat?

PubMed

Bosco-Lauth, Angela M; Bowen, Richard A; Root, J Jeffrey

2016-08-01

Emergent H7N9 influenza A virus has caused multiple public health and financial hardships. While some epidemiological studies have recognized infected chickens as an important bridge for human infections, the generality of this observation, the minimum infectious dose, and the shedding potential of chickens have received conflicting results. We experimentally tested the ability of domestic chickens (Gallus gallus domesticus) to transmit H7N9 to co-housed chickens and to several other animal species in an experimental live animal market. Results indicated that an infected chicken failed to initiate viral shedding of H7N9 to naïve co-housed chickens. The infected chicken did, however, successfully transmit the virus to quail (Coturnix sp.) located directly below the infected chicken cage. Oral shedding by indirectly infected quail was, on average, greater than ten-fold that of directly inoculated chickens. Best management practices in live animal market systems should consider the position of quail in stacked-cage settings. Copyright © 2016 Elsevier Inc. All rights reserved.

A Generalized QMRA Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2016-10-01

Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0

Killing of Serratia marcescens biofilms with chloramphenicol.

PubMed

Ray, Christopher; Shenoy, Anukul T; Orihuela, Carlos J; González-Juarbe, Norberto

2017-03-29

Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate-80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate-80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms.

Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial

PubMed Central

Phongluxa, Khampheng; Ayé Soukhathammavong, Phonepasong; Vonghachack, Youthanavanh; Keiser, Jennifer; Vounatsou, Penelope; Tanner, Marcel; Hatz, Christoph; Utzinger, Jürg; Odermatt, Peter; Akkhavong, Kongsap

2012-01-01

Background Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made. Methodology Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28–30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment. Principal Findings Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6–88.5%) and 80.8% (95% CI: 60.6–93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4–84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups. Conclusions/Significance Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses. Trial Registration Controlled-Trials.com ISRCTN57714676 PMID:22848766

A Spore Counting Method and Cell Culture Model for Chlorine Disinfection Studies of Encephalitozoon syn. Septata intestinalis

PubMed Central

Wolk, D. M.; Johnson, C. H.; Rice, E. W.; Marshall, M. M.; Grahn, K. F.; Plummer, C. B.; Sterling, C. R.

2000-01-01

The microsporidia have recently been recognized as a group of pathogens that have potential for waterborne transmission; however, little is known about the effects of routine disinfection on microsporidian spore viability. In this study, in vitro growth of Encephalitozoon syn. Septata intestinalis, a microsporidium found in the human gut, was used as a model to assess the effect of chlorine on the infectivity and viability of microsporidian spores. Spore inoculum concentrations were determined by using spectrophotometric measurements (percent transmittance at 625 nm) and by traditional hemacytometer counting. To determine quantitative dose-response data for spore infectivity, we optimized a rabbit kidney cell culture system in 24-well plates, which facilitated calculation of a 50% tissue culture infective dose (TCID50) and a minimal infective dose (MID) for E. intestinalis. The TCID50 is a quantitative measure of infectivity and growth and is the number of organisms that must be present to infect 50% of the cell culture wells tested. The MID is as a measure of a system's permissiveness to infection and a measure of spore infectivity. A standardized MID and a standardized TCID50 have not been reported previously for any microsporidian species. Both types of doses are reported in this paper, and the values were used to evaluate the effects of chlorine disinfection on the in vitro growth of microsporidia. Spores were treated with chlorine at concentrations of 0, 1, 2, 5, and 10 mg/liter. The exposure times ranged from 0 to 80 min at 25°C and pH 7. MID data for E. intestinalis were compared before and after chlorine disinfection. A 3-log reduction (99.9% inhibition) in the E. intestinalis MID was observed at a chlorine concentration of 2 mg/liter after a minimum exposure time of 16 min. The log10 reduction results based on percent transmittance-derived spore counts were equivalent to the results based on hemacytometer-derived spore counts. Our data suggest that chlorine treatment may be an effective water treatment for E. intestinalis and that spectrophotometric methods may be substituted for labor-intensive hemacytometer methods when spores are counted in laboratory-based chlorine disinfection studies. PMID:10742198

Treatment of acute bacterial rhinosinusitis caused by antimicrobial-resistant Streptococcus pneumoniae.

PubMed

Anon, Jack B

2004-08-02

Acute bacterial rhinosinusitis (ABRS) is a secondary bacterial infection of the nose and paranasal sinuses, usually preceded by a viral upper respiratory infection or allergy, with symptoms that have not improved after 10 days or that have worsened after 5 to 7 days. Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of ABRS in adults. Increasing rates of antimicrobial resistance among S. pneumoniae and beta-lactamase production among H. influenzae are formidable challenges to the successful treatment of infections caused by these organisms. To this end, various formulations of amoxicillin-clavulanate have been developed, the most recent of which is pharmacokinetically enhanced and provides a total daily dose of 4,000 mg of amoxicillin and 250 mg of clavulanate. This formulation has been shown to be safe and effective in the treatment of infections caused by penicillin-resistant S. pneumoniae (minimum inhibitory concentration 2 microg/mL); the clavulanate component provides adequate coverage of beta-lactamase-producing pathogens.

A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum.

PubMed

Hale, Braden R; Owusu-Agyei, Seth; Fryauff, David J; Koram, Kwadwo A; Adjuik, Martin; Oduro, Abraham R; Prescott, W Roy; Baird, J Kevin; Nkrumah, Francis; Ritchie, Thomas L; Franke, Eileen D; Binka, Fred N; Horton, John; Hoffman, Stephen L

2003-03-01

Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled chemoprophylaxis trial was conducted with adult residents of northern Ghana to determine the minimum effective weekly dose of tafenoquine for the prevention of infection by Plasmodium falciparum. The primary end point was a positive malaria blood smear result during the 13 weeks of study drug coverage. Relative to the placebo, all 4 tafenoquine dosages demonstrated significant protection against P. falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week, 87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine dosage of 250 mg/week also demonstrated significant protection against P. falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was little difference between study groups in the adverse events reported, and there was no evidence of a relationship between tafenoquine dosage and reports of physical complaints or the occurrence of abnormal laboratory parameters. Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and effective against P. falciparum infection in this study population.

Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations.

PubMed

Karlsson, B; Lindquist, C; Steiner, L

1997-03-01

To define the factors of importance for the obliteration of cerebral arteriovenous malformations (AVMs), thus making a prediction of the probability for obliteration possible. In 945 AVMs of a series of 1319 patients treated with the gamma knife during 1970 to 1990, the relationship between patient, AVMs, and treatment parameters on the one hand and the obliteration of the nidus on the other was analyzed. The obliteration rate increased both with increased minimum (lowest periphery) and average dose and decreased with increased AVM volume. The minimum dose to the AVMs was the decisive dose factor for the treatment result. The higher the minimum dose, the higher the chance for total obliteration. The curve illustrating this relation increased logarithmically to a value of 87%. A higher average dose shortened the latency to AVM obliteration. For the obliterated cases, the larger the malformation, the lower the minimum dose used. This prompted us to relate the obliteration rate to the product minimum dose (AVM volume)1/3 (K index). The obliteration rate increased linearly with the K index up to a value of approximately 27, and for higher K values, the obliteration rate had a constant value of approximately 80%. For the group of 273 cases treated with a minimum dose of at least 25 Gy, the obliteration rate at the study end point (defined as 2-yr latency) was 80% (95% confidence interval = 75-85%). If obliterations that occurred beyond the end point are included, the obliteration rate increased to 85% (81-89%). The probability of obliteration of AVMs after gamma knife surgery is related both to the lowest dose to the AVMs and the AVM volume, and it can be predicted using the K index.

Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

PubMed Central

Hirano, Ryuichi; Sakamoto, Yuichi; Kitazawa, Junichi; Yamamoto, Shoji; Tachibana, Naoki

2016-01-01

Background Vancomycin (VCM) requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP) on attaining target VCM trough concentrations and pharmacokinetics (PK)/pharmacodynamics (PD) parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Materials and methods The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation) and from April 2012 to December 2014 (postimplementation), 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51). In 65 patients (pre, n=15; post, n=50), 24-hour area under the concentration–time curve (AUC 0–24 h)/minimum inhibitory concentration (MIC) ratios were calculated. Results Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33). The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL) was significantly higher during postimplementation (84%, 43/51) than during preimplementation (39%, 11/28) (P<0.01). The percentage of patients who attained target PK/PD parameters (AUC 0–24 h/MIC >400) was significantly higher during postimplementation (84%, 42/50) than during preimplementation (53%, 8/15; P=0.013). There were no significant differences in nephrotoxicity or mortality rate. Conclusion Our ASP increased the percentage of patients that attained optimal VCM trough concentrations and PK/PD parameters, which contributed to the appropriate use of VCM in patients with MRSA infections. PMID:27789965

World Association for the Advancement of Veterinary Parasitology (WAAVP): Guideline for the evaluation of drug efficacy against non-coccidial gastrointestinal protozoa in livestock and companion animals.

PubMed

Geurden, T; Olson, M E; O'Handley, R M; Schetters, T; Bowman, D; Vercruysse, J

2014-08-29

The current guideline was written to aid in the design, implementation and interpretation of studies for the assessment of drug efficacy against non-coccidial gastrointestinal protozoan parasites, with Giardia spp. as the leading example. The information provided in this guideline deals with aspects of how to conduct controlled studies using experimental infection models (dose determination and dose confirmation) and efficacy studies in commercial facilities (field effectiveness studies). Furthermore, the selection of suitable animals, housing, infection procedure, choice of diagnostic technique and data analysis are discussed. This guideline is intended to assist investigators in conducting specific studies, to provide specific information for registration authorities involved in the decision-making process, to assist in the approval and registration of new drugs and to facilitate the worldwide adoption of uniform procedures. The primary parameter for drug efficacy is the reduction in either parasite excretion or parasite counts and a minimum efficacy of 90% is required against non-coccidial gastrointestinal protozoa. A supporting efficacy parameter is a significant difference in the proportion of infected animals between treated and non-treated groups. Persistent efficacy is considered as an additional claim to therapeutic efficacy. Copyright © 2014 Elsevier B.V. All rights reserved.

Tracing Personalized Health Curves during Infections

PubMed Central

Schneider, David S.

2011-01-01

It is difficult to describe host–microbe interactions in a manner that deals well with both pathogens and mutualists. Perhaps a way can be found using an ecological definition of tolerance, where tolerance is defined as the dose response curve of health versus parasite load. To plot tolerance, individual infections are summarized by reporting the maximum parasite load and the minimum health for a population of infected individuals and the slope of the resulting curve defines the tolerance of the population. We can borrow this method of plotting health versus microbe load in a population and make it apply to individuals; instead of plotting just one point that summarizes an infection in an individual, we can plot the values at many time points over the course of an infection for one individual. This produces curves that trace the course of an infection through phase space rather than over a more typical timeline. These curves highlight relationships like recovery and point out bifurcations that are difficult to visualize with standard plotting techniques. Only nine archetypical curves are needed to describe most pathogenic and mutualistic host–microbe interactions. The technique holds promise as both a qualitative and quantitative approach to dissect host–microbe interactions of all kinds. PMID:21957398

[The influence of socio-economic conditions in renal posttransplant infection].

PubMed

Ianhez, L E; Sampaio, M; Chocair, P R; Fonseca, J A; Sabbaga, E

1993-01-01

Two hundred and four patients who underwent renal transplantation were followed up as outpatients with a minimum of four years. They were divided into two socio-economic levels: group I - 104 patients who underwent transplantation in a private hospital and 120 patients (group II) with a lower socio-economic standard, treated in a public hospital. In both groups urinary infections and hepatitis were excluded. The incidence of infection in group I was 24% and in group II, 50% (p = 0.0002). There was no difference in relation to viral infection in either groups. However, bacterial infection and infection by opportunistic agents were significantly higher in group II (p = 0.0001 and p = 0.0282). The number of hospitalizations and the number of infections of patients were higher in group II. There was a tendency for an increase in mortality owing to infection in group II. There was no difference in the two groups as the parameters of: age, sex, type of donor, primary disease, number of rejections crises, level of serum creatinine and number of patients with ciclosporine. On the other hand, the dose of azathioprine and prednisone was mildly higher in those patients of group II. Low level of socio-economic conditions is a risk factor in renal transplant patients.

Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline-free acid in red-tailed hawks (Buteo jamaicensis).

PubMed

Sadar, Miranda J; Hawkins, Michelle G; Byrne, Barbara A; Cartoceti, Andrew N; Keel, Kevin; Drazenovich, Tracy L; Tell, Lisa A

2015-12-01

To determine the pharmacokinetics and adverse effects at the injection site of ceftiofur crystalline-free acid (CCFA) following IM administration of 1 dose to red-tailed hawks (Buteo jamaicensis). 7 adult nonreleasable healthy red-tailed hawks. In a randomized crossover study, CCFA (10 or 20 mg/kg) was administered IM to each hawk and blood samples were obtained. After a 2-month washout period, administration was repeated with the opposite dose. Muscle biopsy specimens were collected from the injection site 10 days after each sample collection period. Pharmacokinetic data were calculated. Minimum inhibitory concentrations of ceftiofur for various bacterial isolates were assessed. Mean peak plasma concentrations of ceftiofur-free acid equivalent were 6.8 and 15.1 μg/mL for the 10 and 20 mg/kg doses, respectively. Mean times to maximum plasma concentration were 6.4 and 6.7 hours, and mean terminal half-lives were 29 and 50 hours, respectively. Little to no muscle inflammation was identified. On the basis of a target MIC of 1 μg/mL and target plasma ceftiofur concentration of 4 μg/mL, dose administration frequencies for infections with gram-negative and gram-positive organisms were estimated as every 36 and 45 hours for the 10 mg/kg dose and every 96 and 120 hours for the 20 mg/kg dose, respectively. Study results suggested that CCFA could be administered IM to red-tailed hawks at 10 or 20 mg/kg to treat infections with ceftiofur-susceptible bacteria. Administration resulted in little to no inflammation at the injection site. Additional studies are needed to evaluate effects of repeated CCFA administration.

Use of real-time PCR to detect canine parvovirus in feces of free-ranging wolves.

PubMed

Mech, L David; Almberg, Emily S; Smith, Douglas; Goyal, Sagar; Singer, Randall S

2012-04-01

Using real-time PCR, we tested 15 wolf (Canis lupus) feces from the Superior National Forest (SNF), Minnesota, USA, and 191 from Yellowstone National Park (YNP), USA, collected during summer and 13 during winter for canine parvovirus (CPV)-2 DNA. We also tested 20 dog feces for CPV-2 DNA. The PCR assay was 100% sensitive and specific with a minimum detection threshold of 10(4) 50% tissue culture infective dose. Virus was detected in two winter specimens but none of the summer specimens. We suggest applying the technique more broadly especially with winter feces.

Use of real-time PCR to detect canine parvovirus in feces of free-ranging wolves

USGS Publications Warehouse

Mech, L. David; Almberg, Emily S.; Smith, Douglas; Goyal, Sagar; Singer, Randall S.

2012-01-01

Using real-time PCR, we tested 15 wolf (Canis lupus) feces from the Superior National Forest (SNF), Minnesota, USA, and 191 from Yellowstone National Park (YNP), USA, collected during summer and 13 during winter for canine parvovirus (CPV)-2 DNA. We also tested 20 dog feces for CPV-2 DNA. The PCR assay was 100% sensitive and specific with a minimum detection threshold of 104 50% tissue culture infective dose. Virus was detected in two winter specimens but none of the summer specimens. We suggest applying the technique more broadly especially with winter feces.

Efficacy of high doses of oral penicillin versus amoxicillin in the treatment of adults with non-severe pneumonia attended in the community: study protocol for a randomised controlled trial

PubMed Central

2013-01-01

Background Streptococcus pneumoniae is the bacterial agent which most frequently causes pneumonia. In some Scandinavian countries, this infection is treated with penicillin V since the resistances of pneumococci to this antibiotic are low. Four reasons justify the undertaking of this study; firstly, the cut-off points which determine whether a pneumococcus is susceptible or resistant to penicillin have changed in 2008 and according to some studies published recently the pneumococcal resistances to penicillin in Spain have fallen drastically, with only 0.9% of the strains being resistant to oral penicillin (minimum inhibitory concentration>2 μg/ml); secondly, there is no correlation between pneumococcal infection by a strain resistant to penicillin and therapeutic failure in pneumonia; thirdly, the use of narrow-spectrum antibiotics is urgently needed because of the dearth of new antimicrobials and the link observed between consumption of broad-spectrum antibiotics and emergence and spread of antibacterial resistance; and fourthly, no clinical study comparing amoxicillin and penicillin V in pneumonia in adults has been published. Our aim is to determine whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of uncomplicated community-acquired pneumonia. Methods We will perform a parallel group, randomised, double-blind, trial in primary healthcare centres in Spain. Patients aged 18 to 65 without significant associated comorbidity attending the physician with signs and symptoms of lower respiratory tract infection and radiological confirmation of the diagnosis of pneumonia will be randomly assigned to either penicillin V 1.6 million units thrice-daily during 10 days or amoxicillin 1,000 mg thrice-daily during 10 days. The main outcome will be clinical cure at 14 days, defined as absence of fever, resolution or improvement of cough, improvement of general wellbeing and resolution or reduction of crackles indicating that no other antimicrobial treatment will be necessary. Any clinical result other than the anterior will be considered as treatment failure. A total of 210 patients will be recruited to detect a non-inferiority margin of 15% between the two treatments with a minimum power of 80% considering an alpha error of 2.5% for a unilateral hypothesis and maximum possible losses of 15%. Discussion This pragmatic trial addresses the long-standing hypothesis that the administration of high doses of a narrow-spectrum antibiotic (penicillin V) in patients with non-severe pneumonia attended in the community is not less effective than high doses of amoxicillin (treatment currently recommended) in patients under the age of 65 years. Trial registration EudraCT number 2012-003511-63. PMID:23594463

[Measurements of vancomycin concentrations in the blood - a method of personalization the antibiotic therapy in patients with chronic kidney disease].

PubMed

Pondel, Joanna; Krajewski, Piotr; Królikowska, Natalia; Tobiasz, Aleksandra; Augustyniak-Bartosik, Hanna; Hurkacz, Magdalena

2017-04-21

Therapeutic Drug Monitoring is a recognized method of personalizing treatment, having particular application in patients with chronic kidney disease who have frequent infections, requiring administration of vancomycin. International guidelines indicate the need to adjust the dose of the drug to the state of renal function. The recommended therapeutic ranges of minimum and maximum levels should be achieved in order to increase the effectiveness and safety of treatment. The aim of this study was to evaluate the usefulness of measuring the concentration of vancomycin in patients with chronic kidney disease due to bacterial infection. The study included 96 adult patients with chronic kidney disease of varying severity treated with vancomycin Patients were divided into 3 groups: treated by haemodialysis (hd), after renal transplantations (ktx), do not require renal replacement therapy (nef). In subjects were examined the minimum and maximum concentrations of vancomycin in steady-state and were compared with recommended therapeutic ranges. Statistically significant decrease of inflammatory markers was observed only in patients treated with dialysis. In the other groups not significant changes in values of inflammatory parameters were confirmed. Trough concentrations of vancomycin marked in patients were consistent with the recommendation of EUCAST, but exceeded the value recommended by the manufacturers of the drug. Considering absolute values of the minimum concentrations, only about 50% of patients achieved the therapeutic range (58% for recommendation EUCAST and 36% for the manufacturer's instructions). Peak concentration values indicated in dialyzed patients were below the prescribed range of 20-50 mg/l and averaged 17.7 mg / l. In the other subgroups they were correct. The rating of the absolute values of the peak concentrations of vancomycin also showed that only 46% (64% in the ktx, 30% - hd and 53% - nef) was within the recommended range, while 50% were classified as concentrations of sub-therapeutic (36% in the ktx, 42% of the nef group and 65% in hd). Vancomycin concentrations measured in patients with chronic kidney disease, both minimum and maximum, were not fully comply with the recommended therapeutic ranges, despite the use of doses determined based on a calculation of glomerular filtration rate. This points to the need for particularly careful monitoring of therapy and analysis of antibiotic concentrations to improve the effectiveness and reduce the incidence of undesirable consequences of treatment.

Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting.

PubMed

Hsu, Ching-Yun; Yang, Shih-Chun; Sung, Calvin T; Weng, Yi-Han; Fang, Jia-You

2017-01-01

Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5-125 μg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions.

The direct anti-MRSA effect of emodin via damaging cell membrane.

PubMed

Liu, Ming; Peng, Wei; Qin, Rongxin; Yan, Zifei; Cen, Yanyan; Zheng, Xinchuan; Pan, Xichun; Jiang, Weiwei; Li, Bin; Li, Xiaoli; Zhou, Hong

2015-09-01

Methicillin-resistant Staphylococcus aureus (MRSA) has become an important bacterium for nosocomial infection. Only a few antibiotics can be effective against MRSA. Therefore, searching for new drugs against MRSA is important. Herein, anti-MRSA activities of emodin and its mechanisms were investigated. Firstly, in vitro antimicrobial activity was investigated by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-growth curve, and multipassage resistance testing was performed. Secondly, protection of emodin on mice survival and blood bacterial load in mice challenged with lethal or sublethal dose of MRSA were investigated. Subsequently, the influences of emodin on the bacterial morphology, messenger RNA (mRNA) expressions related to cell wall synthesis and lysis, β-lactamase activity, drug accumulation, membrane fluidity, and integrity were performed to investigate its mechanisms. Lastly, in vitro cytotoxicity assay were performed using the 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) method. The results showed MICs and MBCs of emodin against MRSA252 and 36 clinical MRSA strains were among 2-8 and 4-32 μg/mL, respectively. There was no MIC increase for emodin during 20 passages. In vivo, emodin dose-dependently protected mice challenged with lethal dose of MRSA and decreased bacterial load in mice challenged with sublethal dose of MRSA. Morphology observation showed emodin might disrupt cell wall and membrane of MRSA. Although emodin had no influence on genes related to cell wall synthesis and lysis as well as β-lactamase activity and drug accumulation, emodin reduced membrane fluidity and disrupted membrane integrity. Based on the fact that emodin had no significant cytotoxicity against mammalian cells, it could be further investigated as a membrane-damage bactericide against MRSA in the future.

Minimum Detectable Dose as a Measure of Bioassay Programme Capability

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

Carbaugh, Eugene H.

2003-01-01

This paper suggests that minimum detectable dose (MDD) be used to describe the capability of bioassay programs for which intakes are expected to be rare. This allows expression of the capability in units that correspond directly to primary dose limits. The concept uses the well-established analytical statistic minimum detectable amount (MDA) as the starting point and assumes MDA detection at a prescribed time post intake. The resulting dose can then be used as an indication of the adequacy or capability of the program for demonstrating compliance with the performance criteria. MDDs can be readily tabulated or plotted to demonstrate themore » effectiveness of different types of monitoring programs. The inclusion of cost factors for bioassay measurements can allow optimisation.« less

Minimum detectable dose as a measure of bioassay programme capability.

PubMed

Carbaugh, E H

2003-01-01

This paper suggests that minimum detectable dose (MDD) be used to describe the capability of bioassay programmes for which intakes are expected to be rare. This allows expression of the capability in units that correspond directly to primary dose limits. The concept uses the well established analytical statistic minimum detectable amount (MDA) as the starting point, and assumes MDA detection at a prescribed time post-intake. The resulting dose can then be used as an indication of the adequacy or capability of the programme for demonstrating compliance with the performance criteria. MDDs can be readily tabulated or plotted to demonstrate the effectiveness of different types of monitoring programmes. The inclusion of cost factors for bioassay measurements can allow optimisation.

[Efficacy of sodium hydroxide at 2.5 %, chlorhexidine gluconate at 0.5 % and calcium hydroxide against Candida albicans].

PubMed

Ndiaye, D; Diongue, K; Bane, K; Seck, A; Niang, S O; Lèye Benoist, F; Ndiaye, D; Touré, B

2016-12-01

Endodontic flora is dominated in the apical part of the channels by strict anaerobic and some facultative anaerobic bacteria but also by Candida yeasts, especially Candida albicans species that are involved in the maintenance and persistence of endodontic infections. Their elimination of the canal system in practice by chemo-mechanical methods of disinfection is not always guaranteed. Thus, this in vitro study was performed to determine the sensitivity of C. albicans with sodium hypochlorite (NaOCl) dosed at 2.5 %, the chlorhexidine digluconate 0.5 % and calcium hydroxide used in inter-session medication. The diffusion method was used initially to test the sensitivity of C. albicans strains with the above products. Then a dilution technique has allowed us to determine the minimum inhibitory concentration of these active products on C. albicans. Strains from infected pulp teeth of patients showed a sensitivity of C. albicans to sodium hypochlorite to a minimum inhibitory concentration less than 70μg/mL and 30μg/mL for chlorhexidine. This study demonstrated a sensitivity of C. albicans to sodium hypochlorite and chlorhexidine. Copyright © 2016. Published by Elsevier Masson SAS.

Survey of Occupational Noise Exposure in CF Personnel in Selected High-Risk Trades

DTIC Science & Technology

2003-11-01

peak, maximum level , minimum level , average sound level , time weighted average, dose, projected 8-hour dose, and upper limit time were measured for...10 4.4.2 Maximum Sound Level ...11 4.4.3 Minimum Sound Level

Balancing vancomycin efficacy and nephrotoxicity: should we be aiming for trough or AUC/MIC?

PubMed

Patel, Karisma; Crumby, Ashley S; Maples, Holly D

2015-04-01

Sixty years later, the question that still remains is how to appropriately utilize vancomycin in the pediatric population. The Infectious Diseases Society of America published guidelines in 2011 that provide guidance for dosing and monitoring of vancomycin in adults and pediatrics. However, goal vancomycin trough concentrations of 15-20 μg/mL for invasive infections caused by methicillin-resistant Staphylococcus aureus were based primarily on adult pharmacokinetic and pharmacodynamic data that achieved an area under the curve to minimum inhibitory concentration ratio (AUC/MIC) of ≥400. Recent pediatric literature shows that vancomycin trough concentrations needed to achieve the target AUC/MIC are different than the adult goal troughs cited in the guidelines. This paper addresses several thoughts, including the role of vancomycin AUC/MIC in dosing strategies and safety monitoring, consistency in laboratory reporting, and future directions for calculating AUC/MIC in pediatrics.

Combating resistance: application of the emerging science of pharmacokinetics and pharmacodynamics.

PubMed

Jacobs, Michael R

2007-12-01

During the last 10-15 years understanding of relationships between pharmacokinetic (PK) and pharmacodynamic (PD) parameters and bacteriological and clinical outcomes has expanded allowing correlation between in vitro potency and in vivo efficacy. PK and PD principles can be applied to development of new antibacterials and formulation of existing agents to help address the increasing prevalence of antibacterial resistance. For beta-lactams, such as penicillins, the unbound serum concentration of the drug exceeding the minimum inhibitory concentration of the causative pathogen for 40-50% of the dosing interval is predictive of bacteriologic efficacy (bacterial eradication) and can be used to determine a PK/PD breakpoint for that specific dosing regimen. Amoxicillin/clavulanate was one of the earliest antibacterials to use the unique approach of PK/PD principles to develop new and enhanced formulations, allowing it to remain a significant antibacterial agent in the management of respiratory tract infections.

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

McCulloch, M; Cazoulat, G; Polan, D

Purpose: It is well documented that the delivered dose to patients undergoing radiotherapy (RT) is often different from the planned dose due to geometric variability and uncertainties in patient positioning. Recent work suggests that accumulated dose to the GTV is a better predictor of progression compared to the minimum planned dose to the PTV. The purpose of this study is to evaluate if deviations from the planned dose can contributed to tumor progression. Methods: From 2010 to 2014 an in-house Phase II clinical trial of adaptive stereotactic body RT was completed. Of the 90 patients enrolled, 7 patients had amore » local recurrence defined on contrast enhanced CT or MR imaging 3–21 months after completion of RT. Retrospective dose accumulation was performed using a biomechanical model-based deformable image registration algorithm (DIR) to accumulate the dose based on the kV CBCT acquired prior to each fraction for soft tissue alignment of the patient. The DIR algorithm was previously validated for geometric accuracy in the liver (target registration error = 2.0 mm) and dose accumulation in a homogeneous image, similar to a liver CBCT (gamma index = 91%). Following dose accumulation, the minimum dose to 0.5 cc of the GTV was compared between the planned and accumulated dose. Work is ongoing to evaluate the tumor control probability based on the planned and accumulated dose. Results: DIR and dose accumulation was performed on all fractions for 6 patients with local recurrence. The difference in minimum dose to 0.5 cc of the GTV ranged from −0.3–2.3 Gy over 3–5 fractions. One patient had a potentially significant difference in minimum dose of 2.3 Gy. Conclusion: Dose accumulation can reveal tumor underdosage, improving our ability to understand recurrence and tumor progression patterns, and could aid in adaptive re-planning during therapy to correct for this. This work was supported in part by NIH P01CA059827.« less

Effect of antibiotics on clinical, pathologic and immunologic responses in murine Potomac horse fever: protective effects of doxycycline.

PubMed

Rikihisa, Y; Jiang, B M

1989-03-01

Effects of three antibiotics on clinical, pathologic and immunologic responses in murine Potomac horse fever caused by Ehrlichia risticii infection were examined. When antibiotics were given after the development of clinical signs, antibiotics ranked in the order of reducing clinical signs and in preventing body weight loss and an intestinal enlargement were doxycycline, demeclocycline and rifampin. Infected mice treated with doxycycline and demeclocycline developed greater splenomegaly than rifampin-treated or untreated infected mice. All antibiotics used prevented thymic atrophy due to E. risticii infection. Indirect fluorescent antibody titers were highest with doxycycline treatment. Mice treated with demeclocycline and rifampin produced higher antibody titer than those without treatment. Ehrlichia risticii was reisolated from the spleens of both untreated and rifampin-treated infected mice. The effects of administering single doses of doxycycline at different times after infection were examined. Body weight loss was prevented by the drug given at every treatment day examined, i.e. Days 3, 5 and 7 post-infection (PI). Thymic atrophy was minimum in mice treated at Day 5 PI, while splenomegaly was found on every treatment day. Splenocyte proliferative response to concanavalin A and lipopolysaccharide, and specific antibody development against E. risticii was best in mice treated at Day 5 PI followed by those treated at Day 3 and Day 7 PI.

Appropriate antibiotic therapy improves Ureaplasma sepsis outcome in the neonatal mouse.

PubMed

Weisman, Leonard E; Leeming, Angela H; Kong, Lingkun

2012-11-01

Ureaplasma causes sepsis in human neonates. Although erythromycin has been the standard treatment, it is not always effective. No published reports have evaluated Ureaplasma sepsis in a neonatal model. We hypothesized that appropriate antibiotic treatment improves Ureaplasma sepsis in a neonatal mouse model. Two ATCC strains and two clinical strains of Ureaplasma were evaluated in vitro for antibiotic minimum inhibitory concentration (MIC). In addition, FVB albino mice pups infected with Ureaplasma were randomly assigned to saline, erythromycin, or azithromycin therapy and survival, quantitative blood culture, and growth were evaluated. MICs ranged from 0.125 to 62.5 µg/ml and 0.25 to 1.0 µg/ml for erythromycin and azithromycin, respectively. The infecting strain and antibiotic selected for treatment appeared to affect survival and bacteremia, but only the infecting strain affected growth. Azithromycin improved survival and bacteremia against each strain, whereas erythromycin was effective against only one of four strains. We have established a neonatal model of Ureaplasma sepsis and observed that treatment outcome is related to infecting strain and antibiotic treatment. We speculate that appropriate antibiotic selection and dosing are required for effective treatment of Ureaplasma sepsis in neonates, and this model could be used to further evaluate these relationships.

Antibacterial activity of Litsea cubeba (Lauraceae, May Chang) and its effects on the biological response of common carp Cyprinus carpio challenged with Aeromonas hydrophila.

PubMed

Nguyen, H V; Caruso, D; Lebrun, M; Nguyen, N T; Trinh, T T; Meile, J-C; Chu-Ky, S; Sarter, S

2016-08-01

The aims of this study were to characterize the antibacterial activity and the chemotype of Litsea cubeba leaf essential oil (EO) harvested in North Vietnam and to investigate the biological effects induced by the leaf powder on growth, nonspecific immunity and survival of common carp (Cyprinus carpio) challenged with Aeromonas hydrophila. The EO showed the prevalence of linalool (95%, n = 5). It was bactericidal against the majority of tested strains, with minimum inhibitory concentrations ranging from 0·72 to 2·89 mg ml(-1) (Aer. hydrophila, Edwarsiella tarda, Vibrio furnissii, Vibrio parahaemolyticus, Streptococcus garvieae, Escherichia coli, Salmonella Typhimurium). The fish was fed with 0 (control), 2, 4 and 8% leaf powder supplementation diets for 21 days. Nonspecific immunity parameters (lysozyme, haemolytic and bactericidal activities of plasma) were assessed 21 days after feeding period and before the experimental infection. Weight gain, specific growth rate and feed conversion ratio were improved by supplementation of L. cubeba in a dose-related manner, and a significant difference appeared at the highest dose (8%) when compared to the control. The increase in plasma lysozyme was significant for all the treated groups. Haemolysis activity was higher for the groups fed with 4 and 8% plant powder. Antibacterial activity increased significantly for the 8% dose only. Litsea cubeba leaf powder increased nonspecific immunity of carps in dose-related manner. After infection with Aer. hydrophila, survivals of fish fed with 4 and 8% L. cubeba doses were significantly higher than those fed with 2% dose and the control. A range of 4-8% L. cubeba leaf powder supplementation diet (from specific linalool-rich chemotype) can be used in aquaculture to reduce antibiotic burden and impacts of diseases caused by Aer. hydrophila. © 2016 The Society for Applied Microbiology.

Aloe-emodin inhibits Staphylococcus aureus biofilms and extracellular protein production at the initial adhesion stage of biofilm development.

PubMed

Xiang, Hua; Cao, Fengjiao; Ming, Di; Zheng, Yanyang; Dong, Xiaoyun; Zhong, Xiaobo; Mu, Dan; Li, Bangbang; Zhong, Ling; Cao, Junjie; Wang, Lin; Ma, Hongxia; Wang, Tiedong; Wang, Dacheng

2017-09-01

Staphylococcus aureus (S. aureus) biofilms are clinically serious and play a critical role in the persistence of chronic infections due to their ability to resist antibiotics. The inhibition of biofilm formation is viewed as a new strategy for the prevention of S. aureus infections. Here, we demonstrated that minimum inhibitory concentrations (MICs) of aloe-emodin exhibited no bactericidal activity against S. aureus but affected S. aureus biofilm development in a dose-dependent manner. Further studies indicated that aloe-emodin specifically inhibits the initial adhesion and proliferation stages of S. aureus biofilm development. Scanning electron microscopy (SEM) indicated that the S. aureus ATCC29213 biofilm extracellular matrix is mainly composed of protein. Laser scanning confocal microscope assays revealed that aloe-emodin treatment primarily inhibited extracellular protein production. Moreover, the Congo red assay showed that aloe-emodin also reduced the accumulation of polysaccharide intercellular adhesin (PIA) on the cell surface. These findings will provide new insights into the mode of action of aloe-emodin in the treatment of infections by S. aureus biofilms.

Effects of Mentha suaveolens Essential Oil on Chlamydia trachomatis

PubMed Central

Sessa, Rosa; Di Pietro, Marisa; De Santis, Fiorenzo; Filardo, Simone; Ragno, Rino; Angiolella, Letizia

2015-01-01

Chlamydia trachomatis, the most common cause of sexually transmitted bacterial infection worldwide, has a unique biphasic developmental cycle alternating between the infectious elementary body and the replicative reticulate body. C. trachomatis is responsible for severe reproductive complications including pelvic inflammatory disease, ectopic pregnancy, and obstructive infertility. The aim of our study was to evaluate whether Mentha suaveolens essential oil (EOMS) can be considered as a promising candidate for preventing C. trachomatis infection. Specifically, we investigated the in vitro effects of EOMS towards C. trachomatis analysing the different phases of chlamydial developmental cycle. Our results demonstrated that EOMS was effective towards C. trachomatis, whereby it not only inactivated infectious elementary bodies but also inhibited chlamydial replication. Our study also revealed the effectiveness of EOMS, in combination with erythromycin, towards C. trachomatis with a substantial reduction in the minimum effect dose of antibiotic. In conclusion, EOMS treatment may represent a preventative strategy since it may reduce C. trachomatis transmission in the population and, thereby, reduce the number of new chlamydial infections and risk of developing of severe sequelae. PMID:25685793

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

PubMed Central

Büdingen, Fiona V.; Gonzalez, Daniel; Tucker, Amelia N.

2014-01-01

The liver is a complex organ with great ability to influence drug pharmacokinetics (PK). Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, the effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what effects these changes will have on a particular drug. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling PK/pharmacodynamic targets, such as maximum concentration/minimum inhibitory concentration (Cmax/MIC), area under the curve/minimum inhibitory concentration (AUC/MIC), time above MIC (T>MIC), half-maximal inhibitory concentration (IC50) or half-maximal effective concentration (EC50), or the time above the concentration which inhibits viral replication by 95% (T>EC95). Loss of efficacy and/or an increased risk of toxicity may occur in certain circumstances of liver injury. Although it is important to consider these potential alterations and their effects on specific anti-infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy. PMID:24949199

Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting

PubMed Central

Sung, Calvin T; Weng, Yi-Han; Fang, Jia-You

2017-01-01

Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5–125 μg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions. PMID:29184410

77 FR 40320 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-09

... irradiation treatment of imported fruits and vegetables including a minimum generic dose for the fruit fly family, the minimum dose of irradiation for some specific fruit fly species, and provides for the use of irradiation as a treatment for cut flowers and foliage. Need and Use of the Information: Certain fruits and...

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice

PubMed Central

Jackson, B S; Mokoena, T

2017-01-01

Background People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. Methods A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. Results 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups—HIV-uninfected and HIV-infected patients not on ARVs. Conclusions There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. PMID:28179414

AUC-Guided Vancomycin Dosing in Adolescent Patients With Suspected Sepsis.

PubMed

Lanke, Shankar; Yu, Tian; Rower, Joseph E; Balch, Alfred H; Korgenski, E Kent; Sherwin, Catherine M

2017-01-01

Vancomycin is a first-line treatment for β-lactam-resistant Gram-positive bacterial infections. Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of vancomycin in an adolescent population is of clinical importance in this often overlooked pediatric population. This retrospective study investigated vancomycin PK-PD in an adolescent cohort (12 to 18 years of age) of 463 patients (57% male, 81% white) admitted to the Intermountain Healthcare System between January 2006 and December 2013. Population PK modeling was performed in NONMEM 7.3. Vancomycin PK was well described with a 1-compartment model that identified both body weight (WT) and creatinine clearance (CRCL) as covariates significantly impacting vancomycin disposition. The model was then utilized to determine dosing strategies that achieved the targeted area under the 24-hour time curve vs minimum inhibitory concentration (AUC 0-24 /MIC) ratio of ≥400. Additionally, these data were correlated with minimum steady-state concentrations (C ss,min ) to find an acceptable target trough concentration range in adolescents. This analysis demonstrated that C ss,min ranging from 10 to 12.5 mg/L were highly predictive of achieving an AUC 0-24 /MIC ≥400 when the MIC was ≤1 mg/L. These results suggest that the target trough concentration for adolescents may be lower than that for adults. © 2016, The American College of Clinical Pharmacology.

Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

PubMed

Xu, Lijuan; Wang, Hao; Yang, Xianle; Lu, Liqun

2013-06-25

Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.

Pharmacokinetics of imipenem after intravenous, intramuscular and subcutaneous administration to cats.

PubMed

Albarellos, Gabriela A; Denamiel, Graciela A; Montoya, Laura; Quaine, Pamela C; Lupi, Martín P; Landoni, María F

2013-06-01

The study describes the pharmacokinetics and predicted efficacy of imipenem after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration to five adult cats at a dose of 5 mg/kg. Susceptibility to imipenem [minimum inhibitory concentration (MIC)] was determined for antimicrobial resistant Escherichia coli (n = 13) and staphylococci (n = 3) isolated from domestic cat infections (urinary system, skin and conjunctiva). Maximum plasma concentrations of imipenem were 13.45 µg/ml (IV), 6.47 µg/ml (IM) and 3.83 µg/ml (SC). Bioavailability was 93.18% (IM) and 107.90% (SC). Elimination half-lives for IV, IM and SC administration were 1.17, 1.44 and 1.55 h, respectively. All tested bacteria were susceptible to imipenem; MIC values were 0.03 µg/ml for Staphylococcus species and <0.25-0.5 µg/ml for E coli. Mean imipenem concentrations remained above a MIC of 0.5 µg/ml for approximately 4 h (IV and IM) and 9 h (SC). Imipenem would be predicted to be effective for the treatment of antimicrobial resistant bacterial infections in cats at a dosage of 5 mg/kg every 6-8 h (IV, IM), or longer for the SC route. However, clinical trials are mandatory to establish its efficacy and proper dosing.

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

PubMed Central

Youn, Gilmer; Jones, Brenda; Jelliffe, Roger W.; Drusano, George L.; Rodvold, Keith A.; Lodise, Thomas P.

2014-01-01

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter. PMID:24165176

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2012 CFR

2012-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2014 CFR

2014-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2013 CFR

2013-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

Efficacy of Ethanol against Candida albicans and Staphylococcus aureus Polymicrobial Biofilms

PubMed Central

Peters, Brian M.; Ward, Raven M.; Rane, Hallie S.; Lee, Samuel A.

2013-01-01

Candida albicans, an opportunistic fungus, and Staphylococcus aureus, a bacterial pathogen, are two clinically relevant biofilm-forming microbes responsible for a majority of catheter-related infections, with such infections often resulting in catheter loss and removal. Not only do these pathogens cause a substantial number of nosocomial infections independently, but also they are frequently found coexisting as polymicrobial biofilms on host and environmental surfaces. Antimicrobial lock therapy is a current strategy to sterilize infected catheters. However, the robustness of this technique against polymicrobial biofilms has remained largely untested. Due to its antimicrobial activity, safety, stability, and affordability, we tested the hypothesis that ethanol (EtOH) could serve as a potentially efficacious catheter lock solution against C. albicans and S. aureus biofilms. Therefore, we optimized the dose and time necessary to achieve killing of both monomicrobial and polymicrobial biofilms formed on polystyrene and silicone surfaces in a static microplate lock therapy model. Treatment with 30% EtOH for a minimum of 4 h was inhibitory for monomicrobial and polymicrobial biofilms, as evidenced by XTT {sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide inner salt} metabolic activity assays and confocal microscopy. Experiments to determine the regrowth of microorganisms on silicone after EtOH treatment were also performed. Importantly, incubation with 30% EtOH for 4 h was sufficient to kill and inhibit the growth of C. albicans, while 50% EtOH was needed to completely inhibit the regrowth of S. aureus. In summary, we have systematically defined the dose and duration of EtOH treatment that are effective against and prevent regrowth of C. albicans and S. aureus monomicrobial and polymicrobial biofilms in an in vitro lock therapy model. PMID:23070170

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice.

PubMed

Jackson, B S; Mokoena, T

2017-02-08

People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups-HIV-uninfected and HIV-infected patients not on ARVs. There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

A systematic study of posterior cervical lymph node irradiation with electrons: Conventional versus customized planning.

PubMed

Jankowska, Petra J; Kong, Christine; Burke, Kevin; Harrington, Kevin J; Nutting, Christopher

2007-10-01

High dose irradiation of the posterior cervical lymph nodes usually employs applied electron fields to treat the target volume and maintain the spinal cord dose within tolerance. In the light of recent advances in elective lymph node localisation we investigated optimization of field shape and electron energy to treat this target volume. In this study, three sequential hypotheses were tested. Firstly, that customization of the electron fields based on the nodal PTV outlined gives better PTV coverage than conventional field delineation. Using the consensus guidelines, customization of the electron field shape was compared to conventional fields based on bony landmarks. Secondly, that selection of electron energy using DVHs for spinal cord and PTV improves the minimum dose to PTV. Electron dose-volume histograms (DVHs) for the PTV, spinal cord and para-vertebral muscles, were generated using the Monte Carlo electron algorithm. These DVHs were used to compare standard vs optimized electron energy calculations. Finally, that combination of field customization and electron energy optimization improves both the minimum and mean doses to PTV compared with current standard practice. Customized electron beam shaping based on the consensus guidelines led to fewer geographical misses than standard field shaping. Customized electron energy calculation led to higher minimum doses to the PTV. Overall, the customization of field shape and energy resulted in an improved mean dose to the PTV (92% vs 83% p=0.02) and a 27% improvement in the minimum dose delivered to the PTV (45% vs 18% p=0.0009). Optimization of electron field shape and beam energy based on current consensus guidelines led to significant improvement in PTV coverage and may reduce recurrence rates.

Suppression of ciprofloxacin-induced resistant Pseudomonas aeruginosa in a dynamic kill curve system.

PubMed

Wu, Benjamin M; Sabarinath, Sreedharan N; Rand, Kenneth; Johnson, Judith; Derendorf, Hartmut

2011-06-01

Current dosing approaches for treating microbial infections ignore resistant subpopulations. A clinical isolate of Pseudomonas aeruginosa was cultured in a dynamic in vitro kill curve system designed to simulate the half-lives of drugs in order to evaluate the drug-microbial response relationship. The first dose of ciprofloxacin (CIP) uses a concentration equivalent to the unbound fraction of a 200mg clinical dose. A second dose of 200mg or 600 mg CIP, or ceftriaxone (CFX) or gentamicin (GEN) was administered at 12h. Dynamics of the minimum inhibitory concentration (MIC) were assessed using Etest strips before and throughout the CIP treatment period. In addition, the microbroth dilution method was used to evaluate drug susceptibility across a wide range of antibiotics using samples from before and after CIP exposure. A significant loss of CIP effects was observed at the second dose. Cross-resistance to many antibiotics (cefoxitin, cefuroxime, cefotetan, ampicillin and ertapenem) was observed. GEN, but not CFX or high-dose CIP, was sufficient to suppress the developed resistant subpopulation following the initial CIP exposure. The CIP MIC increased substantially from 0.13 μg/mL pre dose to 4 μg/mL at 12h after a CIP dose. In addition, aztreonam induced a similar resistance pattern as CIP, indicating that induction of resistance was not limited to fluoroquinolones. In conclusion, the in vitro dynamic kill curve system revealed that aminoglycosides, more than other classes of antibiotics, were effective against the CIP-induced resistant subpopulations. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Protein Binding of Lopinavir and Ritonavir During Four Phases of Pregnancy: Implications for Treatment Guidelines

PubMed Central

Patterson, Kristine B.; Dumond, Julie B.; Prince, Heather A.; Jenkins, Amanda J.; Scarsi, Kimberly K.; Wang, Ruili; Malone, Stephanie; Hudgens, Michael G.; Kashuba, Angela DM.

2013-01-01

Objective To investigate the intraindividual pharmacokinetics of total (protein bound + unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100mg/25mg) can overcome any pregnancy-associated changes. Design Prospective longitudinal pharmacokinetic (PK) study Methods HIV-infected pregnant antiretroviral therapy-naïve and experienced women receiving LPV/RTV 400mg/100mg tablets twice daily. Intensive PK evaluations were performed at 20–24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100mg/25mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). Results Twelve women completed pre-specified PK evaluations. Median (range) age was 28 (1–35) years and baseline BMI was 32 (19–41) kg/m2. During pregnancy, total area under the time concentration (AUC0–12hr) for LPV was significantly lower than postpartum [PK1, PK2 or PK3 vs. PK4, p= 0.005]. Protein unbound LPV AUC0–12hr remained unchanged during pregnancy [PK1: 1.6 (1.3–1.9) vs. PK2: 1.6 (1.3–1.9) µg*hr/mL, p=0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3–2.1) µg*hr/mL, p=0.5]. Protein unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08–0.15) vs. PK3: 0.12 (0.10–0.15) µg/mL, p=0.09]. Albumin and LPV AUC0–12h fraction unbound were correlated (rs=0.3, p=0.03). Conclusions Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women. PMID:23221983

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study.

PubMed

Ehmann, Lisa; Zoller, Michael; Minichmayr, Iris K; Scharf, Christina; Maier, Barbara; Schmitt, Maximilian V; Hartung, Niklas; Huisinga, Wilhelm; Vogeser, Michael; Frey, Lorenz; Zander, Johannes; Kloft, Charlotte

2017-10-21

Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCR CG ). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T >MIC , 50%T >4×MIC ) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCR CG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Large inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T >MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T >4×MIC . A hyperbolic relationship between CLCR CG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C 8h ) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed. Clinicaltrials.gov, NCT01793012 . Registered on 24 January 2013.

Analysis of minimum target prices for production of entecavir to treat hepatitis B in high- and low-income countries.

PubMed

Hill, Andrew; Gotham, Dzintars; Cooke, Graham; Bhagani, Sanjay; Andrieux-Meyer, Isabelle; Cohn, Jennifer; Fortunak, Joseph

2015-04-01

In 2013, an estimated 686,000 people died from hepatitis B virus (HBV) infection worldwide. Mass treatment programmes for hepatitis B will require very low drug costs. International treatment guidelines recommend first-line monotherapy with either entecavir or tenofovir disoproxil fumarate (TDF). While the basic patent on TDF expires in 2017/8, entecavir is already generic in several countries, including the US. The chemical structure of entecavir is related to abacavir, which costs <$200 per person-year in low-income countries. The clinical efficacy, chemical structures, daily doses, routes of chemical synthesis, costs of raw materials and patent expiry dates were analysed for entecavir and TDF. Costs of sustainable, generic production were calculated for entecavir, and compared with published originator and generic prices in high- and low-income countries. With a daily dose of 0.5 mg, one year's supply of entecavir treatment requires <0.2 g of active pharmaceutical ingredient (API) per person, estimated to cost $4/year, based on quotations of API production from generic suppliers. With an additional $20 per year for formulation/packaging and a 50% profit margin, entecavir was estimated to cost a minimum of $36/person-year, substantially lower than current originator and generic prices. Entecavir is no longer under patent protection in the USA, China, Brazil and South Africa, with European expiry in 2017. Given differences in daily dosing, production volumes for entecavir would be 600 times lower than TDF (300 mg once daily) for treating the same numbers of patients. Mass treatment for hepatitis B with generic entecavir could be achieved at very low cost in all countries, provided that important projections can be met in terms of pricing for the API and finished dosage form.

Population PK Modeling and Target Attainment Simulations to Support Dosing of Ceftaroline Fosamil in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia.

PubMed

Riccobene, Todd A; Khariton, Tatiana; Knebel, William; Das, Shampa; Li, James; Jandourek, Alena; Carrothers, Timothy J; Bradley, John S

2017-03-01

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented. © 2016, The American College of Clinical Pharmacology.

Reconstruction of Absorbed Doses to Fibroglandular Tissue of the Breast of Women undergoing Mammography (1960 to the Present)

PubMed Central

Thierry-Chef, Isabelle; Simon, Steven L.; Weinstock, Robert M.; Kwon, Deukwoo; Linet, Martha S.

2013-01-01

The assessment of potential benefits versus harms from mammographic examinations as described in the controversial breast cancer screening recommendations of the U.S. Preventive Task Force included limited consideration of absorbed dose to the fibroglandular tissue of the breast (glandular tissue dose), the tissue at risk for breast cancer. Epidemiological studies on cancer risks associated with diagnostic radiological examinations often lack accurate information on glandular tissue dose, and there is a clear need for better estimates of these doses. Our objective was to develop a quantitative summary of glandular tissue doses from mammography by considering sources of variation over time in key parameters including imaging protocols, x-ray target materials, voltage, filtration, incident air kerma, compressed breast thickness, and breast composition. We estimated the minimum, maximum, and mean values for glandular tissue dose for populations of exposed women within 5-year periods from 1960 to the present, with the minimum to maximum range likely including 90% to 95% of the entirety of the dose range from mammography in North America and Europe. Glandular tissue dose from a single view in mammography is presently about 2 mGy, about one-sixth the dose in the 1960s. The ratio of our estimates of maximum to minimum glandular tissue doses for average-size breasts was about 100 in the 1960s compared to a ratio of about 5 in recent years. Findings from our analysis provide quantitative information on glandular tissue doses from mammographic examinations which can be used in epidemiologic studies of breast cancer. PMID:21988547

AUC versus peak-trough dosing of vancomycin: applying new pharmacokinetic paradigms to an old drug.

PubMed

Brown, Daniel L; Lalla, Christina D; Masselink, Andrew J

2013-08-01

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

Role of Berberine in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections

NASA Astrophysics Data System (ADS)

Chu, Ming; Zhang, Ming-Bo; Liu, Yan-Chen; Kang, Jia-Rui; Chu, Zheng-Yun; Yin, Kai-Lin; Ding, Ling-Yu; Ding, Ran; Xiao, Rong-Xin; Yin, Yi-Nan; Liu, Xiao-Yan; Wang, Yue-Dan

2016-04-01

Berberine is an isoquinoline alkaloid widely used in the treatment of microbial infections. Recent studies have shown that berberine can enhance the inhibitory efficacy of antibiotics against clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA). However, the underlying mechanisms are poorly understood. Here, we demonstrated that sub-minimum inhibitory concentrations (MICs) of berberine exhibited no bactericidal activity against MRSA, but affected MRSA biofilm development in a dose dependent manner within the concentration ranging from 1 to 64 μg/mL. Further study indicated that berberine inhibited MRSA amyloid fibrils formation, which consist of phenol-soluble modulins (PSMs). Molecular dynamics simulation revealed that berberine could bind with the phenyl ring of Phe19 in PSMα2 through hydrophobic interaction. Collectively, berberine can inhibit MRSA biofilm formation via affecting PSMs’ aggregation into amyloid fibrils, and thereby enhance bactericidal activity of antibiotics. These findings will provide new insights into the multiple pharmacological properties of berberine in the treatment of microbial-generated amyloid involved diseases.

Testing the mutant selection window hypothesis with Escherichia coli exposed to levofloxacin in a rabbit tissue cage infection model.

PubMed

Ni, W; Song, X; Cui, J

2014-03-01

The purpose of this study was to test the mutant selection window (MSW) hypothesis with Escherichia coli exposed to levofloxacin in a rabbit model and to compare in vivo and in vitro exposure thresholds that restrict the selection of fluoroquinolone-resistant mutants. Local infection with E. coli was established in rabbits, and the infected animals were treated orally with various doses of levofloxacin once a day for five consecutive days. Changes in levofloxacin concentration and levofloxacin susceptibility were monitored at the site of infection. The MICs of E. coli increased when levofloxacin concentrations at the site of infection fluctuated between the lower and upper boundaries of the MSW, defined in vitro as the minimum inhibitory concentration (MIC99) and the mutant prevention concentration (MPC), respectively. The pharmacodynamic thresholds at which resistant mutants are not selected in vivo was estimated as AUC24/MPC > 20 h or AUC24/MIC > 60 h, where AUC24 is the area under the drug concentration time curve in a 24-h interval. Our finding demonstrated that the MSW existed in vivo. The AUC24/MPC ratio that prevented resistant mutants from being selected estimated in vivo is consistent with that observed in vitro, indicating it might be a reliable index for guiding the optimization of antimicrobial treatment regimens for suppression of the selection of antimicrobial resistance.

Population Pharmacokinetics of Combined Intravenous and Local Intrathecal Administration of Meropenem in Aneurysm Patients with Suspected Intracranial Infections After Craniotomy.

PubMed

Li, Xingang; Sun, Shusen; Wang, Qiang; Zhao, Zhigang

2018-02-01

For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method. After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens. A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CL CSF ) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CL CSF , and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume. This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing.

[Therapeutic efficacy of levofloxacin against a model of replicable Legionella pneumophila lung infection in DBA/2 mice].

PubMed

Kashimoto, Yoshinori; Kurosaka, Yuichi; Karibe, Yukie; Uoyama, Saori; Fujikawa, Katsuko; Namba, Kenji; Otani, Tsuyoshi; Yamaguchi, Keizo

2009-10-01

The in vitro and in vivo antibacterial activities of levofloxacin (LVFX), a quinolone antibacterial, against clinically isolated Legionella pneumophila were investigated in comparison with those of existing antimicrobial agents approved for legionnaires disease. The minimum inhibitory concentrations (MICs) of the agents against 42 strains of L. pneumophila isolated in Japan were determined using agar dilution methods with buffered starch yeast extract agar. MIC90 of LVFX was 0.03 microg/ml and this activity was similar to ciprofloxacin and pazufloxacin, and higher than telithromycin and minocycline. Therapeutic efficacy of LVFX was studied against a pneumonia model induced by intranasal of L. pneumophila strain suzuki serogoup 1 in DBA/2 mice. Therapeutic doses in mice were selected that would closely match human exposure profile, area under the concentration-time curve (AUC) for a human oral dose of LVFX at 500 mg once a day. LVFX decreased significantly the bacterial burden in the lungs from the next day of commencing treatment. These results, including in vitro antibacterial activity against clinical isolates and therapeutic efficacy of a humanized dosing regimen, provide good evidence to support the use of LVFX at 500 mg once a day for treating patient with legionnaires disease.

Randomized trial of 3-dose regimens of tafenoquine (WR238605) versus low-dose primaquine for preventing Plasmodium vivax malaria relapse.

PubMed

Walsh, Douglas S; Wilairatana, Polrat; Tang, Douglas B; Heppner, D Gray; Brewer, Thomas G; Krudsood, Srivicha; Silachamroon, Udomsak; Phumratanaprapin, Weerapong; Siriyanonda, Duangsuda; Looareesuwan, Sornchai

2004-10-15

Tafenoquine is an 8-aminoquinoline developed as a more effective replacement for primaquine. In a previous dose-ranging study in Thailand, 3 tafenoquine regimens with total doses ranging from 500 mg to 3000 mg prevented relapse of Plasmodium vivax malaria in most patients when administered 2 days after receipt of a blood schizonticidal dose of chloroquine. To improve convenience and to begin comparison of tafenoquine with primaquine, 80 patients with P. vivax infection were randomized to receive 1 of the following 5 treatments 1 day after receiving a blood schizonticidal dose of chloroquine: (A) tafenoquine, 300 mg per day for 7 days (n=18); (B) tafenoquine, 600 mg per day for 3 days (n=19); (C) tafenoquine, 600 mg as a single dose (n=18); (D) no further treatment (n=13); or (E) primaquine base, 15 mg per day for 14 days (n=12). The minimum duration of protocol follow-up was 8 weeks, with additional follow-up to 24 weeks. Forty-six of 55 tafenoquine recipients, 10 of 13 recipients of chloroquine only, and 12 of 12 recipients of chloroquine plus primaquine completed at least 8 weeks of follow-up (or had relapse). There was 1 relapse among recipients of chloroquine plus tafenoquine, 8 among recipients of chloroquine only, and 3 among recipients of chloroquine plus primaquine. The rate of protective efficacy (determined on the basis of reduction in incidence density) for all recipients of chloroquine plus tafenoquine, compared with recipients of chloroquine plus primaquine, was 92.6% (95% confidence interval, 7.3%-99.9%; P=.042, by Fisher's exact test). Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand.

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV‐1 infected patients

PubMed Central

Moltó, José; Estévez, Javier A.; Miranda, Cristina; Cedeño, Samandhy; Clotet, Bonaventura

2016-01-01

Aims The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV‐1‐infected patients. Methods A Cross‐sectional study was carried out in 83 HIV‐1‐infected adults taking ATV 400 mg or ATV 300 mg/RTV 100 mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed‐effects modelling and used to simulate six dosing scenarios. Results The selected one‐compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg l–1 predicted an 18% decrease in ATV clearance. The percentages of patients with an end‐of‐dose‐interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg l–1 and 0.85 mg l–1 favoured the selection of the simulated ATV/RTV once‐daily regimens (ATV 400 mg, ATV 300 mg/RTV 100 mg, ATV 300 mg/RTV 50 mg, ATV 200/RTV 100 mg) over the unboosted twice‐daily regimens (ATV 300 mg, ATV 200 mg). Conclusions A one‐compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once‐daily doses of ATV 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety. PMID:27447851

Booster and higher antigen doses of inactivated influenza vaccine in HIV-infected patients.

PubMed

Johnston, Jessica A; Tincher, Lindsey B; Lowe, Denise K

2013-12-01

To review the literature regarding booster or higher doses of influenza antigen for increasing immunogenicity of inactivated influenza vaccine (IIV) in HIV-infected patients. MEDLINE (1966 to September 2013) was searched using the terms immunize, influenza, vaccine, and HIV or AIDS in combination with two-dose, booster-dose, increased antigen, or high-dose. One trial of booster dosing with standard doses (SDs) of IIV, trivalent (IIV3); 2 trials of booster dosing with intermediate doses (ID) of H1N1 IIV or IIV3; and 1 trial of high-dose (HD) IIV3 were identified. Trials administering 2-dose, booster-dose, or increased antigen of influenza vaccine to patients with HIV were reviewed. Because adjuvanted IIV is not available and IIV, quadrivalent was recently approved in the United States, studies evaluating these vaccines were excluded. HIV-infected individuals are at high risk for influenza-related complications; however, vaccination with SD IIV may not confer optimal protection. It has been postulated that booster or higher doses of influenza antigen may lead to increased immunogenicity. When ID and SD or ID with boosters were evaluated in HIV-infected patients, significant increases in surrogate markers for influenza protection were not achieved. However, HD IIV3 did result in significant increases in seroprotective antibody levels, though 'clinical' influenza was not evaluated. Currently, evidence is insufficient to reach conclusions about the efficacy of booster dosing, ID, or HD influenza vaccine in HIV-infected patients. Trials evaluating booster or higher-antigen doses of IIV for 'clinical' influenza are necessary before routinely recommending for HIV-infected patients.

Epidemiological characteristics of infectious hematopoietic necrosis virus (IHNV): a review.

PubMed

Dixon, Peter; Paley, Richard; Alegria-Moran, Raul; Oidtmann, Birgit

2016-06-10

Infectious hematopoietic necrosis virus (IHNV, Rhabdoviridae), is the causative agent of infectious hematopoietic necrosis (IHN), a disease notifiable to the World Organisation for Animal Health, and various countries and trading areas (including the European Union). IHNV is an economically important pathogen causing clinical disease and mortalities in a wide variety of salmonid species, including the main salmonid species produced in aquaculture, Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). We reviewed the scientific literature on IHNV on a range of topics, including geographic distribution; host range; conditions required for infection and clinical disease; minimum infectious dose; subclinical infection; shedding of virus by infected fish; transmission via eggs; diagnostic tests; pathogen load and survival of IHNV in host tissues. This information is required for a range of purposes including import risk assessments; parameterisation of disease models; for surveillance planning; and evaluation of the chances of eradication of the pathogen to name just a few. The review focuses on issues that are of relevance for the European context, but many of the data summarised have relevance to IHN globally. Examples for application of the information is presented and data gaps highlighted.

Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus

PubMed Central

van de Ven, Nikolien; Fortunak, Joe; Simmons, Bryony; Ford, Nathan; Cooke, Graham S; Khoo, Saye; Hill, Andrew

2015-01-01

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182) PMID:25482139

Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus.

PubMed

van de Ven, Nikolien; Fortunak, Joe; Simmons, Bryony; Ford, Nathan; Cooke, Graham S; Khoo, Saye; Hill, Andrew

2015-04-01

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. © 2014 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

Impact of West Nile virus dose and incubation period on vector competence of Culex nigripalpus (Diptera: Culicidae).

PubMed

Richards, Stephanie L; Anderson, Sheri L; Lord, Cynthia C; Tabachnick, Walter J

2011-11-01

Female Culex nigripalpus were fed blood containing a low dose (6.3±0.01 logs plaque-forming units (PFU)/mL) or high dose (7.3±0.1 logs PFU/mL) of West Nile virus (WNV) and maintained at 28°C for incubation periods (IPs) of 6 or 12 days. Vector competence was measured using rates of infection (% with WNV-positive bodies), dissemination (% infected with WNV-positive legs), and transmission (% infected with WNV-positive saliva). Infection rates were not influenced by dose or IP. Dissemination rates were significantly higher at the high dose, and this was dependent on IP. Despite 100% infection and 90% dissemination in the most permissive treatment of high dose and 12 days, only 11% transmission was observed. Virus titers in body and leg tissues were significantly lower at the low dose and the titers were not influenced by IP. We show that not all mosquitoes with infections and/or disseminated infections transmit WNV under the conditions of this test. Therefore, characterizing the transmission ability of a vector population using infection or dissemination as indicators of transmission may provide inaccurate information. The complex relationships between infection, dissemination, and transmission must be evaluated under a variety of biological and environmental conditions to begin to assess the epidemiological risk of natural mosquito populations.

Ultra-low-dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model: How Little Can We See?

PubMed Central

Wang, Shiying; Herbst, Elizabeth B.; Mauldin, F. William; Diakova, Galina B.; Klibanov, Alexander L.; Hossack, John A.

2016-01-01

Objectives The objective of this study is to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model. Materials and Methods The pre-burst minus post-burst method was implemented on a Verasonics ultrasound research scanner using a multi-frame compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine, DSPC-based) microbubbles that were conjugated with anti-vascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts. Different injection doses ranging from 5 × 104 to 1 × 107 microbubbles per mouse were evaluated to determine the minimum diagnostically effective dose. Results The proposed imaging sequence was able to achieve statistically significant detection (p < 0.05, n = 5) of VEGFR2 in tumors with a minimum MBVEGFR2 injection dose of only 5 × 104 microbubbles per mouse (DSPC at 0.053 ng/g mouse body mass). Non-specific adhesion of MBControl at the same injection dose was negligible. Additionally, the targeted contrast ultrasound signal of MBVEGFR2 decreased with lower microbubble doses, while non-specific adhesion of MBControl increased with higher microbubble doses. Conclusions 5 × 104 microbubbles per animal is now the lowest injection dose on record for ultrasound molecular imaging to achieve statistically significant detection of molecular targets in vivo. Findings in this study provide us with further guidance for future developments of clinically translatable ultrasound molecular imaging applications using a lower dose of microbubbles. PMID:27654582

Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role.

PubMed

Roberts, Jason A; Paratz, Jennifer; Paratz, Elizabeth; Krueger, Wolfgang A; Lipman, Jeffrey

2007-07-01

Continuous infusion of beta-lactam antibiotics has been widely promoted to optimise their time-dependent activity. Increasing evidence is emerging suggesting potential benefits in patient populations with altered pathophysiology, such as seriously ill patients. From a pharmacokinetic viewpoint, much information supports higher trough concentrations of beta-lactam antibiotics when administered by continuous infusion. This advantage of continuous infusion translates into a superior ability to achieve pharmacodynamic targets, particularly when the minimum inhibitory concentration (MIC) of the pathogen is >or=4 mg/L. One drawback of continuous infusion may be limited physicochemical stability. This issue exists particularly for carbapenem antibiotics whereby prolonged infusions (i.e. >3h) can be used to improve the time above the MIC compared with conventional bolus dosing. Few studies have examined clinical outcomes of bolus and continuous dosing of beta-lactam antibiotics in seriously ill patients. No statistically significant differences have been shown for: mortality; time to normalisation of leukocytosis or pyrexia; or duration of mechanical ventilation, intensive care unit stay or hospital stay. Some evidence suggests improved clinical cure and resolution of illness with continuous infusion in seriously ill patients. Pharmacoeconomic advantages of continuous infusion of beta-lactam antibiotics are well characterised. Available data suggest that seriously ill patients with severe infections requiring significant antibiotic courses (>or=4 days) may be the subgroup that will achieve better outcomes with continuous infusion.

Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance

PubMed Central

2013-01-01

Background Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. Results The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Conclusions Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics. PMID:23800340

External-beam Co-60 radiotherapy for canine nasal tumors: a comparison of survival by treatment protocol.

PubMed

Yoon, J H; Feeney, D A; Jessen, C R; Walter, P A

2008-02-01

A retrospective analysis of survival times in dogs with intranasal tumors was performed comparing those treated using hypofractionated or full course Co-60 radiotherapy protocols alone or with surgical adjuvant therapy and those receiving no radiation treatment. One hundred thirty-nine dogs presented to the University of Minnesota Veterinary Medical Center for treatment of histologically-confirmed nasal neoplasia between July 1983 and October 2001 met the criteria for review. Statistically analyzed parameters included age at diagnosis, tumor histologic classification, fractionation schedule (number of treatments, and number of treatment days/week) (classified as hypofractionated if 2 or less treatments/week); calculated minimum tumor dose/fraction; calculated total minimum tumor dose (classified as hypofractionated if less than 37 Gy in six or fewer fractions); number of radiotherapy portals, a treatment gap of more than 7 days in a full course (3-5 treatments/week, 3-3.5 week treatment time) radiotherapy protocol, the influence of eye shields on survival following single portal DV fields, the survey radiographic extent of the disease, and the presence or absence of cytoreductive surgery. There was a significant relationship only between protocols using 3 or more treatments/week and at least 37 Gy cumulative minimum tumor dose and survival. However, there was no significant relationship between either total minimum tumor dose or dose/fraction and survival and there were no significant relationships between survival and any of the other variables analyzed including tumor histologic type.

Thermoluminescence response of flat optical fiber subjected to 9 MeV electron irradiations

NASA Astrophysics Data System (ADS)

Hashim, S.; Omar, S. S. Che; Ibrahim, S. A.; Hassan, W. M. S. Wan; Ung, N. M.; Mahdiraji, G. A.; Bradley, D. A.; Alzimami, K.

2015-01-01

We describe the efforts of finding a new thermoluminescent (TL) media using pure silica flat optical fiber (FF). The present study investigates the dose response, sensitivity, minimum detectable dose and glow curve of FF subjected to 9 MeV electron irradiations with various dose ranges from 0 Gy to 2.5 Gy. The above-mentioned TL properties of the FF are compared with commercially available TLD-100 rods. The TL measurements of the TL media exhibit a linear dose response over the delivered dose using a linear accelerator. We found that the sensitivity of TLD-100 is markedly 6 times greater than that of FF optical fiber. The minimum detectable dose was found to be 0.09 mGy for TLD-100 and 8.22 mGy for FF. Our work may contribute towards the development of a new dosimeter for personal monitoring purposes.

SU-F-18C-01: Minimum Detectability Analysis for Comprehensive Sized Based Optimization of Image Quality and Radiation Dose Across CT Protocols

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

Smitherman, C; Chen, B; Samei, E

2014-06-15

Purpose: This work involved a comprehensive modeling of task-based performance of CT across a wide range of protocols. The approach was used for optimization and consistency of dose and image quality within a large multi-vendor clinical facility. Methods: 150 adult protocols from the Duke University Medical Center were grouped into sub-protocols with similar acquisition characteristics. A size based image quality phantom (Duke Mercury Phantom) was imaged using these sub-protocols for a range of clinically relevant doses on two CT manufacturer platforms (Siemens, GE). The images were analyzed to extract task-based image quality metrics such as the Task Transfer Function (TTF),more » Noise Power Spectrum, and Az based on designer nodule task functions. The data were analyzed in terms of the detectability of a lesion size/contrast as a function of dose, patient size, and protocol. A graphical user interface (GUI) was developed to predict image quality and dose to achieve a minimum level of detectability. Results: Image quality trends with variations in dose, patient size, and lesion contrast/size were evaluated and calculated data behaved as predicted. The GUI proved effective to predict the Az values representing radiologist confidence for a targeted lesion, patient size, and dose. As an example, an abdomen pelvis exam for the GE scanner, with a task size/contrast of 5-mm/50-HU, and an Az of 0.9 requires a dose of 4.0, 8.9, and 16.9 mGy for patient diameters of 25, 30, and 35 cm, respectively. For a constant patient diameter of 30 cm, the minimum detected lesion size at those dose levels would be 8.4, 5, and 3.9 mm, respectively. Conclusion: The designed CT protocol optimization platform can be used to evaluate minimum detectability across dose levels and patient diameters. The method can be used to improve individual protocols as well as to improve protocol consistency across CT scanners.« less

In-vitro and in-vivo anti-Trichophyton activity of essential oils by vapour contact.

PubMed

Inouye, S; Uchida, K; Yamaguchi, H

2001-05-01

The minimum inhibitory doses (MIDs) of essential oils by vapour contact to inhibit the growth of Trichophyton mentagrophytes and Trichophyton rubrum on agar medium were determined using airtight boxes. Among seven essential oils examined, cinnamon bark oil showed the least MID, followed by lemongrass, thyme and perilla oils. Lavender and tea tree oils showed moderate MID, and citron oil showed the highest MID, being 320 times higher than that of cinnamon bark oil. The MID values were less than the minimum inhibitory concentration (MIC) values determined by agar dilution assay. Furthermore, the minimum agar concentration (MAC) of essential oils absorbed from vapour was determined at the time of MID determination as the second antifungal measure. The MAC value by vapour contact was 1.4 to 4.7 times less than the MAC remaining in the agar at the time of MIC determination by agar dilution assay. Using selected essential oils, the anti-Trichophyton activity by vapour contact was examined in more detail. Lemongrass, thyme and perilla oils killed the conidia, inhibited germination and hyphal elongation at 1-4 micrograms ml-1 air, whereas lavender oil was effective at 40-160 micrograms ml-1 air. The in-vivo efficacy of thyme and perilla oils by vapour contact was shown against an experimental tinea pedis in guinea pigs infected with T. mentagrophytes. These results indicated potent anti-Trichophyton action of essential oils by vapour contact.

Characterization of infectious dose and lethal dose of two strains of infectious hematopoietic necrosis virus (IHNV)

USGS Publications Warehouse

McKenney, Douglas; Kurath, Gael; Wargo, Andrew

2016-01-01

The ability to infect a host is a key trait of a virus, and differences in infectivity could put one virus at an evolutionary advantage over another. In this study we have quantified the infectivity of two strains of infectious hematopoietic necrosis virus (IHNV) that are known to differ in fitness and virulence. By exposing juvenile rainbow trout (Oncorhynchus mykiss) hosts to a wide range of virus doses, we were able to calculate the infectious dose in terms of ID50 values for the two genotypes. Lethal dose experiments were also conducted to confirm the virulence difference between the two virus genotypes, using a range of virus doses and holding fish either in isolation or in batch so as to calculate LD50values. We found that infectivity is positively correlated with virulence, with the more virulent genotype having higher infectivity. Additionally, infectivity increases more steeply over a short range of doses compared to virulence, which has a shallower increase. We also examined the data using models of virion interaction and found no evidence to suggest that virions have either an antagonistic or a synergistic effect on each other, supporting the independent action hypothesis in the process of IHNV infection of rainbow trout.

A step-up test procedure to find the minimum effective dose.

PubMed

Wang, Weizhen; Peng, Jianan

2015-01-01

It is of great interest to find the minimum effective dose (MED) in dose-response studies. A sequence of decreasing null hypotheses to find the MED is formulated under the assumption of nondecreasing dose response means. A step-up multiple test procedure that controls the familywise error rate (FWER) is constructed based on the maximum likelihood estimators for the monotone normal means. When the MED is equal to one, the proposed test is uniformly more powerful than Hsu and Berger's test (1999). Also, a simulation study shows a substantial power improvement for the proposed test over four competitors. Three R-codes are provided in Supplemental Materials for this article. Go to the publishers online edition of Journal of Biopharmaceutical Statistics to view the files.

Exposure of cats to low doses of FeLV: seroconversion as the sole parameter of infection

PubMed Central

Major, Andrea; Cattori, Valentino; Boenzli, Eva; Riond, Barbara; Ossent, Peter; Meli, Marina Luisa; Hofmann-Lehmann, Regina; Lutz, Hans

2009-01-01

In felids, feline leukemia virus (FeLV) infection results in a variety of outcomes that range from abortive (virus readily eliminated and never detectable) to progressive infection (persistent viremia and viral shedding). Recently, a novel outcome was postulated for low FeLV infectious doses. Naïve cats exposed to faeces of persistently infected cats seroconverted, indicating infection, but remained negative for provirus and p27 antigen in blood. FeLV provirus was found in some tissues but not in the bone marrow, infection of which is usually considered a necessary stage for disease progression. To investigate the impact of low FeLV doses on young cats and to test the hypothesis that low dose exposure may lead to an unknown pathogenesis of infection without involvement of the bone marrow, 21 cats were infected oronasally with variable viral doses. Blood p27, proviral and viral loads were followed until week 20 post-infection. Tissue proviral loads were determined as well. The immune response was monitored by measuring FeLV whole virus and p45 antibodies; and feline oncornavirus-associated cell membrane antigen (FOCMA) assay. One cat showed regressive infection (transient antigenemia, persistent provirus-positivity, and seroconversion) with provirus only found in some organs at sacrifice. In 7 of the 20 remaining cats FOCMA assay positivity was the only sign of infection, while all other tests were negative. Overall, the results show that FeLV low dose exposure can result in seroconversion during a presumed abortive infection. Therefore, commonly used detection methods do not detect all FeLV-infected animals, possibly leading to an underestimation of the prevalence of infection. PMID:19861115

Pharmacokinetic Monitoring Of Vancomycin In Cystic Fibrosis: Is It Time To Move Past Trough Concentrations?

PubMed

Fusco, Nicholas M; Prescott, William A; Meaney, Calvin J

2018-05-04

A correlation between vancomycin trough concentrations (VTC) and area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio (AUC/MIC) has not been established in children/adolescents with cystic fibrosis (CF). The primary objective of this study was to determine the correlation between measured VTCs and AUC/MIC using population-based pharmacokinetics. A retrospective cohort study of children/adolescents diagnosed with CF, age 6 to < 18 years, treated with vancomycin (VAN) for methicillin-resistant Staphylococcus aureus (MRSA) infection was conducted. The relationship between final VTCs and calculated AUC/MIC, using models established by Le et al and Stockmann et al, was assessed using Pearson and Spearman correlations. All tests were two-tailed with alpha set at 0.05. Thirty children/adolescents, age 7 to 17 years (median age 15 [IQR 9-17] years), were included. The mean final VAN dose was 58.03±18.58 mg/kg/day and the median final VTC was 12.6 (11-13.6) mg/L. The mean AUC/MIC was 355.34±138.46 (Le model) versus 426.79±178.92 (Stockmann model) (p=0.089). No correlation existed between VTCs and AUC/MIC using either the model by Le (r=0.140, p=0.461) or Stockmann (r=0.115; p=0.564). Using the Stockmann model: VAN dose (mg/kg/dose) was found to have a strong positive correlation with AUC (r=0.8874, p<0.0001) and AUC/MIC (r=0.7877, p<0.0001). VTCs did not correlate with AUC or AUC/MIC. Further research is needed to determine which estimate of VAN treatment efficacy is most appropriate for children and adolescents with CF infected with MRSA.

Pharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitis media in Spain.

PubMed

Isla, Arantxazu; Trocóniz, Iñaki F; Canut, Andrés; Labora, Alicia; Martín-Herrero, José Emilio; Pedraz, José Luis; Gascón, Alicia R

2011-03-01

Acute otitis media is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents. Ninety-three per cent of the cases diagnosed in Spain are treated with antibiotics, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens. The aim of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the empirical treatment of acute otitis media, looking at the pharmacokinetic variability and the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for AOM in Spain, Streptococcus pneumoniae and Haemophilus influenzae. Free-drug plasma concentrations were simulated and the probability of target attainment at each minimum inhibitory concentration and the cumulative fraction of response (CFR) were determined. Microbiological susceptibility information was extracted from SAUCE 3 surveillance. CFR with amoxicillin varied from 83% to 96% against S. pneumoniae and from 78% to 86% against H. influenzae. CFR was always >85% with amoxicillin/clavulanate. With the 3-day ceftriaxone regimen, the probability of achieving free concentrations above MIC at 72 hours significantly increased compared to the single dose, with which CFR ranged from 70% to 84%. High-dose amoxicillin (at least 80 mg/kg/day) should be the first-line therapy in uncomplicated infections, whereas amoxicillin/clavulanate (40 mg/kg/day) should be the choice when additional coverage for H. influenzae is desired. Administration of 3 daily doses of ceftriaxone increases bacteriological eradication probability when compared with one-day regimen, although additional clinical evaluations are necessary to establish the best target attainment with ceftriaxone. Copyright © 2009 Elsevier España, S.L. All rights reserved.

Identification and methods for prevention of Enterococcus mundtii infection in silkworm larvae, Bombyx mori, reared on artificial diet.

PubMed

Nwibo, Don Daniel; Matsumoto, Yasuhiko; Sekimizu, Kazuhisa

2015-06-01

Previously, it was reported that Enterococcus mundtii (E. mundtii) was associated with flacherie disease of silkworm larvae reared on artificial diet. In this study, we report that E. mundtii was isolated from diseased silkworm larvae, and validated as a pathogenic bacterium of the animal. When silkworm larva was infected with 1.04 × 10⁶ colony-forming units of E. mundtii via oral administration of diet, half population died within six days, indicating that the bacterium is pathogenic to silkworm. Less severe infection was found to cause anorexia and hamper the development of larvae. This pathogen was found to proliferate in both time- and dose-dependent manner in the gastrointestinal tract of the animal. The bacterium was isolated from powder of artificial diet made from mulberry leaves, and from mulberry leaves growing at a field. Minimum inhibitory concentration determination revealed that this bacterium was susceptible to tested antibiotics. Vancomycin treatment of diet significantly decreased the number of E. mundtii in intestine of silkworm larvae infected with the bacteria, compared to control. Furthermore, autoclaving or gamma ray irradiation of diet was also effective for exclusion of E. mundtii from the diet without the loss of its nutrient capacities. These results suggest that mulberry leaves used in making artificial diet for silkworm larvae is one of the sources of E. mundtii infection; and that antibiotic treatment, autoclaving or gamma ray irradiation of artificial diet can exclude the bacteria.

Efficacy in cats of a novel topical combination of fipronil, (S)-methoprene, eprinomectin, praziquantel, against induced infestations of Echinococcus multilocularis.

PubMed

Tielemans, Eric; Manavella, Coralie; Visser, Martin; Theodore Chester, S; Rosentel, Joseph

2014-04-28

Although foxes are the main reservoir of Echinococcus multilocularis, it is recognized that dogs and cats also may become infected. In cats the infection and egg production rates are usually low. Nevertheless, cats are a potential source of transmission of E. multilocularis. Due to the high human medical significance of E. multilocularis infection, it is important in endemic areas that owned cats are dewormed regularly. This paper presents the efficacy results of a new topical formulation, Broadline(®) (Merial) tested against E. multilocularis infection in cats. Two blinded laboratory studies were conducted to evaluate this novel topical combination of fipronil, (S)-methoprene, eprinomectin, and praziquantel against E. multilocularis. In each study, purpose-bred cats were assigned randomly to two treatment groups of 10 cats each: one untreated control group and one group treated at the minimum therapeutic dose of 0.12 mL/kg bodyweight to deliver 10mg fipronil, 12 mg (S)-methoprene, 0.5mg eprinomectin and 10mg praziquantel/kg bodyweight. The cats were inoculated orally with E. multilocularis protoscolices, 22 or 23 days before treatment. Based on necropsy and intestinal worm count, 8 or 11 days after treatment, the two studies confirmed 100% efficacy of Broadline(®) against adult E. multilocularis. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Problems of long-term spinal opioid treatment in advanced cancer patients.

PubMed

Mercadante, S

1999-01-01

Epidural and intrathecal techniques are well established techniques in cancer pain. However, several questions remain unresolved. The several problems of long-term spinal opioid treatment in advance cancer patients were reviewed. Indications for the use of spinal opioids include patients treated by systemic opioids with effective pain relief but with unacceptable side effects, or unsuccessful treatment with sequential strong opioid drug trials despite escalating doses. Therefore, the previous aggressive treatment with systemic opioids would leave as failures patients with difficult pain syndromes unresponsive to opioids. The choice of external or totally implanted delivery systems is based on different clinical considerations. The use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications and is easier to place and use at home in debilitated patients late in the course of their disease. The intrathecal administration has a lower incidence of catheter occlusion, lower malfunctioning rate, lower dose requirement, and more effective pain control. Due to the lower daily doses and volumes, intrathecal treatment proved to be more suitable for treatment at home by a continuous infusion than the epidural treatment. Advantages of infusion techniques are more evident when using local anesthetics, since intermittent administration of bupivacaine often results in motor paralysis and hemodynamic instability. Morphine is the opioid of choice. An epidural dose of 10% of the systemic dose is often used. However, intrathecal administration of opioids and bupivacaine may substantially improve pain relief in patients unresponsive to high epidural doses of these drugs, Bupivacaine-induced adverse effects, including sensory deficits, motor complaints, signs of autonomic dysfunction or neurotoxicity have been reported to not occur with bupivacaine doses less than 30-60 mg/day. Adjuvant drugs may further improve analgesia. Different ranges of technical complication rates have been reported in the literature, most of them being associated with epidural catheters. Subcutaneous tunneling and fixation of the catheter, bacterial filters, minimum changes of tubings, careful exit site care weekly, site protection and monitoring of any sign of infection to prevent infection, and training for family under supervision, are recommended. Areas for additional research include the use of spinal adjuvants, the ideal spinal morphine-bupivacaine ratio. methods to improve spinal opioid responsiveness and long-term catheter management with appropriate home care programs.

The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

PubMed Central

Pujol, Josep M.; Eisenberg, Joseph E.; Haas, Charles N.; Koopman, James S.

2009-01-01

Characterizing infectivity as a function of pathogen dose is integral to microbial risk assessment. Dose-response experiments usually administer doses to subjects at one time. Phenomenological models of the resulting data, such as the exponential and the Beta-Poisson models, ignore dose timing and assume independent risks from each pathogen. Real world exposure to pathogens, however, is a sequence of discrete events where concurrent or prior pathogen arrival affects the capacity of immune effectors to engage and kill newly arriving pathogens. We model immune effector and pathogen interactions during the period before infection becomes established in order to capture the dynamics generating dose timing effects. Model analysis reveals an inverse relationship between the time over which exposures accumulate and the risk of infection. Data from one time dose experiments will thus overestimate per pathogen infection risks of real world exposures. For instance, fitting our model to one time dosing data reveals a risk of 0.66 from 313 Cryptosporidium parvum pathogens. When the temporal exposure window is increased 100-fold using the same parameters fitted by our model to the one time dose data, the risk of infection is reduced to 0.09. Confirmation of this risk prediction requires data from experiments administering doses with different timings. Our model demonstrates that dose timing could markedly alter the risks generated by airborne versus fomite transmitted pathogens. PMID:19503605

Zika plasma viral dynamics in nonhuman primates provides insights into early infection and antiviral strategies

PubMed Central

Best, Katharine; Guedj, Jeremie; Madelain, Vincent; de Lamballerie, Xavier; Lim, So-Yon; Osuna, Christa E.; Whitney, James B.; Perelson, Alan S.

2017-01-01

The recent outbreak of Zika virus (ZIKV) has been associated with fetal abnormalities and neurological complications, prompting global concern. Here we present a mathematical analysis of the within-host dynamics of plasma ZIKV burden in a nonhuman primate model, allowing for characterization of the growth and clearance of ZIKV within individual macaques. We estimate that the eclipse phase for ZIKV, the time between cell infection and viral production, is most likely short (∼4 h), the median within-host basic reproductive number R0 is 10.7, the rate of viral production is rapid (>25,000 virions d−1), and the lifetime of an infected cell while producing virus is ∼5 h. We also estimate that the minimum number of virions produced by an infected cell over its lifetime is ∼5,500. We assess the potential effect of an antiviral treatment that blocks viral replication, showing that the median time to undetectable plasma viral load (VL) can be reduced from ∼5 d to ∼3 d with a drug concentration ∼15 times the drug’s EC50 when treatment is given prophylactically starting at the time of infection. In the case of favipiravir, a polymerase inhibitor with activity against ZIKV, we predict a dose of 150 mg/kg given twice a day initiated at the time of infection can reduce the peak median VL by ∼3 logs and shorten the time to undetectable median VL by ∼2 d, whereas treatment given 2 d postinfection is mostly ineffective in accelerating plasma VL loss in macaques. PMID:28765371

Benchmarking the minimum Electron Beam (eBeam) dose required for the sterilization of space foods

NASA Astrophysics Data System (ADS)

Bhatia, Sohini S.; Wall, Kayley R.; Kerth, Chris R.; Pillai, Suresh D.

2018-02-01

As manned space missions extend in length, the safety, nutrition, acceptability, and shelf life of space foods are of paramount importance to NASA. Since food and mealtimes play a key role in reducing stress and boredom of prolonged missions, the quality of food in terms of appearance, flavor, texture, and aroma can have significant psychological ramifications on astronaut performance. The FDA, which oversees space foods, currently requires a minimum dose of 44 kGy for irradiated space foods. The underlying hypothesis was that commercial sterility of space foods could be achieved at a significantly lower dose, and this lowered dose would positively affect the shelf life of the product. Electron beam processed beef fajitas were used as an example NASA space food to benchmark the minimum eBeam dose required for sterility. A 15 kGy dose was able to achieve an approximately 10 log reduction in Shiga-toxin-producing Escherichia coli bacteria, and a 5 log reduction in Clostridium sporogenes spores. Furthermore, accelerated shelf life testing (ASLT) to determine sensory and quality characteristics under various conditions was conducted. Using Multidimensional gas-chromatography-olfactometry-mass spectrometry (MDGC-O-MS), numerous volatiles were shown to be dependent on the dose applied to the product. Furthermore, concentrations of off -flavor aroma compounds such as dimethyl sulfide were decreased at the reduced 15 kGy dose. The results suggest that the combination of conventional cooking combined with eBeam processing (15 kGy) can achieve the safety and shelf-life objectives needed for long duration space-foods.

Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose

PubMed Central

Carlin, Lindsey E.; Hemann, Emily A.; Zacharias, Zeb R.; Heusel, Jonathan W.; Legge, Kevin L.

2018-01-01

Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID:29719539

Comparison of the treatment efficacy between tigecycline plus high-dose cefoperazone-sulbactam and tigecycline monotherapy against ventilator-associated pneumonia caused by extensively drug-resistant Acinetobacter baumannii.

PubMed

Qin, Youfa; Zhang, Jie; Wu, Lei; Zhang, Dailong; Fu, Lunjiao; Xue, Xiaoyan

2018-03-01

The present study examined the effect of high-dose cefoperazone-sulbactam combined with tigecycline against ventilator-associated pneumonia (VAP) caused by extensively drug-resistant Acinetobacter baumannii(XDR-AB). 42 patients with VAP due to XDR-AB infection were randomized into two groups: the TIG group (received tigecycline injection) and the TIG+CFS group (received tigecycline and cefoperazone-sulbactam (1 : 1) injection). Pulsed field gel electrophoresis (PFGE) was used for genotyping the isolated XDR-AB. The microdilution method was used to test the minimum inhibitory concentration (MIC) of cefoperazone-sulbactam or tigecycline in vitro and the combined effect was determined with the checkerboard method. The total combined effectiveness rate (including all patients who demonstrated an improved condition) was significantly higher in the TIG+CFS group (85.7%) compared with the TIG group (47.6%) (p = 0.010). No significant differences were noted with regard to the adverse reactions between the two groups. The 42 isolated XDR-AB strains were classified into four types. The MIC of the two drugs in combination was significantly lower than that of each drug used alone (p < 0.05). High dose of cefoperazone-sulbactam can improve the antimicrobial activity of tigecycline against XDR-AB.
.

The relationship between infecting dose and severity of disease in reported outbreaks of Salmonella infections.

PubMed Central

Glynn, J. R.; Bradley, D. J.

1992-01-01

The relationship between size of the infecting dose and severity of the resulting disease has been investigated for salmonella infections by reanalysis of data within epidemics for 32 outbreaks, and comparing data between outbreaks for 68 typhoid epidemics and 49 food-poisoning outbreaks due to salmonellas. Attack rate, incubation period, amount of infected food consumed and type of vehicle are used as proxy measures of infecting dose, while case fatality rates for typhoid and case hospitalization rates for food poisoning salmonellas were used to assess severity. Limitations of the data are discussed. Both unweighted and logit analysis models are used. There is no evidence for a dose-severity relationship for Salmonella typhi, but evidence of a correlation between dose and severity is available from within-epidemic or between-epidemic analysis, or both, for Salmonella typhimurium, S. enteritidis, S. infantis, S. newport, and S. thompson. The presence of such a relationship affects the way in which control interventions should be assessed. PMID:1468522

Estimating the dose response relationship for occupational radiation exposure measured with minimum detection level.

PubMed

Xue, Xiaonan; Shore, Roy E; Ye, Xiangyang; Kim, Mimi Y

2004-10-01

Occupational exposures are often recorded as zero when the exposure is below the minimum detection level (BMDL). This can lead to an underestimation of the doses received by individuals and can lead to biased estimates of risk in occupational epidemiologic studies. The extent of the exposure underestimation is increased with the magnitude of the minimum detection level (MDL) and the frequency of monitoring. This paper uses multiple imputation methods to impute values for the missing doses due to BMDL. A Gibbs sampling algorithm is developed to implement the method, which is applied to two distinct scenarios: when dose information is available for each measurement (but BMDL is recorded as zero or some other arbitrary value), or when the dose information available represents the summation of a series of measurements (e.g., only yearly cumulative exposure is available but based on, say, weekly measurements). Then the average of the multiple imputed exposure realizations for each individual is used to obtain an unbiased estimate of the relative risk associated with exposure. Simulation studies are used to evaluate the performance of the estimators. As an illustration, the method is applied to a sample of historical occupational radiation exposure data from the Oak Ridge National Laboratory.

Geographical diffusion of prazosin across Veterans Health Administration: Examination of regional variation in daily dosing and quality indicators among veterans with posttraumatic stress disorder.

PubMed

Abrams, Thad E; Lund, Brian C; Alexander, Bruce; Bernardy, Nancy C; Friedman, Matthew J

2015-01-01

Posttraumatic stress disorder (PTSD) is a high-priority treatment area for the Veterans Health Administration (VHA), and dissemination patterns of innovative, efficacious therapies can inform areas for potential improvement of diffusion efforts and quality prescribing. In this study, we replicated a prior examination of the period prevalence of prazosin use as a function of distance from Puget Sound, Washington, where prazosin was first tested as an effective treatment for PTSD and where prazosin use was previously shown to be much greater than in other parts of the United States. We tested the following three hypotheses related to prazosin geographic diffusion: (1) a positive geographical correlation exists between the distance from Puget Sound and the proportion of users treated according to a guideline recommended minimum therapeutic target dose (>/=6 mg/d), (2) an inverse geographic correlation exists between prazosin and benzodiazepine use, and (3) no geographical correlation exists between prazosin use and serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) use. Among a national sample of veterans with PTSD, overall prazosin utilization increased from 5.5 to 14.8% from 2006 to 2012. During this time period, rates at the Puget Sound VHA location declined from 34.4 to 29.9%, whereas utilization rates at locations a minimum of 2,500 miles away increased from 3.0 to 12.8%. Rates of minimum target dosing fell from 42.6 to 34.6% at the Puget Sound location. In contrast, at distances of at least 2,500 miles from Puget Sound, minimum threshold dosing rates remained stable (range, 18.6 to 17.7%). No discernible association was demonstrated between SSRI/SNRI or benzodiazepine utilization and the geographic distance from Puget Sound. Minimal threshold dosing of prazosin correlated positively with increased diffusion of prazosin use, but there was still a distance diffusion gradient. Although prazosin adoption has improved, geographic differences persist in both prescribing rates and minimum target dosing. Importantly, these regional disparities appear to be limited to prazosin prescribing and are not meaningfully correlated with SSRI/SNRI and benzodiazepine use as indicators of PTSD prescribing quality.

Polymicrobial Biofilm Inhibition Effects of Acetate-Buffered Chitosan Sponge Delivery Device.

PubMed

Jennings, Jessica Amber; Beenken, Karen E; Parker, Ashley C; Smith, James Keaton; Courtney, Harry S; Smeltzer, Mark S; Haggard, Warren O

2016-04-01

Polymicrobial biofilm-associated implant infections present a challenging clinical problem. Through modifications of lyophilized chitosan sponges, degradable drug delivery devices for antibiotic solution have been fabricated for prevention and treatment of contaminated musculoskeletal wounds. Elution of amikacin, vancomycin, or a combination of both follows a burst release pattern with vancomycin released above minimum inhibitory concentration for Staphylococcus aureus for 72 h and amikacin released above inhibitory concentrations for Pseudomonas aeruginosa for 3 h. Delivery of a vancomycin, amikacin, or a combination of both reduces biofilm formation on polytetrafluoroethylene catheters in an in vivo model of contamination. Release of dual antibiotics from sponges is more effective at preventing biofilm formation than single-loaded chitosan sponges. Treatment of pre-formed biofilm with high-dose antibiotic release from chitosan sponges shows minimal reduction after 48 h. These results demonstrate infection-preventive efficacy for antibiotic-loaded sponges, as well as the need for modifications in the development of advanced materials to enhance treatment efficacy in removing established biofilm. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection.

PubMed

Demiri, M; Müller-Luda, K; Agace, W W; Svensson-Frej, M

2017-10-01

Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low-dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC. © 2017 John Wiley & Sons Ltd.

/sup 125/I interstitial implants in the RIF-1 murine flank tumor: an animal model for brachytherapy

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

Bernstein, M.; Gutin, P.H.; Weaver, D.A.

1982-09-01

The development of a model for interstitial brachytherapy that uses high-activity, removable /sup 125/I sources in the RIF-1 murine flank tumor is reported. Experimental end points are clonogenic cell and tumor regrowth delay assays. For the clonogenic cell assay, interestitial radiation is delivered at total doses of 500-10,000 rad at dose rates of 0.9-2.7 rad/min to cells in annuli of tissue in the tumor. Dose-survival curves are characterized by an initial shoulder followed by a straight (exponential) portion, with D/sub 0/ similar to that of the curve obtained by external irradiation of the RIF-1 tumor in a self-contained cesium irradiatormore » at similar dose rates. Tumor regrowth curves have been obtained for minimum tumor doses of 500-5000 rad; marked tumor regression has been observed with minimum tumor doses as low as 2000 rad, but results are not as reproducible as the results obtained with the clonogenic cell assay.« less

Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

PubMed

Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas

2015-04-01

To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

Safety and Immunogenicity of 2009 pH1N1 Vaccination in HIV-Infected Pregnant Women

PubMed Central

Abzug, Mark J.; Nachman, Sharon A.; Muresan, Petronella; Handelsman, Edward; Watts, D. Heather; Fenton, Terence; Heckman, Barbara; Petzold, Elizabeth; Weinberg, Adriana; Levin, Myron J.; Siberry, George; Miller, Judi; Levy, Wende; Heckman, Barbara; Ebiasah, Ruth; Palumbo, Paul; Dragavon, Joan; Donelson, Lori; Jurgrau, Andrea; Garry, David; Bloom, Anthony

2013-01-01

Background. Pregnant women infected with human immunodeficiency virus (HIV) may have particular vulnerability to 2009 pandemic H1N1 influenza (pH1N1) infection. The safety and immunogenicity of pH1N1 vaccination in HIV-infected pregnant women are unknown. Methods. HIV-infected women 18–39 years of age and 14–34 weeks’ gestation on antiretroviral therapy received two 30-μg doses of unadjuvanted, inactivated pH1N1 vaccine 21 days apart. Hemagglutination inhibition titers were measured at entry, 21 days after dose 1, and 10 and 21 days after dose 2, and, in mothers and infants, at delivery and 3 and 6 months postdelivery. Results. No severe vaccine-related adverse events were observed among 127 subjects. At entry, 21% had seroprotective (≥1:40) titers. Seroprotection and seroresponse (≥4-fold rise) occurred in 73% and 66% after dose 1 and 80% and 72% after dose 2, respectively. Of women lacking seroprotection at entry, 66% attained seroprotection after dose 1 and 75% after dose 2. Seroprotective titers were present in 67% of mothers and 65% of infants at delivery (median 66 days after dose 2), 60% of mothers and 26% of infants at 3 months postdelivery, and 59% of mothers and 12% of infants at 6 months postdelivery. Conclusions. Two 30-μg doses were moderately immunogenic in HIV-infected pregnant women. No concerning vaccine-related safety signals were observed. Seroprotection persisted in most women postpartum. Efficient transplacental antibody transfer occurred, but seroprotection in infants waned rapidly. Vaccination to protect HIV-infected pregnant women and their newborns from new influenza strains is feasible, but more immunogenic platforms should be evaluated. Clinical Trials Registration. NCT00992017. PMID:23378284

Ultra-low dose of Mycobacterium tuberculosis aerosol creates partial infection in mice.

PubMed

Saini, Divey; Hopkins, Gregory W; Seay, Sarah A; Chen, Ching-Ju; Perley, Casey C; Click, Eva M; Frothingham, Richard

2012-03-01

A murine low dose (LD) aerosol model is commonly used to test tuberculosis vaccines. Doses of 50-400 CFU (24h lung CFU) infect 100% of exposed mice. The LD model measures progression from infection to disease based on organ CFU at defined time points. To mimic natural exposure, we exposed mice to an ultra-low dose (ULD) aerosol. We estimated the presented dose by sampling the aerosol. Female C57BL/6 mice were exposed to Mycobacterium tuberculosis H37Rv aerosol at 1.0, 1.1, 1.6, 5.4, and 11 CFU presented dose, infecting 27%, 36%, 36%, 100%, and 95% of mice, respectively. These data are compatible with a stochastic infection event (Poisson distribution, weighted R(2)=0.97) or with a dose-response relationship (sigmoid distribution, weighted R(2)=0.97). Based on the later assumption, the ID50 was 1.6CFU presented dose (95% confidence interval, 1.2-2.1). We compared organ CFU after ULD and LD aerosols (5.4 vs. 395CFU presented dose). Lung burden was 30-fold lower in the ULD model at 4 weeks (3.4 vs. 4.8 logs, p<0.001) and 18 weeks (≤3.6 vs. 5.0 logs, p=0.01). Mice exposed to ULD aerosols as compared to LD aerosols had greater within-group CFU variability. Exposure to ULD aerosols leads to infection in a subset of mice, and to persistently low organ CFU. The ULD aerosol model may resemble human pulmonary tuberculosis more closely than the standard LD model, and may be used to identify host or bacterial factors that modulate the initial infection event. Copyright © 2011 Elsevier Ltd. All rights reserved.

Antitrichomonal activity of Peganum harmala alkaloid extract against trichomoniasis in pigeon (Columba livia domestica).

PubMed

Tabari, M A; Youssefi, M R; Moghadamnia, A A

2017-06-01

1. This study was designed to evaluate the antitrichomonal effects of P. harmala alkaloid extract against T. gallinae, both in vitro and in vivo, as well as comparing it to that of metronidazole, conventional antitrichomonal medication and harmine and harmaline, the two alkaloids present in P. harmala. 2. T. gallinae were collected by the wet mount method from infected free-living pigeons. The in vitro assay was performed using multi-well plates containing test compounds in final concentrations of 5, 10, 15, 20, 30, 50 or 100 μg/ml. The in vivo assay was done on 60 experimentally infected pigeons dosed with metronidazole at 50 mg/kg body weight (BW) or alkaloids at 25 mg/kg BW. 3. The 24 h minimum inhibitory concentration (MIC) of alkaloid extract was 15 µg/ml while that of metronidazole was 50 µg/ml. Harmine and harmaline revealed 24 h MIC of 30 and 100 µg/ml, respectively. Treatment of infected pigeons with alkaloids led to a full recovery after 3 d but with metronidazole total eradication of trophozoites was not achieved. 4. In conclusion, data of the present study suggested P. harmala is a potent natural anti-trichomonal agent, effective against T. gallinae.

The flame-retardant BDE-99 dose-dependently affects viral replication in CVB3-infected mice.

PubMed

Lundgren, Magnus; Darnerud, Per Ola; Ilbäck, Nils-Gunnar

2013-06-01

The flame retardant component 2,2',4,4',5-penta-BDE (BDE-99) is found in the environment and in human tissues and fluids. In mice the common human coxsackievirus B3 (CVB3) infection has been shown to change the tissue distribution of BDE-99. We now investigate how CVB3 infection in mice affects liver uptake of (14)C at two doses of radiolabelled BDE-99, and whether increased tissue levels are related to changed virus replication and gene expression of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1). Mice were infected on day 0, orally treated either with 200μg or 20mg (14)C-BDE-99/kgbw on day 1, and euthanised on day 3. Serum and liver levels of (14)C-BDE-99, as well as virus levels and gene expressions of MCP-1 in the liver, were measured. In non-infected mice, there was a dose-dependent uptake of BDE-99 in both liver and serum, and in infected animals the liver BDE-99 levels was further increased. When comparing infected mice exposed to the two BDE-99 doses, the higher BDE dose resulted in increased virus amounts in the liver, and decreased infection-induced expression of MCP-1. Consequently, a high enough dose/tissue concentration of BDE-99 may result in a disturbed mobilisation of immune cells into infected tissues that could explain higher virus titres and a possibly altered clinical course of the disease. Moreover, the fact that CVB3 infection increased the BDE-99 levels in liver but not in serum may impair the risk assessment of polybrominated diphenyl ethers (PBDEs) in subclinical and clinically infected individuals, as serum levels is the common marker of exposure. Copyright © 2013 Elsevier Ltd. All rights reserved.

THE STATE OF IMMUNITY IN GUINEA-PIGS IMMUNIZED WITH LIVE BRUCELLOSIS VACCINE AND EXPOSED TO RADIATION

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

Shevtsova, Z.V.

1960-01-01

On immunization with 19-BA live brucellosis vaccine on the 3rd and 10th days after exposure to radiation in a dose of 200 r, guinea pigs died 4 and 2 times more frequently than unvaccinated guinea pigs. If immunization was carried out on the 30th day after irradiation the mortality among irradiated animals showed only a slight increase compared with the mortality among unvaccinated control animals. Immunization carried out before exposure to radiation had no influence upon the mortality of the animals caused by radiation sickness. Guinea pigs immunized after exposure to radiation were insusceptible when infected with the doses ofmore » virulent strains of Brucella usually employed to challenge immunity (2-4 infective doses). If, however, the animals were infected with a dose twice as high (8 infective doses) the degree of immunity proved to be lower in guinea pigs exposed to radiation, than in guinea pigs immunized and not exposed to radiation. Exposure of guinea pigs to radiation at a time when immunity had already developed had no influence upon the degree of immunity on infection with 4 infective doses of the virulent strain. (auth)« less

ON THE EFFECT OF SMALL DOSE X RADIATION ON SEPTICEMIA CAUSED BY PNEUMONIAE FRIEDLANDER. PART II. THE EFFECT OF SMALL TOTAL DOSE X RADIATION ON A SUBCUTANEOUS INFECTION (in German)

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

Birkner, R.; Meyer, R.; Trautmann, J.

1957-01-01

ABS>The effect of small doses of whole-body x radiation on the septicemia caused by Klebsiella pneumoniac Friedlander in white mice depends on the moment of the irradiation, the dose, the temporal dose distribution, the age and the sex of the animals, as well as on the quantity of germs applied. Animals die more rapidly if irradiations have been applied previous to the infection, while irradiations after infections lead to longer life. (auth)

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

Pseudomonas aeruginosa dose response and bathing water infection.

PubMed

Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A

2014-03-01

Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.

Faecal egg counts and expulsion dynamics of the whipworm, Trichuris trichiura following self-infection.

PubMed

Hansen, E P; Tejedor, A M; Thamsborg, S M; Alstrup Hansen, T V; Dahlerup, J F; Nejsum, P

2016-05-01

More than 400 million humans are estimated to be infected with the intestinal helminth parasite, Trichuris trichiura. The infection is chronic in nature and high-intensity infection can lead to colitis, anaemia, Trichuris Dysentery Syndrome and reduced cognitive performance. Single doses of 400 mg albendazole or 500 mg mebendazole (MBZ) are used in mass drug administration programmes, but this has been shown to be insufficient. In this study, worm expulsion dynamics are described after MBZ treatment, given as a multi-dose and single-dose treatment in two separate T. trichiura self-infection studies. Worm expulsion dynamics post-treatment showed a similar pattern regardless of the dose regime, with the first worms observed on day 2 and the last worms expelled on days 9 and 13 post-treatment. Establishment of a chronic infection was observed following the inefficient single-dose treatment. The prepatent period was 13-16 weeks in both studies and worms were found to have a lifespan of at least 1 year and 10 months. These self-infection studies provide key information on the chronicity of T. trichiura infections, expulsion dynamics after anthelmintic treatment and the prepatent period, as well as the fecundity of female worms, which was around 18,000 eggs/female per day.

Effects of time after infection, mosquito genotype, and infectious viral dose on the dynamics of Culex tarsalis vector competence for western equine encephalomyelitis virus.

PubMed

Mahmood, Farida; Chiles, Robert E; Fang, Ying; Green, Emily N; Reisen, William K

2006-06-01

The vector competence of Culex tarsalis Coquillett for the BFS 1703 strain of western equine encephalomyelitis virus (WEEV) changed significantly as a function of time after infection, mosquito genotype, and infectious virus dose. After ingesting a high virus dose (5 log10 plaque-forming units [PFU]/0.1 ml), female of the susceptible high virus producer (HVP) strain rapidly amplified the virus, developed a disseminated infection, and efficiently transmitted WEEV by 4 days postinfection (dpi). The quantity of virus expectorated peaked at 4 dpi (mean 3.4 log10 PFU), and the percentage of females transmitting per os peaked at 7 dpi (80%); both measures of transmission subsequently decreased to low levels throughout the remainder of infected life. HVP females imbibing a low virus dose (3 log10 PFU/0.1 ml) were infected less frequently and took longer to amplify virus to levels recorded for the high virus dose group and did not transmit virus efficiently, thereby indicating midgut infection and escape barriers were dose and time dependent. These data emphasized the importance of elevated avian viremias in Cx. tarsalis vector competence. Females from the WEEV-resistant (WR) strain and two wild-type strains from Kern and Riverside counties were significantly less susceptible to infection at both high and low doses than was the HVP strain. Overall, females with a high virus titer more frequently had a disseminated infection, but there did not seem to be a distinct threshold demarcating this relationship. In marked contrast, all infected females transmitting virus had body titers >4.3 log10 PFU, and most had titers >4.8 log10 PFU. These data indicated that not all females with a disseminated infection transmitted virus because of the presence of one or more salivary gland barriers.

Protective Role of Acetylsalicylic Acid in Experimental Trypanosoma cruzi Infection: Evidence of a 15-epi-Lipoxin A4-Mediated Effect

PubMed Central

Henriquez, Natalia; Faúndez, Mario; Torres, Gloria; Castillo, Christian; Escanilla, Sebastián; Kemmerling, Ulrike; Morello, Antonio; López-Muñoz, Rodrigo A.; Maya, Juan D.

2013-01-01

Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease. PMID:23638194

Alveolar and serum concentrations of imipenem in two lung transplant recipients supported with extracorporeal membrane oxygenation.

PubMed

Welsch, C; Augustin, P; Allyn, J; Massias, L; Montravers, P; Allou, N

2015-02-01

Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly used in patients with respiratory failure who fail conventional treatment. Postoperative pneumonia is the most common infection after lung transplantation (40%). Imipenem is frequently used for empirical treatment of nosocomial pneumonia in the intensive care unit. Nevertheless, few data are available on the impact of ECMO on pharmacokinetics, and no data on imipenem dosing during ECMO. Currently, no guidelines exist for antibiotic dosing during ECMO support. We report the cases of 2 patients supported with venovenous ECMO for refractory acute respiratory distress syndrome following single lung transplantation for pulmonary fibrosis, treated empirically with 1 g of imipenem intravenously every 6 h. Enterobacter cloacae was isolated from the respiratory sample of Patient 1 and Klebsiella pneumoniae was isolated from the respiratory sample of Patient 2. Minimum inhibitory concentrations of the 2 isolated strains were 0.125 and 0.25 mg/L, respectively. Both patients were still alive on day 28. This is the first report, to our knowledge, of imipenem concentrations in lung transplantation patients supported with ECMO. This study confirms high variability in imipenem trough concentrations in patients on ECMO and with preserved renal function. An elevated dosing regimen (4 g/24 h) is more likely to optimize drug exposure, and therapeutic drug monitoring is recommended, where available. Population pharmacokinetic studies are indicated to develop evidence-based dosing guidelines for ECMO patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

SU-E-T-578: On Definition of Minimum and Maximum Dose for Target Volume

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

Gong, Y; Yu, J; Xiao, Y

Purpose: This study aims to investigate the impact of different minimum and maximum dose definitions in radiotherapy treatment plan quality evaluation criteria by using tumor control probability (TCP) models. Methods: Dosimetric criteria used in RTOG 1308 protocol are used in the investigation. RTOG 1308 is a phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC. The prescription dose for planning target volume (PTV) is 70Gy. Maximum dose (Dmax) should not exceed 84Gy and minimum dose (Dmin) should not go below 59.5Gy in order for the plan to be “per protocol” (satisfactory).A mathematicalmore » model that simulates the characteristics of PTV dose volume histogram (DVH) curve with normalized volume is built. The Dmax and Dmin are noted as percentage volumes Dη% and D(100-δ)%, with η and d ranging from 0 to 3.5. The model includes three straight line sections and goes through four points: D95%= 70Gy, Dη%= 84Gy, D(100-δ)%= 59.5 Gy, and D100%= 0Gy. For each set of η and δ, the TCP value is calculated using the inhomogeneously irradiated tumor logistic model with D50= 74.5Gy and γ50=3.52. Results: TCP varies within 0.9% with η; and δ values between 0 and 1. With η and η varies between 0 and 2, TCP change was up to 2.4%. With η and δ variations from 0 to 3.5, maximum of 8.3% TCP difference is seen. Conclusion: When defined maximum and minimum volume varied more than 2%, significant TCP variations were seen. It is recommended less than 2% volume used in definition of Dmax or Dmin for target dosimetric evaluation criteria. This project was supported by NIH grants U10CA180868, U10CA180822, U24CA180803, U24CA12014 and PA CURE Grant.« less

Surgical site infection in lumbar surgeries, pre and postoperative antibiotics and length of stay: a case study.

PubMed

Khan, Inayat Ullah; Janjua, Muhammad Burhanuddin; Hasan, Shumaila; Shah, Shahid

2009-01-01

Postoperative wound infection also called as surgical site infection (SSI), is a trouble some complication of lumbar spine surgeries and they can be associated with serious morbidities, mortalities and increase resource utilization. With the improvement in diagnostic modalities, proper surgical techniques, antibiotic therapy and postoperative care, infectious complications can result in various compromises afterwards. The objective was to study the relation of surgical site infection in clean lumbar surgeries with the doses of antibiotics. This Retrospective study was conducted at Shifa International Hospital, from January 2006 to March 2008. Hundred post operated cases of lumber disc prolapse, lumbar stenosis or both studied retrospectively by tracing their operated data from hospital record section for the development of surgical site infection (SSI). The patients were divided into three groups depending upon whether they received single, three or more than three doses of antibiotics respectively. Complete data analyses and cross tabulation done with SPSS version 16. Of 100 cases, only 6% had superficial surgical site infection; only 1 case with co morbidity of hypertension was detected. Twenty-one cases had single dose of antibiotic (Group-I), 59 cases had 3 doses (Group-II) and 20 cases received multiple doses (Group-III). There was no infection in Group-I. Only one patient in Group-II and 5 patients in Group-III developed superficial SSI. While 4 in Group-II, 3 in Group-III, and none of Group-I had > 6 days length of stay (LOS). The dose of antibiotic directly correlates with the surgical site infection in clean lumbar surgeries. When compared with multiple doses of antibiotics a single preoperative shot of antibiotic is equally effective for patients with SSI.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

PubMed

Dow, Geoffrey S; Gettayacamin, Montip; Hansukjariya, Pranee; Imerbsin, Rawiwan; Komcharoen, Srawuth; Sattabongkot, Jetsumon; Kyle, Dennis; Milhous, Wilbur; Cozens, Simon; Kenworthy, David; Miller, Anne; Veazey, Jim; Ohrt, Colin

2011-07-29

Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

PubMed Central

2011-01-01

Background Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. Methods In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. Results The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Conclusions Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs. PMID:21801400

Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks

PubMed Central

Srivastava, Shashikant; Deshpande, Devyani; Pasipanodya, Jotam; Nuermberger, Eric; Swaminathan, Soumya; Gumbo, Tawanda

2016-01-01

Background. When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0–24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0–24/MIC ratios when treated with the same dose. Methods. We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0–24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0–24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum. Results. The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0–24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3–4 times daily. Conclusions. The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible. PMID:27742641

THE FEATURES OF THE COURSE OF CERTAIN VIRUS INFECTIONS AGAINST A BACKGROUND OF RADIATION AFFLICTION

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

Remezov, P.I.

1960-01-01

Since the combination of radiation sickness with virus infections complicates diagnosis of the etiology of the infectious process, the course of various infections (lymphocytic choriomeningitis, acute multiple encephalomyelitis influenza, tick-borne encephalitis, etc.) was studied in white mice subjected to a single daily 500, 400, 300, 200, 100, 50, or 10 r dose (or 0.33 r twice weekly) of x-radiation for more than 6 months. Six hours before or 6 hours, 7, 21, and 90 days after irradiation the mice were infected cerebrally, per nos, per os, or subcutaneously with virus in a dose of LD/sub 50/ or more. A studymore » was also made of the course of virus infection as affected by a combination of unfavorable factors, such as irradiation plus chilling and exhaustion. After infection, the clinical symptoms and virological characteristics of the disease were studied. The resultant data are of practical value in diagnosing virus infections complicated by the action of ionizing radiation on the body. A detailed description of the results is given. It was found that ionizing radiation greatly altered the clinical and virological picture of virus infections. Even comparatively small doses (300, 200, 100 r, and less) reduced the mice's resistance to many viruses. The course of the virus infection in an irradiated animal depended both on the radiation dose and the time that had elapsed between irradiation and infection. The greatest drop in the animals' resistance to virus was noted during maximum development of their reaction to radiation. Within 3 to 3.5 months after irradiation their resistance returns to normal. Chronic irradiation, even in such small doses as 10 r, also reduced resistance to viruses. In this case the degree of the drop in resistance was directly proportional to the total radiation dose. Prolonged irradiation of mice twice weekly in doses of 0.33 r revealed no deviations in the clinical or virologn-cal characteristics of the virus infections, but the mortality rate was always higher than in non-irradiated animals. (OTS)« less

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

PubMed

Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

2014-05-01

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

Review and comparison between the Wells-Riley and dose-response approaches to risk assessment of infectious respiratory diseases.

PubMed

Sze To, G N; Chao, C Y H

2010-02-01

Infection risk assessment is very useful in understanding the transmission dynamics of infectious diseases and in predicting the risk of these diseases to the public. Quantitative infection risk assessment can provide quantitative analysis of disease transmission and the effectiveness of infection control measures. The Wells-Riley model has been extensively used for quantitative infection risk assessment of respiratory infectious diseases in indoor premises. Some newer studies have also proposed the use of dose-response models for such purpose. This study reviews and compares these two approaches to infection risk assessment of respiratory infectious diseases. The Wells-Riley model allows quick assessment and does not require interspecies extrapolation of infectivity. Dose-response models can consider other disease transmission routes in addition to airborne route and can calculate the infectious source strength of an outbreak in terms of the quantity of the pathogen rather than a hypothetical unit. Spatial distribution of airborne pathogens is one of the most important factors in infection risk assessment of respiratory disease. Respiratory deposition of aerosol induces heterogeneous infectivity of intake pathogens and randomness on the intake dose, which are not being well accounted for in current risk models. Some suggestions for further development of the risk assessment models are proposed. This review article summarizes the strengths and limitations of the Wells-Riley and the dose-response models for risk assessment of respiratory diseases. Even with many efforts by various investigators to develop and modify the risk assessment models, some limitations still persist. This review serves as a reference for further development of infection risk assessment models of respiratory diseases. The Wells-Riley model and dose-response model offer specific advantages. Risk assessors can select the approach that is suitable to their particular conditions to perform risk assessment.

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits

PubMed Central

Cox, Daniel T. C.; Shanahan, Danielle F.; Hudson, Hannah L.; Fuller, Richard A.; Anderson, Karen; Hancock, Steven; Gaston, Kevin J.

2017-01-01

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare. PMID:28208789

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits.

PubMed

Cox, Daniel T C; Shanahan, Danielle F; Hudson, Hannah L; Fuller, Richard A; Anderson, Karen; Hancock, Steven; Gaston, Kevin J

2017-02-09

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

Passive dosimetry aboard the Mir Orbital Station: internal measurements.

PubMed

Benton, E R; Benton, E V; Frank, A L

2002-10-01

Passive radiation dosimeters were exposed aboard the Mir Orbital Station over a substantial portion of the solar cycle in order to measure the change in dose and dose equivalent rates as a function of time. During solar minimum, simultaneous measurements of the radiation environment throughout the habitable volume of the Mir were made using passive dosimeters in order to investigate the effect of localized shielding on dose and dose equivalent. The passive dosimeters consisted of a combination of thermoluminescent detectors to measure absorbed dose and CR-39 PNTDs to measure the linear energy transfer (LET) spectrum from charged particles of LET infinity H2O > or = 5 keV/micrometers. Results from the two detector types were then combined to yield mean total dose rate, mean dose equivalent rate, and average quality factor. Contrary to expectations, both dose and dose equivalent rates measured during May-October 1991 near solar maximum were higher than similar measurements carried out in 1996-1997 during solar minimum. The elevated dose and dose equivalent rates measured in 1991 were probably due to a combination of intense solar activity, including a large solar particle event on 9 June 1991, and the temporary trapped radiation belt created in the slot region by the solar particle event and ensuing magnetic storm of 24 March 1991. During solar minimum, mean dose and dose equivalent rates were found to vary by factors of 1.55 and 1.37, respectively, between different locations through the interior of Mir. More heavily shielded locations tended to yield lower total dose and dose equivalent rates, but higher average quality factor than did more lightly shielding locations. However, other factors such as changes in the immediate shielding environment surrounding a given detector location, changes in the orientation of the Mir relative to its velocity vector, and changes in the altitude of the station also contributed to the variation. Proton and neutron-induced target fragment secondaries, not primary galactic cosmic rays, were found to dominate the LET spectrum above 100 keV/micrometers. This indicates that in low earth orbit, trapped protons in the South Atlantic Anomaly are responsible for the major fraction of the total dose equivalent. c2002 Elsevier Science Ltd. All rights reserved.

Commissioning dosimetry and in situ dose mapping of a semi-industrial Cobalt-60 gamma-irradiation facility using Fricke and Ceric-cerous dosimetry system and comparison with Monte Carlo simulation data

NASA Astrophysics Data System (ADS)

Mortuza, Md Firoz; Lepore, Luigi; Khedkar, Kalpana; Thangam, Saravanan; Nahar, Arifatun; Jamil, Hossen Mohammad; Bandi, Laxminarayan; Alam, Md Khorshed

2018-03-01

Characterization of a 90 kCi (3330 TBq), semi-industrial, cobalt-60 gamma irradiator was performed by commissioning dosimetry and in-situ dose mapping experiments with Ceric-cerous and Fricke dosimetry systems. Commissioning dosimetry was carried out to determine dose distribution pattern of absorbed dose in the irradiation cell and products. To determine maximum and minimum absorbed dose, overdose ratio and dwell time of the tote boxes, homogeneous dummy product (rice husk) with a bulk density of 0.13 g/cm3 were used in the box positions of irradiation chamber. The regions of minimum absorbed dose of the tote boxes were observed in the lower zones of middle plane and maximum absorbed doses were found in the middle position of front plane. Moreover, as a part of dose mapping, dose rates in the wall positions and some selective strategic positions were also measured to carry out multiple irradiation program simultaneously, especially for low dose research irradiation program. In most of the cases, Monte Carlo simulation data, using Monte Carlo N-Particle eXtended code version MCNPX 2.7., were found to be in congruence with experimental values obtained from Ceric-cerous and Fricke dosimetry; however, in close proximity positions from the source, the dose rate variation between chemical dosimetry and MCNP was higher than distant positions.

Gamma Irradiation as a Phytosanitary Treatment of Bactrocera tau (Diptera: Tephritidae) in Pumpkin Fruits.

PubMed

Guoping, Zhan; Lili, Ren; Ying, Shao; Qiaoling, Wang; Daojian, Yu; Yuejin, Wang; Tianxiu, Li

2015-02-01

The fruit fly Bactrocera tau (Walker) is an important quarantine pest that damages fruits and vegetables throughout Asian regions. Host commodities shipped from infested areas should undergo phytosanitary measures to reduce the risk of shipping viable flies. The dose-response tests with 1-d-old eggs and 3-, 5-, 7-, 8-d-old larvae were initiated to determine the most resistant stages in fruits, and the minimum dose for 99.9968% prevention of adult eclosion at 95% confidence level was validated in the confirmatory tests. The results showed that 1) the pupariation rate was not affected by gamma radiation except for eggs and first instars, while the percent of eclosion was reduced significantly in all instars at all radiation dose; 2) the tolerance to radiation increased with increasing age and developmental stage; 3) the estimated dose to 99.9968% preventing adult eclosion from late third instars was 70.9 Gy (95% CL: 65.6-78.2, probit model) and 71.8 Gy (95% CL: 63.0-87.3, logit model); and iv) in total, 107,135 late third instars cage infested in pumpkin fruits were irradiated at the target dose of 70 Gy (62.5-85.0, Gy measured), which resulted in no adult emergence in the two confirmatory tests. Therefore, a minimum dose of 85 and 72 Gy, which could prevent adult emergence at the efficacy of 99.9972 and 99.9938% at the 95% confidence level, respectively, can be recommended as a minimum dose for phytosanitary treatment of B. tau in any host fruits and vegetables under ambient atmospheres. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Subnormal and waning immunity to tetanus toxoid in previously vaccinated HIV-infected children and response to booster doses of the vaccine.

PubMed

Choudhury, Shahana A; Matin, Fazle

2013-12-01

Little is known regarding waning immunity to tetanus toxoid (TT) in HIV-infected children and the need for booster doses before the recommended interval of 5-10 years. Anti-tetanus antibodies were assessed by ELISA in 24 HIV-infected and 24 control children. A protective level (>0.1 IU/ml) of TT antibodies was observed in 62% of HIV-infected children and in 100% of controls. HIV-infected children with five doses had a significantly (p=0.01) lower prevalence of protective immunity compared to controls. Follow-up anti-TT antibody levels in nine HIV-infected children declined from 1.27 to 0.26 IU/ml, but levels did not decline in the seven controls; five of the seven (71%) children with a non-protective level of antibodies responded with a level>0.16 IU/ml following one booster dose of the vaccine. HIV-infected children may need TT boosters before the recommended 5-10 years. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Clinical Toxicities and Dosimetric Parameters After Whole-Pelvis Versus Prostate-Only Intensity-Modulated Radiation Therapy for Prostate Cancer

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

Deville, Curtiland, E-mail: deville@uphs.upenn.ed; Both, Stefan; Hwang, Wei-Ting

2010-11-01

Purpose: To assess whether whole-pelvis (WP) intensity-modulated radiation therapy (IMRT) is associated with increased toxicity compared with prostate-only (PO) IMRT. Methods and Materials: We retrospectively analyzed all patients with prostate cancer undergoing definitive IMRT to 79.2 Gy with concurrent androgen deprivation at our institution from November 2005 to May 2007 with a minimum follow-up of 12 months. Thirty patients received initial WP IMRT to 45 Gy in 1.8-Gy fractions, and thirty patients received PO IMRT. Study patients underwent computed tomography simulation and treatment planning by use of predefined dose constraints. Bladder and rectal dose-volume histograms, maximum genitourinary (GU) and gastrointestinalmore » (GI) Radiation Therapy Oncology Group toxicity grade, and late Grade 2 or greater toxicity-free survival curves were compared between the two groups by use of the Student t test, Fisher exact test, and Kaplan-Meier curve, respectively. Results: Bladder minimum dose, mean dose, median dose, volume receiving 5 Gy, volume receiving 20 Gy, volume receiving 40 Gy, and volume receiving 45 Gy and rectal minimum dose, median dose, and volume receiving 20 Gy were significantly increased in the WP group (all p values < 0.01). Maximum acute GI toxicity was limited to Grade 2 and was significantly increased in the WP group at 50% vs. 13% the PO group (p = 0.006). With a median follow-up of 24 months (range, 12-35 months), there was no difference in late GI toxicity (p = 0.884) or in acute or late GU toxicity. Conclusions: Despite dosimetric differences in the volume of bowel, bladder, and rectum irradiated in the low-dose and median-dose regions, WP IMRT results only in a clinically significant increase in acute GI toxicity, in comparison to PO IMRT, with no difference in GU or late GI toxicity.« less

Heterosubtypic immunity increases infectious dose required to infect Mallard ducks with Influenza A virus.

PubMed

Segovia, Karen M; França, Monique S; Leyson, Christina L; Kapczynski, Darrell R; Chrzastek, Klaudia; Bahnson, Charlie S; Stallknecht, David E

2018-01-01

Previous field and experimental studies have demonstrated that heterosubtypic immunity (HSI) is a potential driver of Influenza A virus (IAV) prevalence and subtype diversity in mallards. Prior infection with IAV can reduce viral shedding during subsequent reinfection with IAV that have genetically related hemagglutinins (HA). In this experiment, we evaluated the effect of HSI conferred by an H3N8 IAV infection against increasing challenge doses of closely (H4N6) and distantly (H6N2) related IAV subtypes in mallards. Two groups of thirty 1-month-old mallards each, were inoculated with 105.9 50% embryo infectious doses (EID50) of an H3N8 virus or a mock-inoculum. One month later, groups of five birds each were challenged with increasing doses of H4N6 or H6N2 virus; age-matched, single infection control ducks were included for all challenges. Results demonstrate that naïve birds were infected after inoculation with 103 and 104 EID50 doses of the H4N6 or H6N2 virus, but not with 102 EID50 doses of either IAV. In contrast, with birds previously infected with H3N8 IAV, only one duck challenged with 104 EID50 of H4N6 IAV was shedding viral RNA at 2 days post-inoculation, and with H6N2 IAV, only birds challenged with the 104 EID50 dose were positive to virus isolation. Viral shedding in ducks infected with H6N2 IAV was reduced on days 2 and 3 post-inoculation compared to control birds. To explain the differences in the dose necessary to produce infection among H3-primed ducks challenged with H4N6 or H6N2 IAV, we mapped the amino acid sequence changes between H3 and H4 or H6 HA on predicted three-dimensional structures. Most of the sequence differences occurred between H3 and H6 at antigenic sites A, B, and D of the HA1 region. These findings demonstrate that the infectious dose necessary to infect mallards with IAV can increase as a result of HSI and that this effect is most pronounced when the HA of the viruses are genetically related.

Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials.

PubMed

Kreimer, Aimée R; Struyf, Frank; Del Rosario-Raymundo, Maria Rowena; Hildesheim, Allan; Skinner, S Rachel; Wacholder, Sholom; Garland, Suzanne M; Herrero, Rolando; David, Marie-Pierre; Wheeler, Cosette M; González, Paula; Jiménez, Silvia; Lowy, Douglas R; Pinto, Ligia A; Porras, Caroline; Rodriguez, Ana Cecilia; Safaeian, Mahboobeh; Schiffman, Mark; Schiller, John T; Schussler, John; Sherman, Mark E; Bosch, F Xavier; Castellsague, Xavier; Chatterjee, Archana; Chow, Song-Nan; Descamps, Dominique; Diaz-Mitoma, Francisco; Dubin, Gary; Germar, Maria Julieta; Harper, Diane M; Lewis, David J M; Limson, Genara; Naud, Paulo; Peters, Klaus; Poppe, Willy A J; Ramjattan, Brian; Romanowski, Barbara; Salmeron, Jorge; Schwarz, Tino F; Teixeira, Julio C; Tjalma, Wiebren A A

2015-07-01

There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group. 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA). Copyright © 2015 Elsevier Ltd. All rights reserved.

A randomized trial of one versus three doses of Augmentin as wound prophylaxis in at-risk abdominal surgery.

PubMed Central

Bates, T.; Roberts, J. V.; Smith, K.; German, K. A.

1992-01-01

In a randomized prospective trial of prophylactic antibiotics in at-risk abdominal surgery, one dose of intravenous Augmentin (amoxycillin 250 mg and clavulanic acid 125 mg) on induction has been compared with three 8 hourly doses in 900 patients. Wound infection rates which included minor and delayed infections were very similar in those given one dose: 48/449 (10.7%) compared with those given three doses: 49/451 (10.9%) 95% confidence limits - 4.25% + 3.9%. There were more septic and sepsis-related deaths in those patients given one dose (14 deaths) than in those given three doses (7 deaths) P > 0.1 95% CL - 0.4% + 3.0%. However, there were more very elderly patients in the one dose group: 64% of the deaths were aged over 80 and all but one had an emergency operation. There was no difference in the other outcome measures studied which included non-fatal deep sepsis, length of postoperative hospital stay, duration of postoperative fever or the use of antibiotics for postoperative infection. One dose of a suitable intravenous antibiotic gives prophylaxis against wound infection in at-risk abdominal surgery which is at least as effective as multiple doses. However, there may be a risk of overwhelming systemic sepsis in very elderly patients having emergency surgery. PMID:1461853

New assay of protective activity of Rocky Mountain spotted fever vaccines.

PubMed Central

Anacker, R L; Smith, R F; Mann, R E; Hamilton, M A

1976-01-01

Areas under the fever curves of guinea pigs inoculated with Rocky Mountain spotted fever vaccine over a restricted dose range and infected with a standardized dose of Rickettsia rickettsii varied linearly with log10 dose of vaccine. A calculator was programmed to plot fever curves and calculate the vaccine dose that reduced the fever of infected animals by 50%. PMID:823177

Sulfadoxine-Pyrimethamine Exhibits Dose-Response Protection Against Adverse Birth Outcomes Related to Malaria and Sexually Transmitted and Reproductive Tract Infections.

PubMed

Chico, R Matthew; Chaponda, Enesia Banda; Ariti, Cono; Chandramohan, Daniel

2017-04-15

We conducted a prospective cohort study in Zambia among pregnant women who received intermittent preventive treatment using sulfadoxine-pyrimethamine (IPTp-SP). We calculated the odds ratios (ORs) of adverse birth outcomes by IPTp-SP exposure, 0-1 dose (n = 126) vs ≥2 doses (n = 590) and ≥2 doses (n = 310) vs ≥3 doses (n = 280) in 7 categories of malaria infection and sexually transmitted and reproductive tract infections (STIs/RTIs). We found no significant differences in baseline prevalence of infection across IPTp-SP exposure groups. However, among women given 2 doses compared to 0-1 dose, the odds of any adverse birth outcome were reduced 45% (OR, 0.55; 95% confidence interval [CI], 0.36, 0.86) and 13% further with ≥3 doses (OR, 0.43; 95% CI, 0.27, 0.68). Two or more doses compared to 0-1 dose reduced preterm delivery by 58% (OR, 0.42; 95% CI, 0.27, 0.67) and 21% further with ≥3 doses (OR, 0.21; 95% CI, 0.13, 0.35). Women with malaria at enrollment who received ≥2 doses vs 0-1 had 76% lower odds of any adverse birth outcome (OR, 0.24; 95% 0.09, 0.66), and Neisseria gonorrhoeae and/or Chlamydia trachomatis had 92% lower odds of any adverse birth outcome (OR, 0.08; 95% CI, 0.01, 0.64). Women with neither a malaria infection nor STIs/RTIs who received ≥2 doses had 73% fewer adverse birth outcomes (OR, 0.27; 95% CI, 0.11, 0.68). IPTp-SP appears to protect against malaria, STIs/RTIs, and other unspecified causes of adverse birth outcome. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Effective dose of salmon GnRha for induction of ovulation in channel catfish, Ictalurus punctatus

USDA-ARS?s Scientific Manuscript database

The present study was conducted to determine the minimum effective salmon Gonadotropin Releasing Hormone analog (sGnRHa) dose to stimulate ovulation in channel catfish. Four doses of sGnRHa (0, 5, 10 and 25 µg /Kg) were compared with commonly used 100 µg mammalian Luteinizing Hormone Releasing Hor...

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia.

PubMed

Packiriswamy, Nandakumar; Steury, Michael; McCabe, Ian C; Fitzgerald, Scott D; Parameswaran, Narayanan

2016-05-01

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Immunogenicity and safety of two doses of catch-up immunization with Haemophilus influenzae type b conjugate vaccine in Indian children living with HIV.

PubMed

Arya, Bikas K; Bhattacharya, Sangeeta Das; Sutcliffe, Catherine G; Saha, Malay K; Bhattacharyya, Subhasish; Niyogi, Swapan Kumar; Moss, William J; Panda, Samiran; Das, Ranjan Saurav; Mallick, Mausom; Mandal, Sutapa

2016-04-27

Children living with HIV are at increased risk of disease from Haemophilus influenzae type b (Hib). Data are limited on the immunogenicity of a two-dose, catch-up schedule for Hib conjugate vaccine (HibCV) among HIV-infected children accessing antiretroviral therapy (ART) late. The objectives of the study were to: (1) evaluate baseline immunity to Hib and the immunogenicity and safety of two doses of HibCV among HIV-infected Indian children; and (2) document the threshold antibody level required to prevent Hib colonization among HIV-infected children following immunization. We conducted a prospective cohort study among HIV-infected children 2-15 years of age and HIV-uninfected children 2-5 years of age. HIV-infected children received two doses of HibCV and uninfected children received one. Serum anti-Hib PRP IgG antibodies were measured at baseline and two months after immunization in the HIV-infected children. Nasopharyngeal (NP) swabs were collected at baseline and follow-up. 125 HIV-infected and 44 uninfected children participated. 40% of HIV-infected children were receiving ART and 26% had a viral load >100,000 copies/mL. The geometric mean concentration of serum anti-Hib PRP antibody increased from 0.25 μg/mL at baseline to 2.65 μg/mL after two doses of HibCV, representing a 10.6-fold increase (p<0.0001). 76% percent of HIV-infected children mounted an immune response. Moderate or severe immune suppression, trimethoprim/sulfamethoxazole prophylaxis, and lower baseline antibody levels were associated with lower post-vaccine serum anti-Hib PRP IgG antibodies. A serum anti-Hib PRP IgG antibody level ≥ 3.3 μg/mL was protective against Hib NP colonization. There were no differences in adverse events between HIV-infected and uninfected children. Including a catch-up immunization schedule for older HIV infected children in countries introducing Hib vaccines is important. Older HIV-infected children with delayed access to ART and without suppressed viral loads mounted an adequate immune response following two doses of HibCV. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Phage Lysin PlySs2 Decolonizes Streptococcus suis from Murine Intranasal Mucosa.

PubMed

Gilmer, Daniel B; Schmitz, Jonathan E; Thandar, Mya; Euler, Chad W; Fischetti, Vincent A

2017-01-01

Streptococcus suis infects pigs worldwide and may be zoonotically transmitted to humans with a mortality rate of up to 20%. S. suis has been shown to develop in vitro resistance to the two leading drugs of choice, penicillin and gentamicin. Because of this, we have pursued an alternative therapy to treat these pathogens using bacteriophage lysins. The bacteriophage lysin PlySs2 is derived from an S. suis phage and displays potent lytic activity against most strains of that species including serotypes 2 and 9. At 64 μg/ml, PlySs2 reduced multiple serotypes of S. suis by 5 to 6-logs within 1 hour in vitro and exhibited a minimum inhibitory concentration (MIC) of 32 μg/ml for a S. suis serotype 2 strain and 64 μg/ml for a serotype 9 strain. Using a single 0.1-mg dose, the colonizing S. suis serotype 9 strain was reduced from the murine intranasal mucosa by >4 logs; a 0.1-mg dose of gentamicin reduced S. suis by <3-logs. A combination of 0.05 mg PlySs2 + 0.05 mg gentamicin reduced S. suis by >5-logs. While resistance to gentamicin was induced after systematically increasing levels of gentamicin in an S. suis culture, the same protocol resulted in no observable resistance to PlySs2. Thus, PlySs2 has both broad and high killing activity against multiple serotypes and strains of S. suis, making it a possible tool in the control and prevention of S. suis infections in pigs and humans.

The Phage Lysin PlySs2 Decolonizes Streptococcus suis from Murine Intranasal Mucosa

PubMed Central

Gilmer, Daniel B.; Schmitz, Jonathan E.; Thandar, Mya; Euler, Chad W.; Fischetti, Vincent A.

2017-01-01

Streptococcus suis infects pigs worldwide and may be zoonotically transmitted to humans with a mortality rate of up to 20%. S. suis has been shown to develop in vitro resistance to the two leading drugs of choice, penicillin and gentamicin. Because of this, we have pursued an alternative therapy to treat these pathogens using bacteriophage lysins. The bacteriophage lysin PlySs2 is derived from an S. suis phage and displays potent lytic activity against most strains of that species including serotypes 2 and 9. At 64 μg/ml, PlySs2 reduced multiple serotypes of S. suis by 5 to 6-logs within 1 hour in vitro and exhibited a minimum inhibitory concentration (MIC) of 32 μg/ml for a S. suis serotype 2 strain and 64 μg/ml for a serotype 9 strain. Using a single 0.1-mg dose, the colonizing S. suis serotype 9 strain was reduced from the murine intranasal mucosa by >4 logs; a 0.1-mg dose of gentamicin reduced S. suis by <3-logs. A combination of 0.05 mg PlySs2 + 0.05 mg gentamicin reduced S. suis by >5-logs. While resistance to gentamicin was induced after systematically increasing levels of gentamicin in an S. suis culture, the same protocol resulted in no observable resistance to PlySs2. Thus, PlySs2 has both broad and high killing activity against multiple serotypes and strains of S. suis, making it a possible tool in the control and prevention of S. suis infections in pigs and humans. PMID:28046082

Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis.

PubMed

Park, A Young J; Wang, Joshua; Jayne, Jordanna; Fukushima, Lynn; Rao, Adupa P; D'Argenio, David Z; Beringer, Paul M

2018-06-18

Over the past decade, the prevalence of infections involving Methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics has shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate 200 mg PO or IV once daily for 3 doses, with minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetics was performed using maximum-likelihood, expectation maximization method, and the disposition of TZD was described by a 2-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean (%CV) sputum-to-unbound plasma penetration ratio of 2.88 (50.3). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 L/h, 61.6 ± 6.94 L, and 1.04 ± 0.232 respectively. The total clearance is higher in CF patients when compared with healthy volunteers; however, it is similar to published data in patients with complicated skin and skin structure infections (cSSSI). This study demonstrates the oral bioavailability of tedizolid is excellent in patients with CF, and the plasma pharmacokinetics are similar to that reported for patients with cSSSI. Copyright © 2018 American Society for Microbiology.

Medical Research and Evaluation Facility (MREF) and studies supporting the medical chemical defense program. Determination of the minimum effective pyridostigmine pretreatment dose in monkeys challenged with 5 x LD50 Soman and treated with atropine/2-PAM. Final report, 22 October 1992-31 August 1993

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

Olson, C.T.; Menton, R.G.; Kiser, R.C.

This task was conducted to determine the minimum dose of pyridostigmine (PYR), and the associated level of erythrocyte acetycholinesterase inhibition (AChE-I), that provides protection from 5 X 48-br GD LD50 of untreated monkeys. Monkeys were injected im with GD and treated with 0.4 mg atropine (ATR) free base and 25.7 mg pralidoxime (2-PAM) per kg BW.

Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

PubMed

Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

2017-01-01

We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

The risk of serious infection with biologics in treating patients with rheumatoid arthritis: A Systematic Review and Meta-analysis

PubMed Central

Singh, Jasvinder A.; Cameron, Chris; Noorbaloochi, Shahrzad; Cullis, Tyler; Tucker, Matthew; Christensen, Robin; Ghogomu, Elizabeth Tanjong; Coyle, Doug; Clifford, Tammy; Tugwell, Peter; Wells, George A.

2015-01-01

Background Serious infections are a major concern for patients considering treatmentsfor rheumatoid arthritis (RA). Evidence is inconsistent on whether biologicsare associated with an increased risk of serious infection compared to traditional disease-modifying anti-rheumatic drugs (DMARDs). Methods A systematic literature search was undertaken using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and www.clinicaltrials.gov from inception through February 11, 2014. Search terms included biologics, rheumatoid arthritis and their synonyms. Trials were eligible for inclusion if they included any of the biologics and reported serious infections. The risk of bias was assessed using the Cochrane Risk of Bias Tool. We conducted a Bayesian network meta-analysis,using a binomial likelihood model, of published trials to assess the risk of serious infections of biologics in RA patients, compared to traditional DMARDs. Findings The systematic review identified 106 trials that included RA patients on biologic and reported on serious infections. Compared to traditional DMARDs, standard-dose biologic (odds ratio [OR],1.31; 95% credible interval [CrI], 1.09 to 1.58) andhigh-dose biologic (OR, 1.90; 95% Crl, 1.50 to 2.39) were associated with an increased risk of serious infections, while low-dose biologics (OR, 0.93; 95% CrI, 0.65 to 1.33) were not. The risk was lower in patients who are methotrexate naïve compared withtraditional DMARD- or anti-TNF-biologic-experienced. The absolute increase in the number of serious infectionsper 1000 patients treated each year compared to traditional DMARDs ranged from 6 for standard-dose biologic to 55 for combination biologic therapy. Interpretation Standard-dose and high-dose biologics (with/without traditional DMARDs) are associated with an increase in serious infections compared to traditional DMARDs in RA, while low-dose biologics are not.Clinicians should discuss the balance between benefit and harm with the individual RA patient before initiating biologic therapy. Funding Rheumatology division at the University of Alabama at Birmingham. PMID:25975452

Analysis of Radiation Impact on White Mice through Radiation Dose Mapping in Medical Physics Laboratory

NASA Astrophysics Data System (ADS)

Sutikno, Madnasri; Susilo; Arya Wijayanti, Riza

2016-08-01

A study about X-ray radiation impact on the white mice through radiation dose mapping in Medical Physic Laboratory is already done. The purpose of this research is to determine the minimum distance of radiologist to X-ray instrument through treatment on the white mice. The radiation exposure doses are measured on the some points in the distance from radiation source between 30 cm up to 80 with interval of 30 cm. The impact of radiation exposure on the white mice and the effects of radiation measurement in different directions are investigated. It is founded that minimum distance of radiation worker to radiation source is 180 cm and X-ray has decreased leukocyte number and haemoglobin and has increased thrombocyte number in the blood of white mice.

Update of the human parvovirus B19 biology.

PubMed

Servant-Delmas, A; Morinet, F

2016-02-01

Since its discovery, the human parvovirus B19 (B19V) has been associated with many clinical situations in addition to the prototype clinical manifestations, i.e. erythema infectiosum and erythroblastopenia crisis. The clinical significance of the viral B19V DNA persistence in sera after acute infection remains largely unknown. Such data may constitute a new clinical entity and is discussed in this manuscript. In 2002, despite the genetic diversity among B19V viruses has been reported to be very low, the description of markedly distinct sequences showed a new organization into three genotypes. The most recent common ancestor for B19V genotypes was estimated at early 1800s. B19V replication is enhanced by hypoxia and this might to explain the high viral load detected by quantitative PCR in the sera of infected patients. The minimum infectious dose necessary to transmit B19V infection by the transfusion of labile blood products remains unclear. At the opposite, the US Food and Drug Administration proposed a limit of 10(4)IU/mL of viral DNA in plasma pools used for the production of plasma derivatives. Recently, a new human parvovirus (PARV4) has been discovered. The consequences on blood transfusion of this blood-borne agent and its pathogenicity are still unknown. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

PubMed

Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

2015-07-31

Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Amhezole, A Novel Fungal Secondary Metabolite from Aspergillus terreus for Treatment of Microbial Mouth Infection.

PubMed

Awaad, Amani S; Al-Mudhayyif, Hind A; Al-Othman, Monerah R; Zain, Mohamed E; El-Meligy, Reham M

2017-03-01

Bio-guided fractionation of Aspergillus terreus extract leads to isolation of a novel terpenoidal secondary metabolite. The isolated compound and the total alcoholic extract of Aspergillus terreus showed a remarkable activity against microbial mouth infections; namely, Candida albicans, Lactobacillus acidophilus, Streptococcus gordonii, and S. mutan. Moreover, the Minimum Inhibitory Concentration of the isolated compound was determined and showed low values. The combination of each of the alcoholic extract of A. terreus and the isolated compound Coe-Comfort tissue conditioner inhibited the growth of Candida albicans at concentrations of 500 and 7.81 µg/mL, respectively, Lactobacillus acidophilus at concentrations of 250 and 7.81 µg/mL, respectively, Streptococcus gordonii at concentrations of 1000 and 62.50 µg/mL, respectively, and S. mutans at concentrations of 1000 and 125 µg/mL, respectively. The oral dosing of the extract and the isolated compound did not show any significant effect on the activity of alanine aminotransferase, aspirate aminotransferase, and the levels of blood urea and serum creatinine. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluation of antibacterial activities of flomoxef against ESBL producing Enterobacteriaceae analyzed by Monte Carlo simulation.

PubMed

Ito, Akinobu; Tatsumi, Yumiko Matsuo; Wajima, Toshihiro; Nakamura, Rio; Tsuji, Masakatsu

2013-04-01

The growing number of infection caused by extended-spectrum beta-lactamase (ESBL) producing pathogens has prompted a more rational use of available antibiotics because of the paucity of new, effective agents. Flomoxef (FMOX) is one of the beta-lactam antibiotic which is stable against beta-lactamase. In this study, the antibacterial activity of FMOX was investigated, and Monte Carlo Simulation was conducted to determine the appropriate dosing regimens of FMOX based on the probability of target attainment (TA%) at the critical drug exposure metric of time that drug concentrations remain above 40% (showing bacteriostatic effect) or 70% (showing bactericidal effect) of time during which plasma concentration above minimum inhibitory concentration (MIC) of the drug (T(>MIC)) against the ESBL producing Enterobacteriaceae. The effective regimens to achieve 80% of TA% at 70% of T(>MIC) were 1 g every 8 hours with 2-4 hours infusion, and 1 g every 6 hours with 1-4 hours infusion. Moreover, all the tested regimens were effective to achieve 80% of TA% at 40% of T(>MIC). These results of pharmacokinetics/ pharmacodynamics (PK/PD) modeling showed the potential efficacy of FMOX against bacterial infections caused by ESBL producing Enterobacteriaceae.

Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine

PubMed Central

Micek, Mark A.; Blanco, Ana Judith; Beck, Ingrid A.; Dross, Sandra; Matunha, Laurinda; Montoya, Pablo; Seidel, Kristy; Gantt, Soren; Matediane, Eduardo; Jamisse, Lilia; Gloyd, Stephen; Frenkel, Lisa M.

2011-01-01

Background In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection. Methods We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time. Results Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P =.006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P =.001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P =.017, compared with established in utero infection). Conclusions The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals. PMID:20384494

Course and transmission characteristics of oral low-dose infection of domestic pigs and European wild boar with a Caucasian African swine fever virus isolate.

PubMed

Pietschmann, Jana; Guinat, Claire; Beer, Martin; Pronin, Valery; Tauscher, Kerstin; Petrov, Anja; Keil, Günther; Blome, Sandra

2015-07-01

In 2007, African swine fever virus (ASFV) was introduced into the Transcaucasian countries and Russia. Since then, it has spread alarmingly and reached the European Union. ASFV strains are highly virulent and lead to almost 100% mortality under experimental conditions. However, the possibility of dose-dependent disease courses has been discussed. For this reason, a study was undertaken to assess the risk of chronic disease and the establishment of carriers upon low-dose oronasal infection of domestic pigs and European wild boar. It was demonstrated that very low doses of ASFV are sufficient to infect especially weak or runted animals by the oronasal route. Some of these animals did not show clinical signs indicative of ASF, and they developed almost no fever. However, no changes were observed in individual animal regarding the onset, course and outcome of infection as assessed by diagnostic tests. After amplification of ASFV by these animals, pen- and stablemates became infected and developed acute lethal disease with similar characteristics in all animals. Thus, we found no indication of prolonged or chronic individual courses upon low-dose infection in either species. The scattered onset of clinical signs and pathogen detection within and among groups confirms moderate contagiosity that is strongly linked with blood contact. In conclusion, the prolonged course at the "herd level" together with the exceptionally low dose that proved to be sufficient to infect a runted wild boar could be important for disease dynamics in wild-boar populations and in backyard settings.

EFFECTS OF WEST NILE VIRUS DOSE AND EXTRINSIC INCUBATION TEMPERATURE ON TEMPORAL PROGRESSION OF VECTOR COMPETENCE IN CULEX PIPIENS QUINQUEFASCIATUS

PubMed Central

ANDERSON, SHERI L.; RICHARDS, STEPHANIE L.; TABACHNICK, WALTER J.; SMARTT, CHELSEA T.

2010-01-01

Culex pipiens quinquefasciatus were fed blood containing either 7.0 ± 0.1 logs plaque-forming units (pfu)/ml (high dose) or 5.9 ± 0.1 logs pfu/ml (low dose) of West Nile virus and held at extrinsic incubation temperatures (EIT) of 28°C or 25°C. Approximately 20 mosquitoes per dose were collected after incubation periods (IP) of 4, 6, 8, and 12 days postinfection (dpi). Infection rates were influenced by EIT and virus dose but not by IP. Body titer was significantly higher for mosquitoes fed the high dose and held at 28°C at the later IPs (6, 8, and 12 dpi). However, leg titer was significantly higher for mosquitoes at the later IPs but did not differ between EITs or doses. Because infection rates varied with EIT and dose, there is likely a midgut infection barrier influenced by these factors that is not influenced by IP. Dissemination rates were influenced by all 3 factors consistent with the presence of a midgut escape barrier. Dissemination rate, body titer, and leg titer were dependent on IP, indicating the need to investigate multiple time points in vector competence studies to elucidate critical events in infection and dissemination. PMID:20402358

Effects of West Nile virus dose and extrinsic incubation temperature on temporal progression of vector competence in Culex pipiens quinquefasciatus.

PubMed

Anderson, Sheri L; Richards, Stephanie L; Tabachnick, Walter J; Smartt, Chelsea T

2010-03-01

Culex pipiens quinquefasciatus were fed blood containing either 7.0 +/- 0.1 logs plaque-forming units (pfu)/ml (high dose) or 5.9 +/- 0.1 logs pfu/ml (low dose) of West Nile virus and held at extrinsic incubation temperatures (EIT) of 28 degrees C or 25 degrees C. Approximately 20 mosquitoes per dose were collected after incubation periods (IP) of 4, 6, 8, and 12 days postinfection (dpi). Infection rates were influenced by EIT and virus dose but not by IP. Body titer was significantly higher for mosquitoes fed the high dose and held at 28 degrees C at the later IPs (6, 8, and 12 dpi). However, leg titer was significantly higher for mosquitoes at the later IPs but did not differ between EITs or doses. Because infection rates varied with EIT and dose, there is likely a midgut infection barrier influenced by these factors that is not influenced by IP. Dissemination rates were influenced by all 3 factors consistent with the presence of a midgut escape barrier. Dissemination rate, body titer, and leg titer were dependent on IP, indicating the need to investigate multiple time points in vector competence studies to elucidate critical events in infection and dissemination.

Blood schizontocidal activity of WR 238605 (Tafenoquine) against Plasmodium cynomolgi and Plasmodium fragile infections in rhesus monkeys.

PubMed

Puri, S K; Dutta, G P

2003-04-01

A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.

Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

PubMed

Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

2018-04-24

To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

Norwalk virus: how infectious is it?

PubMed

Teunis, Peter F M; Moe, Christine L; Liu, Pengbo; Miller, Sara E; Lindesmith, Lisa; Baric, Ralph S; Le Pendu, Jacques; Calderon, Rebecca L

2008-08-01

Noroviruses are major agents of viral gastroenteritis worldwide. The infectivity of Norwalk virus, the prototype norovirus, has been studied in susceptible human volunteers. A new variant of the hit theory model of microbial infection was developed to estimate the variation in Norwalk virus infectivity, as well as the degree of virus aggregation, consistent with independent (electron microscopic) observations. Explicit modeling of viral aggregation allows us to express virus infectivity per single infectious unit (particle). Comparison of a primary and a secondary inoculum showed that passage through a human host does not change Norwalk virus infectivity. We estimate the average probability of infection for a single Norwalk virus particle to be close to 0.5, exceeding that reported for any other virus studied to date. Infected subjects had a dose-dependent probability of becoming ill, ranging from 0.1 (at a dose of 10(3) NV genomes) to 0.7 (at 10(8) virus genomes). A norovirus dose response model is important for understanding its transmission and essential for development of a quantitative risk model. Norwalk virus is a valuable model system to study virulence because genetic factors are known for both complete and partial protection; the latter can be quantitatively described as heterogeneity in dose response models.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

NASA Astrophysics Data System (ADS)

Smith, Amber M.; Smith, Amanda P.

2016-12-01

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza.

PubMed

Smith, Amber M; Smith, Amanda P

2016-12-15

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

Deciphering the Counterplay of Aspergillus fumigatus Infection and Host Inflammation by Evolutionary Games on Graphs

NASA Astrophysics Data System (ADS)

Pollmächer, Johannes; Timme, Sandra; Schuster, Stefan; Brakhage, Axel A.; Zipfel, Peter F.; Figge, Marc Thilo

2016-06-01

Microbial invaders are ubiquitously present and pose the constant risk of infections that are opposed by various defence mechanisms of the human immune system. A tight regulation of the immune response ensures clearance of microbial invaders and concomitantly limits host damage that is crucial for host viability. To investigate the counterplay of infection and inflammation, we simulated the invasion of the human-pathogenic fungus Aspergillus fumigatus in lung alveoli by evolutionary games on graphs. The layered structure of the innate immune system is represented by a sequence of games in the virtual model. We show that the inflammatory cascade of the immune response is essential for microbial clearance and that the inflammation level correlates with the infection-dose. At low infection-doses, corresponding to daily inhalation of conidia, the resident alveolar macrophages may be sufficient to clear infections, however, at higher infection-doses their primary task shifts towards recruitment of neutrophils to infection sites.

Deciphering the Counterplay of Aspergillus fumigatus Infection and Host Inflammation by Evolutionary Games on Graphs

PubMed Central

Pollmächer, Johannes; Timme, Sandra; Schuster, Stefan; Brakhage, Axel A.; Zipfel, Peter F.; Figge, Marc Thilo

2016-01-01

Microbial invaders are ubiquitously present and pose the constant risk of infections that are opposed by various defence mechanisms of the human immune system. A tight regulation of the immune response ensures clearance of microbial invaders and concomitantly limits host damage that is crucial for host viability. To investigate the counterplay of infection and inflammation, we simulated the invasion of the human-pathogenic fungus Aspergillus fumigatus in lung alveoli by evolutionary games on graphs. The layered structure of the innate immune system is represented by a sequence of games in the virtual model. We show that the inflammatory cascade of the immune response is essential for microbial clearance and that the inflammation level correlates with the infection-dose. At low infection-doses, corresponding to daily inhalation of conidia, the resident alveolar macrophages may be sufficient to clear infections, however, at higher infection-doses their primary task shifts towards recruitment of neutrophils to infection sites. PMID:27291424

Decreased ciprofloxacin susceptibility in Salmonella Typhi and Paratyphi infections in ill-returned travellers: the impact on clinical outcome and future treatment options.

PubMed

Hassing, R-J; Goessens, W H F; Mevius, D J; van Pelt, W; Mouton, J W; Verbon, A; van Genderen, P J

2013-10-01

The emergence of decreased ciprofloxacin susceptibility (DCS) in Salmonella enterica serovar Typhi and serovar Paratyphi A, B or C limits treatment options. We studied the impact of DCS isolates on the fate of travellers returning with enteric fever and possible alternative treatment options. We evaluated the clinical features, susceptibility data and efficacy of empirical treatment in patients with positive blood cultures of a DCS isolate compared to patients infected with a ciprofloxacin-susceptible (CS) isolate in the period from January 2002 to August 2008. In addition, the pharmacokinetic and pharmacodynamic parameters of ciprofloxacin, levofloxacin and gatifloxacin were determined to assess if increasing the dose would result in adequate unbound fraction of the drug 24-h area under the concentration-time curve/minimum inhibitory concentration (ƒAUC(0-24)/MIC) ratio. Patients with DCS more often returned from the Indian subcontinent and had a longer fever clearance time and length of hospital stay compared to patients in whom the initial empirical therapy was adequate. The mean ƒAUC(0-24)/MIC was 41.3 ± 18.8 in the patients with DCS and 585.4 ± 219 in patients with a CS isolate. For DCS isolates, the mean ƒAUC0-24/MIC for levofloxacin was 60.5 ± 28.7 and for gatifloxacin, it was 97.9 ± 28.0. Increasing the dose to an adequate ƒAUC(0-24)/MIC ratio will lead to conceivably toxic drug levels in 50% of the patients treated with ciprofloxacin. Emerging DCS isolates has led to the failure of empirical treatment in ill-returned travellers. We demonstrated that, in some cases, an adequate ƒAUC(0-24)/MIC ratio could be achieved by increasing the dose of ciprofloxacin or by the use of alternative fluoroquinolones.

Cost-effectiveness of single dose cefotaxime plus metronidazole compared with three doses each of cefuroxime plus metronidazole for the prevention of wound infection after colorectal surgery.

PubMed

Davey, P; Lynch, B; Malek, M; Byrne, D; Thomas, P

1992-12-01

The cost-effectiveness of prophylaxis for colonic surgery with single dose cefotaxime plus metronidazole has been compared with that of three doses each of cefuroxime plus metronidazole, by analysing data from a previously published study supplemented with additional data on the hospital and community costs of wound infection after colonic surgery. The original trial included 942 patients having elective colonic surgery in 14 hospitals. The data on costs of wound infection were collected from a further 124 patients undergoing elective colonic surgery at Ninewells Hospital. All these patients received a three dose regimen of cefuroxime plus metronidazole. The Dundee patients received three injections of 0.75 g cefuroxime at 8-hourly intervals whereas the trial patients received a single dose of 1.5 g followed by two further doses of 0.75 g at 8-hourly intervals. The cefuroxime prophylaxis regimen used in the trial cost 24.16 pounds per patient more than the cefotaxime regimen. The components of the excess cost were drugs (15.18 pounds), equipment (6.14 pounds) and staff time (2.84 pounds). The median cost to the hospital of a wound infection was 978.04 pounds (95% CI 482.04 pounds to 1521.22 pounds). The components of the hospital cost of wound infection were: hotel costs 858 pounds (88%), dressing costs 83.02 pounds (8%) and drug costs (excluding prophylaxis) 37.02 pounds (4%). Only five patients received additional antibiotic treatment in the community, and only one required home visits from the District Nurse. Applying the difference in costs of prophylaxis as 21 pounds (costs of drugs plus equipment) and the cost per wound infection as 1000 pounds to the observed wound infection rate of 7% in the cefuroxime group, the wound infection rate in the cefotaxime group would have to be 2.1% higher for the two regimens to be equally cost-effective. The probability that such a difference in efficacy exists is 0.088. A model was developed to calculate the probability of equal cost-effectiveness over a range of costs of wound infection.

Rapid Antibiotic Susceptibility Testing of Uropathogenic E. coli by Tracking Submicron Scale Motion of Single Bacterial Cells.

PubMed

Syal, Karan; Shen, Simon; Yang, Yunze; Wang, Shaopeng; Haydel, Shelley E; Tao, Nongjian

2017-08-25

To combat antibiotic resistance, a rapid antibiotic susceptibility testing (AST) technology that can identify resistant infections at disease onset is required. Current clinical AST technologies take 1-3 days, which is often too slow for accurate treatment. Here we demonstrate a rapid AST method by tracking sub-μm scale bacterial motion with an optical imaging and tracking technique. We apply the method to clinically relevant bacterial pathogens, Escherichia coli O157: H7 and uropathogenic E. coli (UPEC) loosely tethered to a glass surface. By analyzing dose-dependent sub-μm motion changes in a population of bacterial cells, we obtain the minimum bactericidal concentration within 2 h using human urine samples spiked with UPEC. We validate the AST method using the standard culture-based AST methods. In addition to population studies, the method allows single cell analysis, which can identify subpopulations of resistance strains within a sample.

Infectivity, transmission and pathogenicity of H5 highly pathogenic avian influenza clade 2.3.4.4 (H5N8 and H5N2) United States index viruses in Pekin ducks and Chinese geese.

PubMed

Pantin-Jackwood, Mary J; Costa-Hurtado, Mar; Bertran, Kateri; DeJesus, Eric; Smith, Diane; Swayne, David E

2017-06-07

In late 2014, a H5N8 highly pathogenic avian influenza (HPAI) virus, clade 2.3.4.4, spread by migratory waterfowl into North America reassorting with low pathogenicity AI viruses to produce a H5N2 HPAI virus. Since domestic waterfowl are common backyard poultry frequently in contact with wild waterfowl, the infectivity, transmissibility, and pathogenicity of the United States H5 HPAI index viruses (H5N8 and H5N2) was investigated in domestic ducks and geese. Ducks infected with the viruses had an increase in body temperature but no or mild clinical signs. Infected geese did not show increase in body temperature and most only had mild clinical signs; however, some geese presented severe neurological signs. Ducks became infected and transmitted the viruses to contacts when inoculated with high virus doses [(10 4 and 10 6 50% embryo infective dose (EID 50 )], but not with a lower dose (10 2 EID 50 ). Geese inoculated with the H5N8 virus became infected regardless of the virus dose given, and transmitted the virus to direct contacts. Only geese inoculated with the higher doses of the H5N2 and their contacts became infected, indicating differences in infectivity between the two viruses and the two waterfowl species. Geese shed higher titers of virus and for a longer period of time than ducks. In conclusion, the H5 HPAI viruses can infect domestic waterfowl and easily transmit to contact birds, with geese being more susceptible to infection and disease than ducks. The disease is mostly asymptomatic, but infected birds shed virus for several days representing a risk to other poultry species.

Virulence evolution in response to anti-infection resistance: toxic food plants can select for virulent parasites of monarch butterflies.

PubMed

de Roode, J C; de Castillejo, C Lopez Fernandez; Faits, T; Alizon, S

2011-04-01

Host resistance to parasites can come in two main forms: hosts may either reduce the probability of parasite infection (anti-infection resistance) or reduce parasite growth after infection has occurred (anti-growth resistance). Both resistance mechanisms are often imperfect, meaning that they do not fully prevent or clear infections. Theoretical work has suggested that imperfect anti-growth resistance can select for higher parasite virulence by favouring faster-growing and more virulent parasites that overcome this resistance. In contrast, imperfect anti-infection resistance is thought not to select for increased parasite virulence, because it is assumed that it reduces the number of hosts that become infected, but not the fitness of parasites in successfully infected hosts. Here, we develop a theoretical model to show that anti-infection resistance can in fact select for higher virulence when such resistance reduces the effective parasite dose that enters a host. Our model is based on a monarch butterfly-parasite system in which larval food plants confer resistance to the monarch host. We carried out an experiment and showed that this environmental resistance is most likely a form of anti-infection resistance, through which toxic food plants reduce the effective dose of parasites that initiates an infection. We used these results to build a mathematical model to investigate the evolutionary consequences of food plant-induced resistance. Our model shows that when the effective infectious dose is reduced, parasites can compensate by evolving a higher per-parasite growth rate, and consequently a higher intrinsic virulence. Our results are relevant to many insect host-parasite systems, in which larval food plants often confer imperfect anti-infection resistance. Our results also suggest that - for parasites where the infectious dose affects the within-host dynamics - vaccines that reduce the effective infectious dose can select for increased parasite virulence. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.

Retrospective cohort study of bronchial doses and radiation-induced atelectasis after stereotactic body radiation therapy of lung tumors located close to the bronchial tree.

PubMed

Karlsson, Kristin; Nyman, Jan; Baumann, Pia; Wersäll, Peter; Drugge, Ninni; Gagliardi, Giovanna; Johansson, Karl-Axel; Persson, Jan-Olov; Rutkowska, Eva; Tullgren, Owe; Lax, Ingmar

2013-11-01

To evaluate the dose-response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm(3) up to 2.0 cm(3)]) was statistically evaluated with survival analysis models. Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm(3) (D(0.1cm3)) was used for further analysis. The median value of D(0.1cm3) (α/β = 3 Gy) was EQD(2,LQ) = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD(2,LQ) = 210 Gy3, and for patients who did not develop atelectasis, EQD(2,LQ) = 105 Gy3. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). In this retrospective study a significant dose-response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown. Copyright © 2013 Elsevier Inc. All rights reserved.

SU-F-BRD-08: Guaranteed Epsilon-Optimal Treatment Plans with Minimum Number of Beams for SBRT Using RayStation

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

Yarmand, H; Winey, B; Craft, D

2014-06-15

Purpose: To efficiently find quality-guaranteed treatment plans with the minimum number of beams for stereotactic body radiation therapy using RayStation. Methods: For a pre-specified pool of candidate beams we use RayStation (a treatment planning software for clinical use) to identify the deliverable plan which uses all the beams with the minimum dose to organs at risk (OARs) and dose to the tumor and other structures in specified ranges. Then use the dose matrix information for the generated apertures from RayStation to solve a linear program to find the ideal plan with the same objective and constraints allowing use of allmore » beams. Finally we solve a mixed integer programming formulation of the beam angle optimization problem (BAO) with the objective of minimizing the number of beams while remaining in a predetermined epsilon-optimality of the ideal plan with respect to the dose to OARs. Since the treatment plan optimization is a multicriteria optimization problem, the planner can exploit the multicriteria optimization capability of RayStation to navigate the ideal dose distribution Pareto surface and select a plan of desired target coverage versus OARs sparing, and then use the proposed technique to reduce the number of beams while guaranteeing quality. For the numerical experiments two liver cases and one lung case with 33 non-coplanar beams are considered. Results: The ideal plan uses an impractically large number of beams. The proposed technique reduces the number of beams to the range of practical application (5 to 9 beams) while remaining in the epsilon-optimal range of 1% to 5% optimality gap. Conclusion: The proposed method can be integrated into a general algorithm for fast navigation of the ideal dose distribution Pareto surface and finding the treatment plan with the minimum number of beams, which corresponds to the delivery time, in epsilon-optimality range of the desired ideal plan. The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center and partially by RaySearch Laboratories.« less

Pyrantel

MedlinePlus

Reese's® Pinworm Medicine ... antiworm medication, is used to treat roundworm, hookworm, pinworm, and other worm infections.This medication is sometimes ... usually is taken as a single dose for pinworm and roundworm infections. The dose usually is repeated ...

Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients.

PubMed

Sung, Cynthia; Wei, Yuan; Watanabe, Satoru; Lee, How Sung; Khoo, Yok Moi; Fan, Lu; Rathore, Abhay P S; Chan, Kitti Wing-Ki; Choy, Milly M; Kamaraj, Uma S; Sessions, October M; Aw, Pauline; de Sessions, Paola F; Lee, Bernett; Connolly, John E; Hibberd, Martin L; Vijaykrishna, Dhanasekaran; Wijaya, Limin; Ooi, Eng Eong; Low, Jenny Guek-Hong; Vasudevan, Subhash G

2016-08-01

CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir's potential value for treatment of other flaviruses such as Zika virus should be investigated urgently. ClinicalTrials.gov NCT01619969.

FREQUENCY OF WOUND INFECTION IN NON-PERFORATED APPENDICITIS WITH USE OF SINGLE DOSE PREOPERATIVE ANTIBIOTICS.

PubMed

Ali, Kishwar; Latif, Humera; Ahmad, Sajjad

2015-01-01

Antibiotics are used both pre and post-operatively in acute appendicitis for preventing wound infection. It has been observed that the routine use of post-operative antibiotics is not necessary in cases of non-perforated appendicitis as only prophylactic antibiotics are sufficient to prevent wound infection. The aim of this study was to see the frequency of wound infection in non-perforated appendicitis with single dose preoperative antibiotics only. This observational study was conducted at the Department of Surgery, Ayub Medical College, Abbottabad from May to November 2014. A total of 121 patients with non-perforated appendicitis were included in the study. Only single dose preoperative antibiotics were used. The patients were followed for wound infection till 8th post-operative day. 121 patients, 56 (46.28%) male and 65 (53.72%) female were included in the study. The mean age of patients was 27.41 +/- 7.12 years with an age range of 18 to 45 years. In the entire series, 7 (5.78%) patients developed wound infection. The infection was minor which settled with conservative therapy. Prophylactic antibiotics were found efficacious in 114 (94.21%) patients. There was no significant association between wound infection and age and gender. Single dose preoperative antibiotics were found effective in controlling post-operative wound infection without the need of extending the antibiotics to post-operative period in cases of non-perforated appendicitis.

Simvastatin in the treatment of asthma: lack of steroid-sparing effect.

PubMed

Cowan, Douglas C; Cowan, Jan O; Palmay, Rochelle; Williamson, Avis; Taylor, D Robin

2010-10-01

Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the steroid-sparing effect of statin treatment has not been carried out. A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control ('minimum' dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥ 2%. 43 patients completed the study. There was no significant difference in 'minimum' inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 μg daily (0-250) vs 100 μg daily (0-250), p=0.931). 'Minimum' dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 μg daily (0-100) for both, p=0.620). In those patients who reached 0 μg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV(1)) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033). Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.

Incidental irradiation of mediastinal and hilar lymph node stations during 3D-conformal radiotherapy for non-small cell lung cancer.

PubMed

Kepka, Lucyna; Bujko, Krzysztof; Zolciak-Siwinska, Agnieszka; Garmol, Dariusz

2008-01-01

To estimate the doses of incidental irradiation in particular lymph node stations (LNS) in different extents of elective nodal irradiation (ENI) in 3D-conformal radiotherapy (3D-CRT) for non-small cell lung cancer (NSCLC). METHODS; Doses of radiotherapy were estimated for particular LNS delineated according to the recommendations of the University of Michigan in 220 patients treated using 3D-CRT with different (extended, limited and omitted) extents of ENI. Minimum doses and volumes of LNS receiving 40 Gy or more (V40) were compared for omitted vs. limited+ extended ENI and limited vs. extended ENI. For omission of the ENI the minimum doses and V40 for particular LNS were significantly lower than for patients treated with ENI. For the limited ENI group, the minimum doses for LNS 5, 6 lower parts of 3A and 3P (not included in the elective area) did not differ significantly from doses given to respective LNS for extended ENI group. When the V40 values for extended and limited ENI were compared, no significant differences were seen for any LNS, except for group 1/2R, 1/2L. Incidental irradiation of untreated LNS seems play a part in case of limited ENI, but not in cases without ENI. For subclinical disease the delineation of uninvolved LNS 5, 6, and lower parts of 3A, 3P may be not necessary, because these stations receive the substantial part of irradiation incidentally, if LNS 4R, 4L, 7, and ipsilateral hilum are included in the elective area while this is not case for stations 1 and 2.

Safety and infectivity of two doses of live-attenuated recombinant cold-passaged human parainfluenza type 3 virus vaccine rHPIV3cp45 in HPIV3-seronegative young children.

PubMed

Englund, Janet A; Karron, Ruth A; Cunningham, Coleen K; Larussa, Philip; Melvin, Ann; Yogev, Ram; Handelsman, Ed; Siberry, George K; Thumar, Bhavanji; Schappell, Elizabeth; Bull, Catherine V; Chu, Helen Y; Schaap-Nutt, Anne; Buchholz, Ursula; Collins, Peter L; Schmidt, Alexander C

2013-11-19

Human parainfluenza virus type 3 (HPIV3) is a common cause of upper and lower respiratory tract illness in infants and young children. Live-attenuated cold-adapted HPIV3 vaccines have been evaluated in infants but a suitable interval for administration of a second dose of vaccine has not been defined. HPIV3-seronegative children between the ages of 6 and 36 months were randomized 2:1 in a blinded study to receive two doses of 10⁵ TCID₅₀ (50% tissue culture infectious dose) of live-attenuated, recombinant cold-passaged human PIV3 vaccine (rHPIV3cp45) or placebo 6 months apart. Serum antibody levels were assessed prior to and approximately 4-6 weeks after each dose. Vaccine virus infectivity, defined as detection of vaccine-HPIV3 in nasal wash and/or a≥4-fold rise in serum antibody titer, and reactogenicity were assessed on days 3, 7, and 14 following immunization. Forty HPIV3-seronegative children (median age 13 months; range 6-35 months) were enrolled; 27 (68%) received vaccine and 13 (32%) received placebo. Infectivity was detected in 25 (96%) of 26 evaluable vaccinees following doses 1 and 9 of 26 subject (35%) following dose 2. Among those who shed virus, the median duration of viral shedding was 12 days (range 6-15 days) after dose 1 and 6 days (range 3-8 days) after dose 2, with a mean peak log₁₀ viral titer of 3.4 PFU/mL (SD: 1.0) after dose 1 compared to 1.5 PFU/mL (SD: 0.92) after dose 2. Overall, reactogenicity was mild, with no difference in rates of fever and upper respiratory infection symptoms between vaccine and placebo groups. rHPIV3cp45 was immunogenic and well-tolerated in seronegative young children. A second dose administered 6 months after the initial dose was restricted in those previously infected with vaccine virus; however, the second dose boosted antibody responses and induced antibody responses in two previously uninfected children. Copyright © 2013 Elsevier Ltd. All rights reserved.

Susceptibility patterns of Staphylococcus aureus biofilms in diabetic foot infections.

PubMed

Mottola, Carla; Matias, Carina S; Mendes, João J; Melo-Cristino, José; Tavares, Luís; Cavaco-Silva, Patrícia; Oliveira, Manuela

2016-06-23

Foot infections are a major cause of morbidity in people with diabetes and the most common cause of diabetes-related hospitalization and lower extremity amputation. Staphylococcus aureus is by far the most frequent species isolated from these infections. In particular, methicillin-resistant S. aureus (MRSA) has emerged as a major clinical and epidemiological problem in hospitals. MRSA strains have the ability to be resistant to most β-lactam antibiotics, but also to a wide range of other antimicrobials, making infections difficult to manage and very costly to treat. To date, there are two fifth-generation cephalosporins generally efficacious against MRSA, ceftaroline and ceftobripole, sharing a similar spectrum. Biofilm formation is one of the most important virulence traits of S. aureus. Biofilm growth plays an important role during infection by providing defence against several antagonistic mechanisms. In this study, we analysed the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains isolated from diabetic foot infections. The antibiotic minimum inhibitory concentration (MIC) was determined for ten antimicrobial compounds, along with the minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC), followed by PCR identification of genetic determinants of biofilm production and antimicrobial resistance. Results demonstrate that very high concentrations of the most used antibiotics in treating diabetic foot infections (DFI) are required to inhibit S. aureus biofilms in vitro, which may explain why monotherapy with these agents frequently fails to eradicate biofilm infections. In fact, biofilms were resistant to antibiotics at concentrations 10-1000 times greater than the ones required to kill free-living or planktonic cells. The only antibiotics able to inhibit biofilm eradication on 50 % of isolates were ceftaroline and gentamicin. The results suggest that the antibiotic susceptibility patterns cannot be applied to biofilm established infections. Selection of antimicrobial therapy is a critical step in DFI and should aim at overcoming biofilm disease in order to optimize the outcomes of this complex pathology.

Interactive effects of N-acetylcysteine and antidepressants.

PubMed

Costa-Campos, Luciane; Herrmann, Ana P; Pilz, Luísa K; Michels, Marcus; Noetzold, Guilherme; Elisabetsky, Elaine

2013-07-01

N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression. Copyright © 2013 Elsevier Inc. All rights reserved.

RadNuc: A graphical user interface to deliver dose rate patterns encountered in nuclear medicine with a 137Cs irradiator

PubMed Central

Pasternack, Jordan B.; Howell, Roger W.

2012-01-01

The temporal variations in absorbed dose rates to organs and tissues in the body are very large in diagnostic and therapeutic nuclear medicine. The response of biological endpoints of relevance to radiation safety and therapeutic efficacy are generally modulated by dose rate. Therefore, it is important to understand how the complex dose rate patterns encountered in nuclear medicine impact relevant biological responses. Accordingly, a graphical user interface (GUI) was created to control a cesium-137 irradiator to deliver such dose rate patterns. Methods Visual Basic 6.0 was used to create a user-friendly GUI to control the dose rate by varying the thickness of a mercury attenuator. The GUI facilitates the delivery of a number of dose rate patterns including constant, exponential increase or decrease, and multi-component exponential. Extensive visual feedback is provided by the GUI during both the planning and delivery stages. Results The GUI controlled irradiator can achieve a maximum dose rate of 40 cGy/hr and a minimum dose rate of 0.01 cGy/hr. Addition of machined lead blocks can be used to further reduce the minimum dose rate to 0.0001 cGy/hr. Measured dose rate patterns differed from programmed dose rate patterns in total dose by 3.2% to 8.4%. Conclusion The GUI controlled irradiator is able to accurately create dose rate patterns encountered in nuclear medicine and other related fields. This makes it an invaluable tool for studying the effects of chronic constant and variable low dose rates on biological tissues in the contexts of both radiation protection and clinical administration of internal radionuclides. PMID:23265668

RadNuc: a graphical user interface to deliver dose rate patterns encountered in nuclear medicine with a 137Cs irradiator.

PubMed

Pasternack, Jordan B; Howell, Roger W

2013-02-01

The temporal variations in absorbed dose rates to organs and tissues in the body are very large in diagnostic and therapeutic nuclear medicine. The response of biological endpoints of relevance to radiation safety and therapeutic efficacy is generally modulated by dose rate. Therefore, it is important to understand how the complex dose rate patterns encountered in nuclear medicine impact relevant biological responses. Accordingly, a graphical user interface (GUI) was created to control a cesium-137 irradiator to deliver such dose rate patterns. Visual Basic 6.0 was used to create a user-friendly GUI to control the dose rate by varying the thickness of a mercury attenuator. The GUI facilitates the delivery of a number of dose rate patterns including constant, exponential increase or decrease, and multi-component exponential. Extensive visual feedback is provided by the GUI during both the planning and delivery stages. The GUI controlled irradiator can achieve a maximum dose rate of 40 cGy/h and a minimum dose rate of 0.01 cGy/h. Addition of machined lead blocks can be used to further reduce the minimum dose rate to 0.0001 cGy/h. Measured dose rate patterns differed from programmed dose rate patterns in total dose by 3.2% to 8.4%. The GUI controlled irradiator is able to accurately create dose rate patterns encountered in nuclear medicine and other related fields. This makes it an invaluable tool for studying the effects of chronic constant and variable low dose rates on biological tissues in the contexts of both radiation protection and clinical administration of internal radionuclides. Copyright © 2013 Elsevier Inc. All rights reserved.

Estimation of the Antirelapse Efficacy of Tafenoquine, Using Plasmodium vivax Genotyping

PubMed Central

Beck, Hans-Peter; Wampfler, Rahel; Carter, Nick; Koh, Gavin; Osorio, Lyda; Rueangweerayut, Ronnatrai; Krudsood, Srivcha; Lacerda, Marcus V.; Llanos-Cuentas, Alejandro; Duparc, Stephan; Rubio, Justin P.; Green, Justin A.

2016-01-01

Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse. Clinical Trials Registration. NCT01376167. PMID:26500351

Estimation of the Antirelapse Efficacy of Tafenoquine, Using Plasmodium vivax Genotyping.

PubMed

Beck, Hans-Peter; Wampfler, Rahel; Carter, Nick; Koh, Gavin; Osorio, Lyda; Rueangweerayut, Ronnatrai; Krudsood, Srivcha; Lacerda, Marcus V; Llanos-Cuentas, Alejandro; Duparc, Stephan; Rubio, Justin P; Green, Justin A

2016-03-01

Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse. NCT01376167. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Oncocin derivative Onc72 is highly active against Escherichia coli in a systemic septicaemia infection mouse model.

PubMed

Knappe, Daniel; Fritsche, Stefanie; Alber, Gottfried; Köhler, Gabriele; Hoffmann, Ralf; Müller, Uwe

2012-10-01

The antimicrobial oncocin derivative Onc72 is highly active against a number of Gram-negative bacteria, including resistant strains. Here we study its toxicity and efficacy in a lethal mouse infection model. In an acute toxicity study, purified Onc72 was administered to NMRI mice in four consecutive injections within a period of 24 h as an intraperitoneal bolus. The animals' behaviour was monitored for 5 days, before several organs were examined by histopathology. A lethal Escherichia coli infection model was established and the efficacy of Onc72 was evaluated for different peptide doses considering the survival rates of each dose group and the bacterial counts in blood, lavage and organs. Intraperitoneal bolus injections with single doses of 20 or 40 mg of Onc72 per kg of body weight did not result in any abnormal animal behaviour. No mouse became moribund or died within the studied period. Histopathological examinations revealed no toxic effects. When infected with E. coli at a lethal dose, none of the untreated animals survived the next 24 h, whereas all animals treated three times with Onc72 at doses of ≥5 mg/kg survived the observation period of 5 days. No bacteria were detected in the blood of treated animals after day 5 post-infection. The effective dose (ED(50)) was ∼2 mg/kg. No toxic effects were observed for Onc72 within the studied dose range up to 40 mg/kg, indicating a safety margin of >20.

Vitamin E reduces hepatic fibrosis in mice with Schistosoma japonicum infection.

PubMed

Wang, Xuefeng; Zhang, Rongbo; Du, Jiuwei; Hu, Youying; Xu, Lifa; Lu, Jun; Ye, Song

2012-02-01

To investigate whether vitamin E protects against hepatic fibrosis in mice with Schistosoma japonicum infection, 24 pathogen-free Kunming mice were selected and randomly divided into four groups: control (uninfected, untreated), model (infected, untreated), low-dose intervention (infected, vitamin E-treated, 30 mg/g bodyweight/day) and high-dose intervention (infected, vitamin E-treated, 60 mg/g bodyweight/day). Mice were infected with Schistosoma japonicum by inoculating abdominal skin with snail hosts. The activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were detected in hepatic tissue by colorimetry. The expression levels of laminin (LN), hyaluronic acid (HA), procollagen type Ⅲ (PC-III) and type Ⅳ collagen (IV-C) were detected in the serum by radioimmunoassay. Finally, areas and numbers of granulomas were assessed through histopathology 42 days following treatment. The results revealed that mean areas of granulomas were smaller in the low- and high-dose intervention groups compared to those in the model group. Furthermore, the higher dose of vitamin E resulted in smaller granulomas than the low dose. The levels of LN, HA, PC-III and IV-C in the serum were lower following vitamin E treatment than in the model group. By contrast, activity of SOD, GPx and CAT in hepatic tissue was higher following vitamin E treatment compared to the model group. The activity of MDA was lower in hepatic tissue following vitamin E treatment compared to the model group, but was higher compared to controls. In general, the higher dose of vitamin E affected measurements to a greater extent than the lower dose. In conclusion, vitamin E treatment may reduce the growth of granulomas, slowing the process of hepatic fibrosis, and this effect may be the result of the altered activity of the oxidation-reduction enzyme system.

Accuracy of the dose-shift approximation in estimating the delivered dose in SBRT of lung tumors considering setup errors and breathing motions.

PubMed

Karlsson, Kristin; Lax, Ingmar; Lindbäck, Elias; Poludniowski, Gavin

2017-09-01

Geometrical uncertainties can result in a delivered dose to the tumor different from that estimated in the static treatment plan. The purpose of this project was to investigate the accuracy of the dose calculated to the clinical target volume (CTV) with the dose-shift approximation, in stereotactic body radiation therapy (SBRT) of lung tumors considering setup errors and breathing motion. The dose-shift method was compared with a beam-shift method with dose recalculation. Included were 10 patients (10 tumors) selected to represent a variety of SBRT-treated lung tumors in terms of tumor location, CTV volume, and tumor density. An in-house developed toolkit within a treatment planning system allowed the shift of either the dose matrix or a shift of the beam isocenter with dose recalculation, to simulate setup errors and breathing motion. Setup shifts of different magnitudes (up to 10 mm) and directions as well as breathing with different peak-to-peak amplitudes (up to 10:5:5 mm) were modeled. The resulting dose-volume histograms (DVHs) were recorded and dose statistics were extracted. Generally, both the dose-shift and beam-shift methods resulted in calculated doses lower than the static planned dose, although the minimum (D 98% ) dose exceeded the prescribed dose in all cases, for setup shifts up to 5 mm. The dose-shift method also generally underestimated the dose compared with the beam-shift method. For clinically realistic systematic displacements of less than 5 mm, the results demonstrated that in the minimum dose region within the CTV, the dose-shift method was accurate to 2% (root-mean-square error). Breathing motion only marginally degraded the dose distributions. Averaged over the patients and shift directions, the dose-shift approximation was determined to be accurate to approximately 2% (RMS) within the CTV, for clinically relevant geometrical uncertainties for SBRT of lung tumors.

Dosimetric verification of IMRT treatment planning using Monte Carlo simulations for prostate cancer

NASA Astrophysics Data System (ADS)

Yang, J.; Li, J.; Chen, L.; Price, R.; McNeeley, S.; Qin, L.; Wang, L.; Xiong, W.; Ma, C.-M.

2005-03-01

The purpose of this work is to investigate the accuracy of dose calculation of a commercial treatment planning system (Corvus, Normos Corp., Sewickley, PA). In this study, 30 prostate intensity-modulated radiotherapy (IMRT) treatment plans from the commercial treatment planning system were recalculated using the Monte Carlo method. Dose-volume histograms and isodose distributions were compared. Other quantities such as minimum dose to the target (Dmin), the dose received by 98% of the target volume (D98), dose at the isocentre (Diso), mean target dose (Dmean) and the maximum critical structure dose (Dmax) were also evaluated based on our clinical criteria. For coplanar plans, the dose differences between Monte Carlo and the commercial treatment planning system with and without heterogeneity correction were not significant. The differences in the isocentre dose between the commercial treatment planning system and Monte Carlo simulations were less than 3% for all coplanar cases. The differences on D98 were less than 2% on average. The differences in the mean dose to the target between the commercial system and Monte Carlo results were within 3%. The differences in the maximum bladder dose were within 3% for most cases. The maximum dose differences for the rectum were less than 4% for all the cases. For non-coplanar plans, the difference in the minimum target dose between the treatment planning system and Monte Carlo calculations was up to 9% if the heterogeneity correction was not applied in Corvus. This was caused by the excessive attenuation of the non-coplanar beams by the femurs. When the heterogeneity correction was applied in Corvus, the differences were reduced significantly. These results suggest that heterogeneity correction should be used in dose calculation for prostate cancer with non-coplanar beam arrangements.

Influence of Age and Dose of African Swine Fever Virus Infections on Clinical Outcome and Blood Parameters in Pigs.

PubMed

Post, Jacob; Weesendorp, Eefke; Montoya, Maria; Loeffen, Willie L

African swine fever (ASF) is a fatal disease for domestic pigs, leading to serious economic losses in countries where ASF is endemic. Despite extensive research, efficient vaccines against ASF are lacking. Since peripheral blood cells are important mediators for vaccines, we study the impact of ASF on blood parameters in pigs with different ages and infected with different doses of ASF virus. Four different groups were studied: (1) 12 weeks of age/low virus dose; (2) 12 weeks of age/high virus dose; (3) 18 weeks of age/low virus dose; and (4) 18 weeks of age/high virus dose. By varying in age and/or ASFV inoculation dose, we monitor blood parameters during different degrees of disease. Thirty percent of the pigs survived the infection with a moderately virulent strain of African swine fever virus (ASFV). Animals that did survive infection were generally older, independent from the inoculation dose used. A firm reduction in many different cell types at 3-5 days postinfection (DPI) was accompanied by an increase in body temperature, followed by clinical signs and mortality from day 6 PI. While blood parameters generally normalized in survivors, γδ T cells and IL-10 levels could be related to mortality. These conclusions should be considered in new approaches for protection against ASF.

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

PubMed

Jacobs, Michael R

2005-06-01

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry.

PubMed

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng; Olsen, Rikke Heidemann

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry

PubMed Central

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens. PMID:29020098

A single-dose regimen for antimicrobial prophylaxis to prevent perioperative infection in urological clean and clean-contaminated surgery.

PubMed

Higuchi, Yoshihide; Takesue, Yoshio; Yamada, Yusuke; Ueda, Yasuo; Suzuki, Toru; Aihara, Kinue; Maruyama, Takuo; Kondoh, Nobuyuki; Nojima, Michio; Yamamoto, Shingo

2011-04-01

A single dose of antimicrobial prophylaxis (AMP) was administered parenterally for the prevention of perioperative infection in a total of 788 patients undergoing urological surgery, including 380 endoscopic-instrumental, 328 clean, and 80 clean-contaminated operations performed at our institute between January 2007 and December 2009. Surgical site infections (SSIs), urinary tract infections (UTIs), and remote infections (RIs) were prospectively surveyed. The definition for a single dose of AMP allowed for the administration of an additional dose of an antimicrobial during surgery if the procedure was longer than 3 h, but not for the parenteral or oral administration at the end of the procedure in the recovery room, or at a later time over a period of more than 24 h. UTI was observed in 12 (3.2%) patients after endoscopic-instrumental operation, 1 (0.3%) after clean operation, and 1 (0.9%) after clean-contaminated operation. SSI was observed in 2 (0.6%) patients after clean operation but in none after clean-contaminated operations. RI was observed in 1 (0.3%) patient after endoscopic-instrumental operation, 3 (0.9%) after clean operation, and none after clean-contaminated operations. A single-dose regimen of AMP was effective and feasible for the prevention of perioperative infections, including SSIs, UTIs, and RIs, in endoscopic-instrumental, clean, and clean-contaminated urological surgical procedures.

Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection

PubMed Central

Karuppiah, Ponmurugan; Mustaffa, Muhammed

2013-01-01

Objective To investigate different Musa sp. leave extracts of hexane, ethyl acetate and methanol were evaluated for antibacterial activity against multi-drug resistant pathogens causing nosocomial infection by agar well diffusion method and also antioxidant activities. Methods The four different Musa species leaves were extracted with hexane, ethyl acetate and methanol. Antibacterial susceptibility test, minimum inhibitory concentration and minimum inhibitory bacterial concentration were determined by agar well diffusion method. Total phenolic content and in vitro antioxidant activity was determined. Results All the Musa sp. extracts showed moderate antibacterial activities expect Musa paradisiaca with the inhibition zone ranging from 8.0 to 18.6 mm. Among four species ethyl acetate extracts of Musa paradisiaca showed highest activity against tested pathogens particularly E. coli, P. aeruginosa and Citrobacter sp. The minimum inhibitory concentrations were within the value of 15.63- 250 µg/mL and minimum bactericidal concentrations were ranging from 31.25- 250 µg/mL. Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species. Conclusions The present study concluded that among the different Musa species, Musa paradisiaca displayed efficient antibacterial activity followed by Musa acuminata against multi-drug resistant nosocomial infection causing pathogens. Further, an extensive study is needed to identify the bioactive compounds, mode of action and toxic effect in vivo of Musa sp. PMID:23998016

Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection.

PubMed

Karuppiah, Ponmurugan; Mustaffa, Muhammed

2013-09-01

To investigate different Musa sp. leave extracts of hexane, ethyl acetate and methanol were evaluated for antibacterial activity against multi-drug resistant pathogens causing nosocomial infection by agar well diffusion method and also antioxidant activities. The four different Musa species leaves were extracted with hexane, ethyl acetate and methanol. Antibacterial susceptibility test, minimum inhibitory concentration and minimum inhibitory bacterial concentration were determined by agar well diffusion method. Total phenolic content and in vitro antioxidant activity was determined. All the Musa sp. extracts showed moderate antibacterial activities expect Musa paradisiaca with the inhibition zone ranging from 8.0 to 18.6 mm. Among four species ethyl acetate extracts of Musa paradisiaca showed highest activity against tested pathogens particularly E. coli, P. aeruginosa and Citrobacter sp. The minimum inhibitory concentrations were within the value of 15.63- 250 µg/mL and minimum bactericidal concentrations were ranging from 31.25- 250 µg/mL. Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species. The present study concluded that among the different Musa species, Musa paradisiaca displayed efficient antibacterial activity followed by Musa acuminata against multi-drug resistant nosocomial infection causing pathogens. Further, an extensive study is needed to identify the bioactive compounds, mode of action and toxic effect in vivo of Musa sp.

SU-F-T-18: The Importance of Immobilization Devices in Brachytherapy Treatments of Vaginal Cuff

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

Shojaei, M; Dumitru, N; Pella, S

2016-06-15

Purpose: High dose rate brachytherapy is a highly localized radiation therapy that has a very high dose gradient. Thus one of the most important parts of the treatment is the immobilization. The smallest movement of the patient or applicator can result in dose variation to the surrounding tissues as well as to the tumor to be treated. We will revise the ML Cylinder treatments and their localization challenges. Methods: A retrospective study of 25 patients with 5 treatments each looking into the applicator’s placement in regard to the organs at risk. Motion possibilities for each applicator intra and inter fractionationmore » with their dosimetric implications were covered and measured in regard with their dose variance. The localization immobilization devices used were assessed for the capability to prevent motion before and during the treatment delivery. Results: We focused on the 100% isodose on central axis and a 15 degree displacement due to possible rotation analyzing the dose variations to the bladder and rectum walls. The average dose variation for bladder was 15% of the accepted tolerance, with a minimum variance of 11.1% and a maximum one of 23.14% on the central axis. For the off axis measurements we found an average variation of 16.84% of the accepted tolerance, with a minimum variance of 11.47% and a maximum one of 27.69%. For the rectum we focused on the rectum wall closest to the 120% isodose line. The average dose variation was 19.4%, minimum 11.3% and a maximum of 34.02% from the accepted tolerance values Conclusion: Improved immobilization devices are recommended. For inter-fractionation, localization devices are recommended in place with consistent planning in regards with the initial fraction. Many of the present immobilization devices produced for external radiotherapy can be used to improve the localization of HDR applicators during transportation of the patient and during treatment.« less

[Antiviral activity of phosprenyl and gamapren against infection caused by influenza a (H5N1) virus in cell culture].

PubMed

Sanin, A V; Deryabin, P G; Narovlyansky, A N; Pronin, A V; Kozhevnikova, T N

2017-01-01

The antiviral activity of Phosprenyl and Gamapren in vitro against highly pathogenic strain of avian influenza H5N1 virus was studied. Inoculation of the virus to the susceptible cell culture led to development of the cytopathogenic effect. Preliminary introduction of Phosprenyl and Gamapren an hour prior to infecting the cells with virus 10.0 TCID50 dose completely inhibited the cytopathogenic activity of the virus. At higher doses of virus (100.0 TCID50) significant inhibition of the infectious activity of the virus was observed: 70% of infected cells survived under the action of Phosprenyl, and 90% under the action of Gamapren. With the introduction of the preparations simultaneously with the infection of cells with virus at a dose of 10.0 TCID50 virtually 100% of infected cells survived, while in control cultures death of 100% of the cells occurred. After infection with the virus at a dose of 100.0 TCID50 Phosprenyl and Gamapren caused 50% protection of the cells. The antiviral effect of the drugs Phosprenyl and Gamapren may be associated not only with their virulicidal, but with anti-viral activity as well.

Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.

PubMed

Singh, Jasvinder A; Cameron, Chris; Noorbaloochi, Shahrzad; Cullis, Tyler; Tucker, Matthew; Christensen, Robin; Ghogomu, Elizabeth Tanjong; Coyle, Doug; Clifford, Tammy; Tugwell, Peter; Wells, George A

2015-07-18

Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. Rheumatology Division at the University of Alabama at Birmingham. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immune responses in Eimeria acervulina infected one-day-old broilers compared to amount of Eimeria in the duodenum, measured by real-time PCR.

PubMed

Swinkels, W J C; Post, J; Cornelissen, J B; Engel, B; Boersma, W J A; Rebel, J M J

2006-06-15

T-cell responses are supposed to be the major immune reactions in broilers infected with Eimeria. The nature of such T-cell responses is influenced by the species of Eimeria involved, age of the host, amount of parasites and the preceding infection history. In young chicks the intestine is still developing in length while the lymphocyte populations in the gut develop and differentiate. In chicks infected at young age the immune response may be different in quality as compared to responses in adults. We investigated the (T-cell) immune responses of young broilers to a primary Eimeria acervulina infection in relation to the number of parasites used for infection. In our experiment we infected one-day-old broilers with a low (5 x 10(2) oocysts) and a high (5 x 10(4) oocysts) dose of E. acervulina. We used a newly developed species specific real-time PCR to quantify total amount of parasites in the duodenum as the number of oocysts in faeces may not be representative for the exposure of the gut immune system. We characterized T-cell subsets in the duodenum by means of FACS-analyses, lymphocyte proliferation assays with spleen lymphocytes and the mRNA profiles of different cytokines (TGF-beta2, -4, IFN-gamma, IL-2, -6, -8 and -18) in the duodenum by means of real-time PCR. From day 5 p.i. broilers with a high dose of E. acervulina had a significantly lower body weight than the control group. No increase in CD4(+) cells, but a strong increase in CD8(+) cells was observed at days 7 and 9 p.i. in the duodenum of broilers infected with a high dose E. acervulina. IL-8 mRNA responses were observed after infection with low and with high infection doses, but no IFN-gamma and TGF-beta mRNA responses were found in the duodenum. The specific proliferative T-cell responses to a low infectious dose were not significantly different as compared to the control group. In conclusion, based on the kinetics of observed responses a primary infection with a high dose of E. acervulina in one-day-old broilers seems to generate an immune response that shows a peak at the time of oocyst excretion, whereas the immune response to a low dose is less explicit.

Determination of Optimal Amikacin Dosing Regimens for Pediatric Patients With Burn Wound Sepsis.

PubMed

Yu, Tian; Stockmann, Chris; Healy, Daniel P; Olson, Jared; Wead, Stephanie; Neely, Alice N; Kagan, Richard J; Spigarelli, Michael G; Sherwin, Catherine M T

2015-01-01

This study aimed to develop optimal amikacin dosing regimens for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries. A pharmacodynamic (PD) target in which the peak concentration (Cmax) is ≥8 times the minimum inhibitory concentration (MIC) (Cmax/MIC ≥ 8) is reflective of optimal bactericidal activity and has been used to predict clinical outcomes. Population pharmacokinetic modeling was performed in NONMEM 7.2 for pediatric patients with and without burn injuries. Amikacin pharmacokinetic parameters were compared between the two groups and multiple dosing regimens were simulated using MATLAB to achieve the PD target in ≥90% of patients with burn injuries. The pharmacokinetic analysis included 282 amikacin concentrations from 70 pediatric patients with burn injuries and 99 concentrations from 32 pediatric patients without burns. A one-compartment model with first-order elimination described amikacin pharmacokinetics well for both groups. Clearance (CL) was significantly higher in patients with burn injuries than in patients without (7.22 vs 5.36 L/h, P < .001). The volume of distribution (V) was also significantly increased in patients with burn injuries (22.7 vs 18.7 L, P < .01). Weight significantly influenced amikacin CL (P < .001) and V (P < .001) for both groups. Model-based simulations showed that a higher amikacin dose (≥25 mg/kg) achieved a Cmax/MIC ≥8 in ≥90% of patients with assumed infections of organisms with an MIC = 8 mg/L. Amikacin pharmacokinetics are altered in patients with burn injuries, including a significant increase in CL and V. In simulations, increased doses (≥25 mg/kg) led to improved PD target attainment rates. Further clinical evaluation of this proposed dosing regimen is warranted to assess clinical and microbiological outcomes in pediatric patients with burn wound sepsis.

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

Suzuki, Minoru; Sakurai, Yoshinori; Masunaga, Shinichiro

Purpose: To investigate the feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma (MPM) from a viewpoint of dose distribution analysis using Simulation Environment for Radiotherapy Applications (SERA), a currently available BNCT treatment planning system. Methods and Materials: The BNCT treatment plans were constructed for 3 patients with MPM using the SERA system, with 2 opposed anterior-posterior beams. The {sup 1}B concentrations in the tumor and normal lung in this study were assumed to be 84 and 24 ppm, respectively, and were derived from data observed in clinical trials. The maximum, mean, and minimum doses to the tumorsmore » and the normal lung were assessed for each plan. The doses delivered to 5% and 95% of the tumor volume, D{sub 05} and D{sub 95}, were adopted as the representative dose for the maximum and minimum dose, respectively. Results: When the D{sub 05} to the normal ipsilateral lung was 5 Gy-Eq, the D{sub 95} and mean doses delivered to the normal lung were 2.2-3.6 and 3.5-4.2 Gy-Eq, respectively. The mean doses delivered to the tumors were 22.4-27.2 Gy-Eq. The D{sub 05} and D{sub 95} doses to the tumors were 9.6-15.0 and 31.5-39.5 Gy-Eq, respectively. Conclusions: From a viewpoint of the dose-distribution analysis, BNCT has the possibility to be a promising treatment for MPM patients who are inoperable because of age and other medical illnesses.« less

Dose-response assessment for influenza A virus based on data sets of infection with its live attenuated reassortants.

PubMed

Watanabe, Toru; Bartrand, Timothy A; Omura, Tatsuo; Haas, Charles N

2012-03-01

Reported data sets on infection of volunteers challenged with wild-type influenza A virus at graded doses are few. Alternatively, we aimed at developing a dose-response assessment for this virus based on the data sets for its live attenuated reassortants. Eleven data sets for live attenuated reassortants that were fit to beta-Poisson and exponential dose-response models. Dose-response relationships for those reassortants were characterized by pooling analysis of the data sets with respect to virus subtype (H1N1 or H3N2), attenuation method (cold-adapted or avian-human gene reassortment), and human age (adults or children). Furthermore, by comparing the above data sets to a limited number of reported data sets for wild-type virus, we quantified the degree of attenuation of wild-type virus with gene reassortment and estimated its infectivity. As a result, dose-response relationships of all reassortants were best described by a beta-Poisson model. Virus subtype and human age were significant factors determining the dose-response relationship, whereas attenuation method affected only the relationship of H1N1 virus infection to adults. The data sets for H3N2 wild-type virus could be pooled with those for its reassortants on the assumption that the gene reassortment attenuates wild-type virus by at least 63 times and most likely 1,070 times. Considering this most likely degree of attenuation, 10% infectious dose of H3N2 wild-type virus for adults was estimated at 18 TCID50 (95% CI = 8.8-35 TCID50). The infectivity of wild-type H1N1 virus remains unknown as the data set pooling was unsuccessful. © 2011 Society for Risk Analysis.

Fractional dosing of yellow fever vaccine to extend supply: a modelling study.

PubMed

Wu, Joseph T; Peak, Corey M; Leung, Gabriel M; Lipsitch, Marc

2016-12-10

The ongoing yellow fever epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa, Democratic Republic of the Congo, in July-August, 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidation of the conditions under which dose fractionation would reduce transmission. We estimate the effective reproductive number for yellow fever in Angola using disease natural history and case report data. With simple mathematical models of yellow fever transmission, we calculate the infection attack rate (the proportion of population infected over the course of an epidemic) with various levels of transmissibility and 5-fold fractional-dose vaccine efficacy for two vaccination scenarios, ie, random vaccination in a hypothetical population that is completely susceptible, and the Kinshasa vaccination campaign in July-August, 2016, with different age cutoff for fractional-dose vaccines. We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (ie, a proportion of vaccine recipients receive complete protection [VE] and the remainder receive no protection), n-fold fractionation can greatly reduce infection attack rate as long as VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (ie, the susceptibility of each vaccine recipient is reduced by a factor that is equal to the vaccine efficacy). The age cutoff for fractional-dose vaccines chosen by WHO for the Kinshasa vaccination campaign (2 years) provides the largest reduction in infection attack rate if the efficacy of 5-fold fractional-dose vaccines exceeds 20%. Dose fractionation is an effective strategy for reduction of the infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected. NIH-MIDAS, HMRF-Hong Kong. Copyright © 2016 Elsevier Ltd. All rights reserved.

Toxicity associated with high dosage 9-[(2R,5R-2,5-dihydro-5-phosphonomethoxy)-2-furanyl]adenine therapy off attempts to abort early FIV infection.

PubMed

Hartmann, K; Ferk, G; North, T W; Pedersen, N C

1997-09-01

9-[(2R,5R-2,5-dihydro-5-phosphonomethoxy)-2-furanyl]adenine, or D4API, was tested in the feline immunodeficiency virus (FIV) infection model and found to be significantly more inhibitory in vitro than its parent compound 9-phosphonylmethoxethyl adenine (PMEA). Cytotoxicity was less than for PMEA or azidothymidine (AZT) for culture periods of 7 days, but more toxic after 10 days. D4API was rapidly absorbed by cats following subcutaneous inoculation, with a plasma half-life of less than 1 h after intravenous inoculation and between 2 and 3 h after subcutaneous injection. Peripheral blood mononuclear cells collected from cats given a single dose of D4API were refractory, however, to FIV infection in vitro for up to 24 h. Given its prolonged intracellular phase and high selectivity index, high dose D4API therapy was tested for its ability to abort an acute (i.e. 2 week) FIV infection. A divided daily dose of D4API, which was one-fourth the toxic dose and 125 times the concentration that would totally inhibit virus replication in vitro, completely abrogated the anticipated viremia and antibody responses. Unfortunately, a majority of treated/uninfected and treated/infected test cats died acutely of drug toxicity after 47 days of treatment. Toxicity in vivo mirrored what was observed in vitro, being precipitous and cumulative in nature. Toxic signs included widespread hepatic and lymphoid necrosis. A surviving treated/FIV infected cat remained healthy to day 175 when the study was terminated; antibodies appeared 2 months later than in untreated/infected cats and virus was only detectable at low levels on day 175. In contrast, untreated/infected cats were viremic and antibody positive from 3 to 4 weeks post-infection onwards. Therefore, it was possible to alter, but not abort, an early FIV infection with prolonged, high-dose D4API treatment.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Cysteine proteinases from papaya (Carica papaya) in the treatment of experimental Trichuris suis infection in pigs: two randomized controlled trials.

PubMed

Levecke, Bruno; Buttle, David J; Behnke, Jerzy M; Duce, Ian R; Vercruysse, Jozef

2014-05-30

Cysteine proteinases (CPs) from papaya (Carica papaya) possess anthelmintic properties against human soil-transmitted helminths (STH, Ascaris lumbricoides, Trichuris trichiura and hookworm), but there is a lack of supportive and up-to-date efficacy data. We therefore conducted two randomized controlled trials in pigs to assess the efficacy of papaya CPs against experimental infections with T. suis. First, we assessed efficacy by means of egg (ERR) and adult worm reduction rate (WRR) of a single-oral dose of 450 μmol active CPs (CP450) against low (inoculum of 300 eggs) and high (inoculum of 3,000 eggs) intensity T. suis infections and compared the efficacy with those obtained after a single-oral dose of 400 mg albendazole (ALB). In the second trial, we determined and compared the efficacy of a series of CP doses (45 [CP45], 115 [CP115], 225 [CP225], and 450 [CP450] μmol) against high intensity infections. CP450 was highly efficacious against both levels of infection intensity, resulting in ERR and WRR of more than 97%. For both levels of infection intensity, CP450 was significantly more efficacious compared to ALB by means of WRR (low infection intensity: 99.0% vs. 39.0%; high infection intensity; 97.4% vs. 23.2%). When the efficacy was assessed by ERR, a significant difference was only observed for high intensity infections, CP450 being more efficacious than ALB (98.9% vs. 59.0%). For low infection intensities, there was no significant difference in ERR between CP450 (98.3%) and ALB (64.4%). The efficacy of CPs increased as a function of increasing dose. When determined by ERR, the efficacy ranged from 2.1% for CP45 to 99.2% for CP450. For WRR the results varied from -14.0% to 99.0%, respectively. Pairwise comparison revealed a significant difference in ERR and WRR only between CP45 and CP450, the latter being more efficacious. A single dose of 450 μmol CPs provided greater efficacy against T. suis infections in pigs than a single-oral dose of 400 mg ALB. Although these results highlight the possibility of papaya CPs for controlling human STH, further development is needed in order to obtain and validate an oral formulation for human application.

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction

PubMed Central

Keller, Frieder; Schröppel, Bernd; Ludwig, Ulla

2015-01-01

Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations. PMID:26167456

Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature.

PubMed

Sherwin, Jennifer; Heath, Travis; Watt, Kevin

2016-09-01

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that is used to temporarily support the most critically ill of patients with respiratory and/or cardiac failure. Infection and its sequelae may be an indication for ECMO or infections may be acquired while on ECMO and are associated with a mortality >50%. Effective therapy requires optimal dosing. However, optimal dosing can be different in patients on ECMO because the ECMO circuit can alter drug pharmacokinetics. This review assessed the current literature for pharmacokinetic data and subsequent dosing recommendations for anti-infective drugs in patients on ECMO. We searched the PubMed and Embase databases (1965 to February 2016) and included case reports, case series, or studies that provided pharmacokinetic data for anti-infective drugs including antibiotics, antifungals, and antivirals being used to treat patients of all age groups on ECMO. Pharmacokinetic parameters and dosing recommendations based on these data are presented. The majority of data on this topic comes from neonatal studies of antibiotics from the 1980s and 1990s. These studies generally demonstrate a larger volume of distribution due to ECMO and therefore higher doses are needed initially. More adult data are now emerging, but with a predominance of case reports and case series without comparison with critically ill controls. The available pharmacokinetic analyses do suggest that volume of distribution and clearance are unchanged in the adult population, and therefore dosing recommendations largely remain unchanged. There is a lack of data on children older than 1 year of age. The data support the importance of therapeutic drug monitoring when available in this population of patients. This review found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infectives. In order to better determine optimal dosing for patients on ECMO, a systematic approach is needed. Approaches that combine ex vivo ECMO experiments, animal studies, specialized pharmacokinetic modeling, and human clinical trials are being developed. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections.

PubMed

Ankomah, Peter; Levin, Bruce R

2014-06-10

The successful treatment of bacterial infections is the product of a collaboration between antibiotics and the host's immune defenses. Nevertheless, in the design of antibiotic treatment regimens, few studies have explored the combined action of antibiotics and the immune response to clearing infections. Here, we use mathematical models to examine the collective contribution of antibiotics and the immune response to the treatment of acute, self-limiting bacterial infections. Our models incorporate the pharmacokinetics and pharmacodynamics of the antibiotics, the innate and adaptive immune responses, and the population and evolutionary dynamics of the target bacteria. We consider two extremes for the antibiotic-immune relationship: one in which the efficacy of the immune response in clearing infections is directly proportional to the density of the pathogen; the other in which its action is largely independent of this density. We explore the effect of antibiotic dose, dosing frequency, and term of treatment on the time before clearance of the infection and the likelihood of antibiotic-resistant bacteria emerging and ascending. Our results suggest that, under most conditions, high dose, full-term therapy is more effective than more moderate dosing in promoting the clearance of the infection and decreasing the likelihood of emergence of antibiotic resistance. Our results also indicate that the clinical and evolutionary benefits of increasing antibiotic dose are not indefinite. We discuss the current status of data in support of and in opposition to the predictions of this study, consider those elements that require additional testing, and suggest how they can be tested.

An analysis of interplanetary space radiation exposure for various solar cycles

NASA Technical Reports Server (NTRS)

Badhwar, G. D.; Cucinotta, F. A.; O'Neill, P. M.; Wilson, J. W. (Principal Investigator)

1994-01-01

The radiation dose received by crew members in interplanetary space is influenced by the stage of the solar cycle. Using the recently developed models of the galactic cosmic radiation (GCR) environment and the energy-dependent radiation transport code, we have calculated the dose at 0 and 5 cm water depth; using a computerized anatomical man (CAM) model, we have calculated the skin, eye and blood-forming organ (BFO) doses as a function of aluminum shielding for various solar minima and maxima between 1954 and 1989. These results show that the equivalent dose is within about 15% of the mean for the various solar minima (maxima). The maximum variation between solar minimum and maximum equivalent dose is about a factor of three. We have extended these calculations for the 1976-1977 solar minimum to five practical shielding geometries: Apollo Command Module, the least and most heavily shielded locations in the U.S. space shuttle mid-deck, center of the proposed Space Station Freedom cluster and sleeping compartment of the Skylab. These calculations, using the quality factor of ICRP 60, show that the average CAM BFO equivalent dose is 0.46 Sv/year. Based on an approach that takes fragmentation into account, we estimate a calculation uncertainty of 15% if the uncertainty in the quality factor is neglected.

Predictors of Cosmetic Outcome Following MammoSite Breast Brachytherapy: A Single-Institution Experience of 100 Patients With Two Years of Follow-Up

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

Dragun, Anthony E.; Harper, Jennifer L.; Jenrette, Joseph M.

2007-06-01

Purpose: To identify the factors that predict for excellent cosmesis in patients who receive MammoSite breast brachytherapy (MBT). Methods and Materials: One hundred patients with Stage 0, I, or II adenocarcinoma of the breast underwent adjuvant therapy using MBT. A dose of 34 Gy, delivered in 10 fractions twice daily, was prescribed to 1-cm depth using {sup 192}Ir high-dose-rate brachytherapy. Patients were assessed for acute toxicity on the day of therapy completion, 4 weeks after therapy, and at least every 3 months by radiation, surgical, and/or medical oncologists. All available data were reviewed for documentation of cosmesis and rated usingmore » the Harvard Scale. All patients had a minimum follow-up of 6 months (median = 24 months). Results: Of 100 patients treated, 90 had adequate data and follow-up. Cosmesis was excellent in 62 (68.9%), good in 19 (21.1%), fair in 8 (8.9%), and poor in 1 (1.1%) patient. Using stepwise logistic regression, the factors that predicted for excellent cosmesis were as follows: the absence vs. presence of infection (p = 0.017), and the absence vs. presence of acute skin toxicity (p = 0.026). There was a statistically significant association between acute skin toxicity (present vs. absent) and balloon-to-skin distance (<8 vs. >8 mm, p = 0.001). Factors that did not predict for cosmesis were age, balloon placement technique, balloon volume, catheter days in situ, subcutaneous toxicity, and chemotherapy or hormonal therapy. Conclusions: The acute and late-term toxicity profiles of MBT have been acceptable. Cosmetic outcome is improved by proper patient selection and infection prevention.« less

Use of computer code for dose distribution studies in A 60CO industrial irradiator

NASA Astrophysics Data System (ADS)

Piña-Villalpando, G.; Sloan, D. P.

1995-09-01

This paper presents a benchmark comparison between calculated and experimental absorbed dose values tor a typical product, in a 60Co industrial irradiator, located at ININ, México. The irradiator is a two levels, two layers system with overlapping product configuration with activity around 300kCi. Experimental values were obtanied from routine dosimetry, using red acrylic pellets. Typical product was Petri dishes packages, apparent density 0.13 g/cm3; that product was chosen because uniform size, large quantity and low density. Minimum dose was fixed in 15 kGy. Calculated values were obtained from QAD-CGGP code. This code uses a point kernel technique, build-up factors fitting was done by geometrical progression and combinatorial geometry is used for system description. Main modifications for the code were related with source sumilation, using punctual sources instead of pencils and an energy and anisotropic emission spectrums were included. Results were, for maximum dose, calculated value (18.2 kGy) was 8% higher than experimental average value (16.8 kGy); for minimum dose, calculated value (13.8 kGy) was 3% higher than experimental average value (14.3 kGy).

Assessment of radiation exposure from cesium-137 contaminated roads for epidemiological studies in Seoul, Korea.

PubMed

Lee, Yun-Keun; Ju, Young-Su; Lee, Won Jin; Hwang, Seung Sik; Yim, Sang-Hyuk; Yoo, Sang-Chul; Lee, Jieon; Choi, Kyung-Hwa; Burm, Eunae; Ha, Mina

2015-01-01

We aimed to assess the radiation exposure for epidemiologic investigation in residents exposed to radiation from roads that were accidentally found to be contaminated with radioactive cesium-137 ((137)Cs) in Seoul. Using information regarding the frequency and duration of passing via the (137)Cs contaminated roads or residing/working near the roads from the questionnaires that were obtained from 8875 residents and the measured radiation doses reported by the Nuclear Safety and Security Commission, we calculated the total cumulative dose of radiation exposure for each person. Sixty-three percent of the residents who responded to the questionnaire were considered as ever-exposed and 1% of them had a total cumulative dose of more than 10 mSv. The mean (minimum, maximum) duration of radiation exposure was 4.75 years (0.08, 11.98) and the geometric mean (minimum, maximum) of the total cumulative dose was 0.049 mSv (<0.001, 35.35) in the exposed. An individual exposure assessment was performed for an epidemiological study to estimate the health risk among residents living in the vicinity of (137)Cs contaminated roads. The average exposure dose in the exposed people was less than 5% of the current guideline.

Optimal allocation of the limited oral cholera vaccine supply between endemic and epidemic settings.

PubMed

Moore, Sean M; Lessler, Justin

2015-10-06

The World Health Organization (WHO) recently established a global stockpile of oral cholera vaccine (OCV) to be preferentially used in epidemic response (reactive campaigns) with any vaccine remaining after 1 year allocated to endemic settings. Hence, the number of cholera cases or deaths prevented in an endemic setting represents the minimum utility of these doses, and the optimal risk-averse response to any reactive vaccination request (i.e. the minimax strategy) is one that allocates the remaining doses between the requested epidemic response and endemic use in order to ensure that at least this minimum utility is achieved. Using mathematical models, we find that the best minimax strategy is to allocate the majority of doses to reactive campaigns, unless the request came late in the targeted epidemic. As vaccine supplies dwindle, the case for reactive use of the remaining doses grows stronger. Our analysis provides a lower bound for the amount of OCV to keep in reserve when responding to any request. These results provide a strategic context for the fulfilment of requests to the stockpile, and define allocation strategies that minimize the number of OCV doses that are allocated to suboptimal situations. © 2015 The Authors.

Are two doses of human papillomavirus vaccine sufficient for girls aged 15-18 years? Results from a cohort study in India.

PubMed

Bhatla, Neerja; Nene, Bhagwan M; Joshi, Smita; Esmy, Pulikottil O; Poli, Usha Rani Reddy; Joshi, Geeta; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Prabhu, Priya R; Basu, Partha; Muwonge, Richard; Hingmire, Sanjay; Sauvaget, Catherine; Lucas, Eric; Pawlita, Michael; Gheit, Tarik; Jayant, Kasturi; Malvi, Sylla G; Siddiqi, Maqsood; Michel, Angelika; Butt, Julia; Sankaran, Subha; Kannan, Thiraviam Pillai Rameshwari Ammal; Varghese, Rintu; Divate, Uma; Willhauck-Fleckenstein, Martina; Waterboer, Tim; Müller, Martin; Sehr, Peter; Kriplani, Alka; Mishra, Gauravi; Jadhav, Radhika; Thorat, Ranjit; Tommasino, Massimo; Pillai, M Radhakrishna; Sankaranarayanan, Rengaswamy

2018-06-01

Extending two-dose recommendations of HPV vaccine to girls between 15 and 18 years will reduce program cost and improve compliance. Immunogenicity and vaccine targeted HPV infection outcomes were compared between 1795 girls aged 15-18 years receiving two (1-180 days) and 1515 girls of same age receiving three (1-60-180 days) doses. Immunogenicity outcomes in 15-18 year old two-dose recipients were also compared with the 10-14 year old three-dose (N = 2833) and two-dose (N = 3184) recipients. The 15-18 year old two-dose recipients had non-inferior L1-binding antibody titres at seven months against vaccine-targeted HPV types compared to three-dose recipients at 15-18 years and three-dose recipients at 10-14 years of age. Neutralizing antibody titres at 18 months in 15-18 year old two-dose recipients were non-inferior to same age three-dose recipients for all except HPV 18. The titres were inferior to those in the 10-14 year old three-dose recipients for all targeted types. Frequency of incident infections from vaccine-targeted HPV types in the 15-18 year old two-dose recipients was similar to the three dose recipients. None of the girls receiving two or three doses had persistent infection from vaccine-targeted types. These findings support that two doses of HPV vaccine can be extended to girls aged 15-18 years. Copyright © 2018. Published by Elsevier B.V.

Efficacy of a novel formulation of metaflumizone plus amitraz for the treatment of sarcoptic mange in dogs.

PubMed

Fourie, L J; Kok, D J; du Plessis, A; Rugg, D

2007-12-15

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated for efficacy against sarcoptic mange mites in naturally infested dogs. Sixteen dogs were allocated to two equal groups and were housed individually. Eight of the dogs were treated topically with metaflumizone plus amitraz at the proposed minimum dose rate (20mg/kg of each of metaflumizone and amitraz, at a dose volume of 0.133ml/kg) on Days 0 and 28. The other eight were treated with metaflumizone plus amitraz at the proposed minimum dose rate on Days 0, 14, 28 and 42. To enumerate Sarcoptes scabiei mites, skin scrapings were taken on each of Days 2, 14, 28, 42 and 56. Clinical signs of mange and the extent of sarcoptic lesions were evaluated on each dog when scrapings were made. Evaluation of the efficacy of the treatment was based on the absence of mites supported by the absence of clinical signs associated with canine sarcoptic mange. Treatment with metaflumizone plus amitraz at the minimum proposed dose rate at monthly (two treatments) or two-weekly (four treatments) intervals resulted in a rapid reduction of mites and improved clinical signs. The overall cure rates at Day 56, based on zero mite counts and/or resolution of clinical signs were 75% and 83% of dogs for the monthly and two-weekly regimens, respectively.

Clinical and microbiological characteristics of Rhodotorula mucilaginosa infections in a tertiary-care facility.

PubMed

Capoor, M R; Aggarwal, S; Raghvan, C; Gupta, D K; Jain, A K; Chaudhary, R

2014-01-01

Rhodotorula spp. are an emergent opportunistic pathogen, particularly in immunocompromised individuals. The aim of the study was to review reported cases of Rhodotorula infection over a period of 9 years to determine epidemiology, risk factors, treatment and outcome. The Rhodotorula spp. were isolated from cerebrospinal fluid (9) and blood (5). The most common pre-disposing factors were prolonged hospital stay (>1 month) and prolonged usage of broad-spectrum antibiotics (>1 month). All the isolates were identified as R. mucilaginosa by conventional methods. Amphotericin B demonstrated lowest minimum inhibitory concentration (MIC) as compared with other anti-fungal agents (fluconazole, itraconazole and voriconazole). The recognition of unusual yeasts as an agent of life-threatening infection and their intrinsic resistance increases the burden on the mycology laboratory for complete species identification and to determine minimum inhibitory concentration.

Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination.

PubMed Central

Norden, C W; Keleti, E

1980-01-01

Rifampin and trimethoprim were used alone and in combination in the treatment of chronic osteomyelitis due to Staphylococcus aureus in rabbits. Rifampicin levels in infected bone were well above the minimum inhibitory concentration of the infecting strain of S. aureus for at least 4 h after injection. In contrast, trimethoprim levels in diseased bone were below the minimum inhibitory concentration as early as 1 h after injection. Trimethoprim or rifampin, administered alone for 14 days, were ineffective in sterilizing infected rabbit bones. The combination of rifampin plus trimethoprim was significantly more effective (P less than 0.005) than either agents given alone for a comparable duration of time. Staphylococci isolated from the bones of rabbits treated with rifampin alone or rifampin plus trimethoprim were uniformly resistant to rifampin, but retained their susceptibility to trimethoprim. PMID:7396451

Immunohematopoietic modulation by oral β-1,3-glucan in mice infected with Listeria monocytogenes.

PubMed

Torello, Cristiane O; de Souza Queiroz, Julia; Oliveira, Sueli C; Queiroz, Mary L S

2010-12-01

In this study we demonstrated that the oral administration of β-1,3-glucan (Imunoglucan®) protects mice from a lethal dose of Listeria monocytogenes (LM) when administered prophylactically for 10 days at the doses of 150 and 300 mg/kg, with survival rates up to 40%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with LM, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Investigation of the production of colony-stimulating factors revealed an increased colony-stimulating activity (CSA) in the serum of infected mice pre-treated with Imunoglucan®. The treatment also restored the reduced ability of stromal cells to display myeloid progenitors in long-term bone marrow cultures (LTBMC) and up-regulated IL-6 and IL-1α production by these cells in the infected mice, which was consistent with higher number of non-adherent cells. Additional studies to investigate the levels of interferon-gamma (INF-γ) in the supernatant of splenocyte cultures demonstrated a further increase in the level of this cytokine in infected-treated mice, compared to infected controls. In all cases, no differences were observed between the responses of the two optimal biologically effective doses. In contrast, no significant changes were produced by the treatment with the 50mg/kg dose. In addition, no changes were observed in normal mice treated with the three doses used. All together our results suggest that orally given Imunoglucan® indirectly modulates immune activity and probably disengages Listeria induced suppression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1α, IL-6, and INF-γ). Copyright © 2010 Elsevier B.V. All rights reserved.

Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice

PubMed Central

Zhou, Chenguang; Lehar, Sophie; Gutierrez, Johnny; Rosenberger, Carrie M.; Ljumanovic, Nina; Dinoso, Jason; Koppada, Neelima; Hong, Kyu; Baruch, Amos; Saad, Ola; Mariathasan, Sanjeev; Kamath, Amrita V.

2016-01-01

ABSTRACT DSTA4637A, a novel THIOMAB™ antibody antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy against S. aureus infections. Structurally, TAC is composed of an anti-S. aureus antibody linked to a potent antibiotic, dmDNA31. The goal of the current study was to characterize the pharmacokinetics (PK) of TAC in mice, assess the effect of S. aureus infection on its PK, and evaluate its pharmacodynamics (PD) by measuring the bacterial load in various organs at different timepoints following TAC treatment. Plasma concentrations of 3 analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured in these studies. In non-infected mice (target antigen absent), following intravenous (IV) administration of a single dose of TAC, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential and characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested (5 to 50 mg/kg). In a mouse model of systemic S. aureus infection (target antigen present), a single IV dose of TAC demonstrated PK behavior similar to that in the non-infected mice, and substantially reduced bacterial load in the heart, kidney, and bones on 7 and 14 d post dosing. These findings have increased our understanding of the PK and PK/PD of this novel molecule, and have shown that at efficacious dose levels the presence of S. aureus infection had minimal effect on TAC PK. PMID:27653831

Choice of antibiotics for infection prophylaxis in emergency cesarean sections in low-income countries: a cost-benefit study in Mozambique.

PubMed

Kayihura, Vicente; Osman, Nafissa Bique; Bugalho, Antonio; Bergström, Staffan

2003-07-01

There is a need to assess the cost-benefit of different models of antibiotic administration for the prevention of post cesarean infection, particularly in resource-scarce settings. Randomized, nonblinded comparative study of a single combined preoperative dose of gentamicin and metronidazole vs. a post cesarean scheme for infection prophylaxis. Pregnant women (n = 288) with indication for emergency cesarean section were randomly allotted to two groups. Group 1 (n = 143) received the single, combined dose of prophylactic antibiotics and group 2 (n = 145) received, over 7 days, the postoperative standard scheme of antibiotics followed in the department. Both groups were followed up during 7 days for detection of signs of wound infection, endometritis, peritonitis and urinary tract infection. Prevalence of postoperative infection, mean hospital stay and costs of antibiotics used. Women completing the study (n = 241) were distributed into group 1 (n = 116) and group 2 (n = 125). No significant difference was found neither in the prevalence of postoperative infection nor in the mean hospital stay. No death occurred. The cost of the single dose of prophylactic antibiotics was less than one-tenth of the cost of the standard postoperative scheme. In our setting, the administration of a single dose of 160 mg of gentamicin in combination with 500 mg of metronidazole before emergency cesarean section for prevention of infection is clinically equivalent to existing conventional week-long postoperative therapy, but at approximately one-tenth of the cost.

Low-dose radiation induces Drosophila innate immunity through Toll pathway activation.

PubMed

Seong, Ki Moon; Kim, Cha Soon; Lee, Byung-Sub; Nam, Seon Young; Yang, Kwang Hee; Kim, Ji-Young; Park, Joong-Jean; Min, Kyung-Jin; Jin, Young-Woo

2012-01-01

Numerous studies report that exposing certain organisms to low-dose radiation induces beneficial effects on lifespan, tumorigenesis, and immunity. By analyzing survival after bacterial infection and antimicrobial peptide gene expression in irradiated flies, we demonstrate that low-dose irradiation of Drosophila enhances innate immunity. Low-dose irradiation of flies significantly increased resistance against gram-positive and gram-negative bacterial infections, as well as expression of several antimicrobial peptide genes. Additionally, low-dose irradiation also resulted in a specific increase in expression of key proteins of the Toll signaling pathway and phosphorylated forms of p38 and JNK. These results indicate that innate immunity is activated after low-dose irradiation through Toll signaling pathway in Drosophila.

Fluconazole levels in serum and cerebrospinal fluid according to daily dosage in patients with cryptococcosis and other fungal infections.

PubMed

Schiave, Letícia Aparecida; Nascimento, Erika; Vilar, Fernando Crivelenti; de Haes, Tissiana Marques; Takayanagui, Osvaldo Massaiti; Gaitani, Cristiane Masetto de; Martinez, Roberto

Fluconazole is extensively used for the treatment of candidiasis and cryptococcosis. Among other factors, successful treatment is related to appropriate fluconazole levels in blood and cerebrospinal fluid. In the present study, fluconazole levels were determined in 15 patients, 14 of whom had AIDS and 13 had neurocryptococcosis. The only selection criterion was treatment with fluconazole, which was performed with a generic or similar form of the drug. Fluconazole level was determined by high performance liquid chromatography and the susceptibility profile of Cryptococcus spp. isolated from the patients was assessed by broth microdilution. Blood and cerebrospinal fluid fluconazole levels were found to be related to the fluconazole daily dose, and exceeded the minimum inhibitory concentration of this antifungal for the Cryptococcus spp. isolates. A good correlation was observed between serum and cerebrospinal fluid drug concentration. In conclusion, treatment with non-original fluconazole under usual medical practice conditions results in appropriate blood and cerebrospinal fluid levels of the drug for inhibiting Cryptococcus spp. susceptible to this antifungal drug. The relatively common failures of neurocryptococcosis treatment appear not to be due to insufficient fluconazole levels in the cerebrospinal fluid, especially with the use of daily doses of 400-800mg. Copyright © 2017 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

PubMed

Cohen-Wolkowiez, Michael; Sampson, Mario; Bloom, Barry T; Arrieta, Antonio; Wynn, James L; Martz, Karen; Harper, Barrie; Kearns, Gregory L; Capparelli, Edmund V; Siegel, David; Benjamin, Daniel K; Smith, P Brian

2013-09-01

Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.

Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples from Premature Infants

PubMed Central

Cohen-Wolkowiez, Michael; Sampson, Mario; Bloom, Barry T.; Arrieta, Antonio; Wynn, James L.; Martz, Karen; Harper, Barrie; Kearns, Gregory L.; Capparelli, Edmund V.; Siegel, David; Benjamin, Daniel K.; Smith, P. Brian

2013-01-01

Background Limited pharmacokinetic (PK) data of metronidazole in premature infants has led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. Methods We evaluated the PK of metronidazole using plasma and dried blood spot (DBS) samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N=3) study using population PK modeling (NONMEM). Monte Carlo simulations (N=1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. Results Twenty-four premature infants (111 plasma and 51 DBS samples) were enrolled: median (range) gestational age at birth 25 (23–31) weeks, postnatal age 27 (1–82) days, postmenstrual age (PMA) 31 (24–39) weeks, and weight 740 (431–1466) g. Population clearance (CL, L/h/kg) was 0.038 × (PMA/30)2.45 and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and DBS samples. Metabolic ratios correlated with CL. Conclusion Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using PMA-based dosing. PMID:23587979

Metformin exhibits preventive and therapeutic efficacy against experimental cystic echinococcosis

PubMed Central

Loos, Julia A.; Dávila, Valeria A.; Rodrígues, Christian R.; Petrigh, Romina; Zoppi, Jorge A.; Crocenzi, Fernando A.; Cumino, Andrea C.

2017-01-01

Metformin (Met) is an anti-hyperglycemic and potential anti-cancer agent which may exert its anti-proliferative effects via the induction of energetic stress. In this study we investigated the in vitro and in vivo efficacy of Met against the larval stage of Echinococcus granulosus. Metformin showed significant dose- and time-dependent killing effects on in vitro cultured protoscoleces and metacestodes. Notably, the combination of Met together with the minimum effective concentration of ABZSO had a synergistic effect after days 3 and 12 on metacestodes and protoscoleces, respectively. Oral administration of Met (50 mg/kg/day) in E. granulosus-infected mice was highly effective in reducing the weight and number of parasite cysts, yet its combination with the lowest recommended dose of ABZ (5 mg/kg/day) was even more effective. Coincidentally, intracystic Met accumulation was higher in animals treated with both drugs compared to those administered Met alone. Furthermore, the safe plant-derived drug Met exhibited remarkable chemopreventive properties against secondary hydatidosis in mice. In conclusion, based on our experimental data, Met emerges as a promising anti-echinococcal drug as it has proven to efficiently inhibit the development and growth of the E. granulosus larval stage and its combination with ABZ may improve the current anti-parasitic therapy. PMID:28182659

Western Australian cigarette smokers have fewer small lung nodules than North Americans on CT screening for lung cancer.

PubMed

Murray, C P; Wong, P M; Louw, J; Waterer, G W

2009-08-01

To determine the prevalence of small lung nodules on low-dose helical computed tomography (CT) in a Western Australian cohort of asymptomatic long-term cigarette smokers and to compare this with a large, similarly derived cohort of North Americans from the Mayo Clinic Lung Cancer Screening Trial. Forty-nine asymptomatic long-term cigarette smokers of minimum age 50 years underwent a low-dose 64-slice helical CT of the lungs. Images were viewed on a soft copy reporting station with thin section axial and coronal images, maximum intensity projection images, and advanced image manipulation tools. The prevalence of all nodules was 39%, significantly lower than the Mayo Clinic cohort prevalence of 51% (P < 0.01, Fisher's exact test), despite the use of more advanced imaging technology and image manipulation designed to increase the sensitivity for nodules. The prevalence of small nodules in asymptomatic long-term cigarette smokers in Western Australia is high, though significantly less than that found in a large study in North America. The authors postulate this is due to the relatively low rates of mycobacterium tuberculosis and soil-derived fungal pulmonary infections in Western Australia, as well as a lower degree of urban air pollution.

[Respiratory syncytial virus prophylaxis among preterm infants--four seasons' experience].

PubMed

Klimek, Małgorzata; Kwinta, Przemko; Kruczek, Piotr; Pietrzyk, Jacek J

2009-01-01

Respiratory syncitial virus (RSV) is the main reason of hospitalizations due to respiratory tract infection in children within the first year of life. The course of infection is more severe in children from a risk group, which includes children who were born preterm, these with bronchopulmonary dysplasia (BPD), children with heart defects significantly influencing their hemodynamics, and immunocompromised children. Palivizumab is a humanized monoclonal antibody class IgG-1 used to prevent RSV infection. To assess the results of treatment and to evaluate factors influencing the efficacy of RSV infection prophylaxis in preterm newborns. The study included 55 preterm newborns (mean birth weight-970g, mean gestational age-27 weeks), who were given a dose of palmivizumab of 15mg per kg body weight every four weeks in autumn and winter from season 2004/ 2005 to season 2007/2008. Ten children (18%) required hospitalization between the doses and within 28 days after the last dose of palmivizumab. Among these, 2 children (3.6%) were hospitalized because of very severe RSV infection. Eight children (16%) were hospitalized due to respiratory tract infection within 12 months after completing the prophylaxis; none of them was infected with RSV. The episodes of respiratory tract infection between the doses and within 28 days after the last dose occurred in 19 children (31%), and in 26 patients included in the follow-up (51%) within 12 months after completing the prophylaxis. The effect of treatment was most beneficial in preterm neonates with extremely low birth weight and in children who did not require respiratory medications at the moment of discharge from the neonatal unit. RSV infection prophylaxis is of most benefit in children born with extremely low birth weight. In this group of children the prophylaxis should be considered both for children suffering from BPD and in children free of this disease.

Analysis of nodal coverage utilizing image guided radiation therapy for primary gynecologic tumor volumes

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

Ahmed, Faisal; Loma Linda University Medical Center, Department of Radiation Oncology, Loma Linda, CA; Sarkar, Vikren

Purpose: To evaluate radiation dose delivered to pelvic lymph nodes, if daily Image Guided Radiation Therapy (IGRT) was implemented with treatment shifts based on the primary site (primary clinical target volume [CTV]). Our secondary goal was to compare dosimetric coverage with patient outcomes. Materials and methods: A total of 10 female patients with gynecologic malignancies were evaluated retrospectively after completion of definitive intensity-modulated radiation therapy (IMRT) to their pelvic lymph nodes and primary tumor site. IGRT consisted of daily kilovoltage computed tomography (CT)-on-rails imaging fused with initial planning scans for position verification. The initial plan was created using Varian's Eclipsemore » treatment planning software. Patients were treated with a median radiation dose of 45 Gy (range: 37.5 to 50 Gy) to the primary volume and 45 Gy (range: 45 to 64.8 Gy) to nodal structures. One IGRT scan per week was randomly selected from each patient's treatment course and re-planned on the Eclipse treatment planning station. CTVs were recreated by fusion on the IGRT image series, and the patient's treatment plan was applied to the new image set to calculate delivered dose. We evaluated the minimum, maximum, and 95% dose coverage for primary and nodal structures. Reconstructed primary tumor volumes were recreated within 4.7% of initial planning volume (0.9% to 8.6%), and reconstructed nodal volumes were recreated to within 2.9% of initial planning volume (0.01% to 5.5%). Results: Dosimetric parameters averaged less than 10% (range: 1% to 9%) of the original planned dose (45 Gy) for primary and nodal volumes on all patients (n = 10). For all patients, ≥99.3% of the primary tumor volume received ≥ 95% the prescribed dose (V95%) and the average minimum dose was 96.1% of the prescribed dose. In evaluating nodal CTV coverage, ≥ 99.8% of the volume received ≥ 95% the prescribed dose and the average minimum dose was 93%. In evaluating individual IGRT sessions, we found that 6 patients had an estimated minimal nodal CTV dose less than 90% (range: 78 to 99%) of that planned. With a median follow-up of 42.5 months, 2 patients experienced systemic disease progression at an average of 19.6 months. One patient was found to have a local or regional failure with an average follow-up of 42 months. Conclusion: Using only 3 dimensional IGRT corrections in gynecological radiation allows excellent coverage of the primary target volume and good average nodal CTV coverage. If IGRT corrections are based on alignment to the primary tumor volume, and is only able to be corrected in 3 degrees, this can create situations in which nodal volumes may be under dosed. Utilizing multiple IGRT sessions appears to average out dose discrepancies over the course of treatment. The implication of underdosing in a single IGRT session needs further evaluation in future studies. Based on the concern of minimum dose to a nodal target volume, these findings may signal caution when using IGRT and IMRT in gynecological radiation patients. Possible techniques to overcome this situation may include averaging shifts between tumor and nodal volume, use of a treatment couch with 6° of freedom, deformable registration, or adaptive planning.« less

Exercise frequency and bone mineral density development in exercising postmenopausal osteopenic women. Is there a critical dose of exercise for affecting bone? Results of the Erlangen Fitness and Osteoporosis Prevention Study.

PubMed

Kemmler, Wolfgang; von Stengel, Simon; Kohl, Matthias

2016-08-01

Due to older people's low sports participation rates, exercise frequency may be the most critical component for designing exercise protocols that address bone. The aims of the present article were to determine the independent effect of exercise frequency (ExFreq) and its corresponding changes on bone mineral density (BMD) and to identify the minimum effective dose that just relevantly affects bone. Based on the 16-year follow-up of the intense, consistently supervised Erlangen Fitness and Osteoporosis Prevention-Study, ExFreq was retrospectively determined in the exercise-group of 55 initially early-postmenopausal females with osteopenia. Linear mixed-effect regression analysis was conducted to determine the independent effect of ExFreq on BMD changes at lumbar spine and total hip. Minimum effective dose of ExFreq based on BMD changes less than the 90% quantile of the sedentary control-group (n=43). Cut-offs were determined after 4, 8, 12 and 16years using bootstrap with 5000 replications. After 16years, average ExFreq ranged between 1.02 and 2.96sessions/week (2.28±0.40sessions/week). ExFreq has an independent effect on LS-BMD (p<.001) and hip-BMD (p=.005) changes. Bootstrap analysis detected a minimum effective dose at about 2sessions/week/16years (cut-off LS-BMD: 2.11, 95% CI: 2.06-2.12; total hip-BMD: 2.22, 95% CI: 2.00-2.78sessions/week/16years). In summary, the minimum effective dose of exercise frequency that relevantly addresses BMD is quite high, at least compared with the low sport participation rate of older adults. This result might not be generalizable across all exercise types, protocols and cohorts, but it does indicate at least that even when applying high impact/high intensity programs, exercise frequency and its maintenance play a key role in bone adaptation. Copyright © 2016 Elsevier Inc. All rights reserved.

Retrospective Cohort Study of Bronchial Doses and Radiation-Induced Atelectasis After Stereotactic Body Radiation Therapy of Lung Tumors Located Close to the Bronchial Tree

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

Karlsson, Kristin, E-mail: kristin.karlsson@karolinska.se; Department of Oncology-Pathology, Karolinska Institute, Stockholm; Nyman, Jan

2013-11-01

Purpose: To evaluate the dose–response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. Methods and Materials: Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm{sup 3} up to 2.0 cm{sup 3}]) was statistically evaluated with survival analysis models. Results: Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showedmore » a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm{sup 3} (D{sub 0.1cm3}) was used for further analysis. The median value of D{sub 0.1cm3} (α/β = 3 Gy) was EQD{sub 2,LQ} = 147 Gy{sub 3} (range, 20-293 Gy{sub 3}). For patients who developed atelectasis the median value was EQD{sub 2,LQ} = 210 Gy{sub 3}, and for patients who did not develop atelectasis, EQD{sub 2,LQ} = 105 Gy{sub 3}. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). Conclusion: In this retrospective study a significant dose–response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown.« less

Mars surface radiation exposure for solar maximum conditions and 1989 solar proton events

NASA Technical Reports Server (NTRS)

Simonsen, Lisa C.; Nealy, John E.

1992-01-01

The Langley heavy-ion/nucleon transport code, HZETRN, and the high-energy nucleon transport code, BRYNTRN, are used to predict the propagation of galactic cosmic rays (GCR's) and solar flare protons through the carbon dioxide atmosphere of Mars. Particle fluences and the resulting doses are estimated on the surface of Mars for GCR's during solar maximum conditions and the Aug., Sep., and Oct. 1989 solar proton events. These results extend previously calculated surface estimates for GCR's at solar minimum conditions and the Feb. 1956, Nov. 1960, and Aug. 1972 solar proton events. Surface doses are estimated with both a low-density and a high-density carbon dioxide model of the atmosphere for altitudes of 0, 4, 8, and 12 km above the surface. A solar modulation function is incorporated to estimate the GCR dose variation between solar minimum and maximum conditions over the 11-year solar cycle. By using current Mars mission scenarios, doses to the skin, eye, and blood-forming organs are predicted for short- and long-duration stay times on the Martian surface throughout the solar cycle.

Radiation Risks From A Weak Field in the Coming Years

NASA Astrophysics Data System (ADS)

Rahmanifard, F.; Schwadron, N.; Smith, C. W.; Joyce, C. J.; Townsend, L.

2017-12-01

Recent solar conditions, including a prolonged solar minimum (2005-2009) and the recent small solar maximum, indicate that we are entering an era of lower solar activity than observed at other times during the space age- possibly similar to the past solar grand minima. During such periods of extremely low activity, the fluxes of galactic cosmic rays (GCRs) increase dramatically and limit the allowable days for human space missions. We use data from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) on the Lunar Reconnaissance Orbiter (LRO) to examine the correlation between the heliospheric magnetic field at 1AU and the modulation potential of the GCRs. We apply past grand solar minima conditions, including the Maunder minimum (1645-1715) and the Dalton minimum (1790-1830), to predict the modulation potential and the dose rates of the GCRs throughout the next solar cycle. The heliospheric magnetic field can drop to 4.21 (3.72) nT, leading to a modulation potential of 448.51 (235.96) MV and dose rates as high as 11.72 (16.68) cGy/yr for the case of conditions similar to the Dalton minimum (Maunder minimum). We use these results to predict the most conservative estimations of the time to 3% risk of exposure-induced death (REID) and the allowable mission durations in interplanetary space.

Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition

PubMed Central

Jane Cassidy, Elizabeth; Vitt Meyling, Nicolai

2018-01-01

Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta—flour beetle Tenebrio molitor model—has been used extensively for ecological and evolutionary host–parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7–10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition. PMID:29401652

Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition.

PubMed

Dhakal, Suraj; Micki Buss, Sebastian; Jane Cassidy, Elizabeth; Vitt Meyling, Nicolai; Lund Fredensborg, Brian

2018-02-03

Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta -flour beetle Tenebrio molitor model-has been used extensively for ecological and evolutionary host-parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7-10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition.

Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus

PubMed Central

Negri, Clara E; Johnson, Adam; McEntee, Laura; Box, Helen; Whalley, Sarah; Schwartz, Julie A; Ramos-Martín, V; Livermore, Joanne; Kolamunnage-Dona, Ruwanthi; Colombo, Arnaldo L; Hope, William W

2018-01-01

Abstract Background Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships. Results F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9–19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan. Conclusions F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents. PMID:28968675

The recombinant fusion protein CFP10-ESAT6-dIFN has protective effect against tuberculosis in guinea pigs.

PubMed

Permyakova, Natalya V; Belavin, Pavel A; Pirozhkova, Dariya S; Ufimtseva, Elena G; Rozov, Sergey M; Mursalimov, Sergey R; Sidorchuk, Yuriy V; Uvarova, Elena A; Zagorskaya, Alla A; Marenkova, Tatiana V; Bannikova, Svetlana V; Demidov, Evgeniy A; Starostin, Konstantin V; Kravchenko, Marionella A; Vakhrusheva, Diana V; Berdnikov, Roman B; Eremeeva, Natalya I; Skornyakov, Sergey N; Peltek, Sergey E; Deineko, Elena V

2018-03-01

Development of effective vaccine candidates against tuberculosis (TB) is currently the most important challenge in the prevention of this disease since the BCG vaccine fails to guarantee a lifelong protection, while any other approved vaccine with better efficiency is still absent. The protective effect of the recombinant fusion protein CFP10-ESAT6-dIFN produced in a prokaryotic expression system (Escherichia coli) has been assessed in a guinea pig model of acute TB. The tested antigen comprises the Mycobacterium tuberculosis (Mtb) proteins ESAT6 and CFP10 as well as modified human γ-interferon (dIFN) for boosting the immune response. Double intradermal immunization of guinea pigs with the tested fusion protein (2 × 0.5 µg) induces a protective effect against subsequent Mtb infection. The immunized guinea pigs do not develop the symptoms of acute TB and their body weight gain was five times more as compared with the non-immunized infected guinea pigs. The animal group immunized with this dose of antigen displays the minimum morphological changes in the internal organs and insignificant inflammatory lesions in the liver tissue, which complies with a decrease in the bacterial load in the spleen and average Mtb counts in macrophages.

Antibiotic therapy of fulminant E. coli K1 sepsis in infant rabbits.

PubMed

Law, B J; Rettig, P J; Marks, M I

1984-04-01

A model of overwhelming E. coli K1 sepsis and early meningitis was developed in infant rabbits and used to compare clinical and bacteriologic efficacy of ampicillin, moxalactam, cephalothin and chloramphenicol. Intraperitoneal injection of 10(7) E. coli K1 into 1- or 2-wk-old rabbits produced a rapidly progressive infection which, if left untreated, produced bacteremia in 100% of animals, meningitis in 78%, and mortality in 100%. Therapy was initiated 4 h after ip infection at which time mean bacterial concentration (log10 CFU/ml) ranged from 4.4-4.8 in the blood and from 1.8-2.3 in the cerebral spinal fluid (CSF). Pre-treatment frequency of bacteremia (100%) and meningitis (17-23%) was similar for all experimental groups. Antibiotic concentrations in blood and CSF 2 h after a dose exceeded the E. coli minimum inhibitory concentration with the exception of CSF cephalothin, which was undetectable. Moxalactam, ampicillin, and chloramphenicol significantly reduced the incidence of bacteremia and meningitis relative to cephalothin or saline controls (P less than 0.02). Mortality rates among the former three groups were high (64-82%) but significantly less than in saline or cephalothin-treated rabbits (100%). In this neonatal model of fulminant sepsis with early meningitis, moxalactam provided no therapeutic advantage over ampicillin or chloramphenicol.

Measurements of the radiation quality factor Q at aviation altitudes during solar minimum (2006-2008)

NASA Astrophysics Data System (ADS)

Meier, Matthias M.; Hubiak, Melina

2010-05-01

In radiation protection, the Q-factor has been defined to describe the biological effectiveness of the energy deposition or absorbed dose to humans in the mixed radiation fields at aviation altitudes. This particular radiation field is generated by the interactions of primary cosmic particles with the atoms of the constituents of the Earth’s atmosphere. Thus the intensity, characterized by the ambient dose equivalent rate H∗(10), depends on the flight altitude and the energy spectra of the particles, mainly protons and alpha particles, impinging on the atmosphere. These charged cosmic projectiles are deflected both by the interplanetary and the Earth’s magnetic field such that the corresponding energy spectra are modulated by these fields. The solar minimum is a time period of particular interest since the interplanetary magnetic field is weakest within the 11-year solar cycle and the dose rates at aviation altitudes reach their maximum due to the reduced shielding of galactic cosmic radiation. For this reason, the German Aerospace Center (DLR) performed repeated dosimetric on-board measurements in cooperation with several German airlines during the past solar minimum from March 2006 to August 2008. The Q-factors measured with a TEPC range from 1.98 at the equator to 2.60 in the polar region.

The infection rate of Daphnia magna by Pasteuria ramosa conforms with the mass-action principle.

PubMed

Regoes, R R; Hottinger, J W; Sygnarski, L; Ebert, D

2003-10-01

In simple epidemiological models that describe the interaction between hosts with their parasites, the infection process is commonly assumed to be governed by the law of mass action, i.e. it is assumed that the infection rate depends linearly on the densities of the host and the parasite. The mass-action assumption, however, can be problematic if certain aspects of the host-parasite interaction are very pronounced, such as spatial compartmentalization, host immunity which may protect from infection with low doses, or host heterogeneity with regard to susceptibility to infection. As deviations from a mass-action infection rate have consequences for the dynamics of the host-parasite system, it is important to test for the appropriateness of the mass-action assumption in a given host-parasite system. In this paper, we examine the relationship between the infection rate and the parasite inoculum for the water flee Daphnia magna and its bacterial parasite Pasteuria ramosa. We measured the fraction of infected hosts after exposure to 14 different doses of the parasite. We find that the observed relationship between the fraction of infected hosts and the parasite dose is largely consistent with an infection process governed by the mass-action principle. However, we have evidence for a subtle but significant deviation from a simple mass-action infection model, which can be explained either by some antagonistic effects of the parasite spores during the infection process, or by heterogeneity in the hosts' susceptibility with regard to infection.

Metronidazole-but not IL-10 or prednisolone-rescues Trichuris muris infected C57BL/6 IL-10 deficient mice from severe disease.

PubMed

Kopper, Jamie J; Patterson, Jon S; Mansfield, Linda S

2015-09-15

Trichuris muris infected C57BL/6 mice are a frequently studied model of immune mediated resistance to helminths. Our objective was to characterize dose-dependent gastrointestinal (GI) disease and pathology due to Trichuris in C57BL/6 mice with varying degrees of IL-10 sufficiency. These mice can serve as a model for other animals (dogs, cattle) and humans where IL-10 polymorphisms have been associated with disease susceptibility and may affect susceptibility to whipworm. C57BL/6 IL-10(+/+), IL-10(+/-) and IL-10(-/-) mice were infected with T. muris (J strain) in a dose response study. T. muris produced dose-dependent disease in IL-10(-/-) mice. Ninety percent of mice receiving the high dose (75 ova) had severe disease necessitating early euthanasia, while the medium dose (50 ova) resulted in 100% early euthanasia of males/75% of females, and the low dose (25 ova) in 100% early euthanasia of males/25% of females. Having some IL-10 as in heterozygotes did not rescue all infected mice from effects of the high dose. 2/21 IL-10(-/-), 1/17 IL-10(+/-), and 0/17 IL-10(+/+) mice in the high dose group had severe peritonitis and extra-intestinal bacteria confirmed by fluorescent 16S rDNA analysis of peritoneal organ surfaces. Three of twenty one IL-10(-/-) had demonstrable extra-intestinal T. muris adults. Although free from viral pathogens, 12/21 IL-10(-/-), 6/17 IL-10(+/-), and 4/17 IL-10(+/+) infected mice had hepatitis, while control mice of all genotypes did not. Mice had evidence of inflammation of serosal surfaces of liver, spleen and GI tract even when extraintestinal Trichuris were not found. Blinded histopathology scoring revealed that even when infected IL-10(-/-) mice displayed few, if any, clinical signs, levels of gut inflammation did not vary significantly from those mice euthanized early due to severe disease. To examine whether antibiotics or corticosteroids could reverse severe disease and lesions, IL-10(-/-) mice infected with T. muris were treated with metronidazole or prednisolone prior to and throughout 40 days of infection. Mice given prednisolone had severe disease and lesions with the highest mortality rate. Mice given metronidazole had a significantly lower mortality rate than those given prednisolone, but GI lesions were of similar severity and distribution including peritonitis. Mortality was associated with extraintestinal worms and bacteria and further supported a role for enteric bacteria in this pathogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.

Evidence for a cost of immunity when the crustacean Daphnia magna is exposed to the bacterial pathogen Pasteuria ramosa.

PubMed

Little, Tom J; Killick, Stuart C

2007-11-01

The deployment of the immune system has the obvious potential to ameliorate infection outcomes, but immune responses can also harm hosts by either damaging host tissues or monopolizing resources, leading to enhanced mortality. To gain insight into such a 'cost of immunity' when the crustacean Daphnia magna is challenged with the bacterium Pasteuria ramosa, we measured survivorship among hosts that resisted infection following exposure to various strains and doses of the parasite. In the first of two experiments, these exposures were: single exposures with relatively non-aggressive strains, double exposures with non-aggressive strains, and exposure to aggressive strains. Mortality increased across this gradient of exposure. In a second experiment, we varied the dose of the most aggressive P. ramosa strain and found that resisting infection when a large dose was applied resulted in greater mortality than when a medium or low dose was applied. Assuming that resistance is accomplished with an immune response, and that more aggressive parasites and/or larger doses of parasites are more immunostimulatory, these data are compatible with a cost of immunity. Indeed, in terms of survival, resisting parasites can be more harmful than infection.

Preclinical evaluation of multi antigenic HCV DNA vaccine for the prevention of Hepatitis C virus infection.

PubMed

Lee, Hyojin; Jeong, Moonsup; Oh, Jooyeon; Cho, Youngran; Shen, Xuefei; Stone, John; Yan, Jian; Rothkopf, Zachary; Khan, Amir S; Cho, Byung Mun; Park, Young K; Weiner, David B; Son, Woo-Chan; Maslow, Joel N

2017-03-07

Direct-acting antiviral treatment for hepatitis C virus (HCV) infection is costly and does not protect from re-infection. For human and chimpanzees, recovery from acute HCV infection correlates with host CD4+ and CD8+ T cell responses. DNA plasmids targeting the HCV non-structural antigens NS3, NS4, and NS5, were previously reported to induce robust and sustained T cell responses in mice and primates. These plasmids were combined with a plasmid encoding cytokine IL-28B, together named as VGX-6150. The dose-dependent T cell response and safety of VGX-6150 administered intramuscularly and followed by electroporation was assessed in mice. Immune responses plateaued at 20 μg/dose with IL-28B demonstrating significant immunoadjuvant activity. Mice administered VGX-6150 at 40, 400, and 800 μg given either as a single injection or as 14 injections given bi-weekly over 26 weeks showed no vaccine related changes in any clinical parameter compared to placebo recipients. There was no evidence of VGX-6150 accumulation at the injection site or in any organ 1 month following the 14 th vaccination. Based on these studies, the approximate lethal dose (ALD) exceeds 800 μg/dose and the NOAEL was 800 μg/dose in mouse. In conclusion, VGX-6150 appears safe and a promising preventive vaccine candidate for HCV infection.

Preclinical evaluation of multi antigenic HCV DNA vaccine for the prevention of Hepatitis C virus infection

PubMed Central

Lee, Hyojin; Jeong, Moonsup; Oh, Jooyeon; Cho, Youngran; Shen, Xuefei; Stone, John; Yan, Jian; Rothkopf, Zachary; Khan, Amir S.; Cho, Byung Mun; Park, Young K.; Weiner, David B.; Son, Woo-Chan; Maslow, Joel N.

2017-01-01

Direct-acting antiviral treatment for hepatitis C virus (HCV) infection is costly and does not protect from re-infection. For human and chimpanzees, recovery from acute HCV infection correlates with host CD4+ and CD8+ T cell responses. DNA plasmids targeting the HCV non-structural antigens NS3, NS4, and NS5, were previously reported to induce robust and sustained T cell responses in mice and primates. These plasmids were combined with a plasmid encoding cytokine IL-28B, together named as VGX-6150. The dose-dependent T cell response and safety of VGX-6150 administered intramuscularly and followed by electroporation was assessed in mice. Immune responses plateaued at 20 μg/dose with IL-28B demonstrating significant immunoadjuvant activity. Mice administered VGX-6150 at 40, 400, and 800 μg given either as a single injection or as 14 injections given bi-weekly over 26 weeks showed no vaccine related changes in any clinical parameter compared to placebo recipients. There was no evidence of VGX-6150 accumulation at the injection site or in any organ 1 month following the 14th vaccination. Based on these studies, the approximate lethal dose (ALD) exceeds 800 μg/dose and the NOAEL was 800 μg/dose in mouse. In conclusion, VGX-6150 appears safe and a promising preventive vaccine candidate for HCV infection. PMID:28266565

NON-FATAL INFECTION OF MICE FOLLOWING INTRACEREBRAL INOCULATION OF YELLOW FEVER VIRUS

PubMed Central

Fox, John P.

1943-01-01

Observations have been reported which indicate that mice inoculated intracerebrally with active yellow fever virus may develop an infection which is not only non-fatal but may also be completely inapparent. The most extensive observations were made on mice which showed signs of infection but were still alive 22 days after inoculation with virus of one or another of several 17D substrains. In such cases, the infection usually progressed no further and partial or complete recovery often ensued. Agents other than yellow fever virus were excluded as a significant cause of such nonfatal infections by the failure of repeated attempts to isolate other infective agents, by the demonstration of antibodies against yellow fever virus in the sera of the mice, and by the demonstration of a high degree of resistance on the part of such surviving mice to reinoculation with large doses of neurotropic yellow fever virus. Completely inapparent infections with 17D virus were also shown to occur. Studies of apparently normal survivors of 17D virus titrations revealed a small but significant number of animals resistant to intracerebral challenge with neurotropic yellow fever virus. Further, pooled sera from such mice were shown to contain specific protective antibodies. The occurrence of non-fatal infections with 17D virus was found related to virus dose and substrain. Small doses of virus provoked a significantly higher proportion of non-fatal infections than large doses; while different 17D substrains, tested over equivalent ranges of virus dose, varied greatly with respect to the proportion of infections which did not terminate with death. In the case of two substrains (17DD low and 17D3), non-fatal infections (as demonstrated by resistance to intracerebral challenge with neurotropic virus) were sufficiently frequent to cause an increase, when included in the computation of the infective titers, of 25 per cent above the figures based on deaths alone. The demonstration of non-fatal infections, thus, may be important to the accuracy of quantitative determinations of infectivity. Limited observations with virus of the French neurotropic and the pantropic Asibi strains revealed that non-fatal infections do occur, but only rarely. Somewhat more extensive observations with unmodified virus of strains isolated from Brazilian cases of jungle yellow fever, in contrast, revealed an occurrence of non-fatal infections much greater than that observed with the most productive 17D substrains. With these jungle strains, the demonstration of non-fatal infections proved indispensable to any measure of the level of infectivity of virus preparations. The demonstration of the proportional occurrence in mice of non-fatal infections with yellow fever virus provides an additional means by which different virus strains and substrains may be characterized. PMID:19871300

Interaction between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs and/or low-dose aspirin use: Old question new insights

PubMed Central

Sostres, Carlos; Gargallo, Carla Jerusalen; Lanas, Angel

2014-01-01

Previous reports clearly demonstrated that Helicobacter pylori (H. pylori) infection, nonsteroidal anti-inflammatory drugs (NSAID) or low dose aspirin (ASA) use significantly and independently increased the risk for the development of peptic ulcer disease. Today, the presence of H. pylori infection associated with low dose ASA and/or NSAID use in the same patient is becoming more frequent and therefore the potential interaction between these factors and the consequences of it has important implications. Whether NSAID intake in the presence of H. pylori infection may further increase the risk of peptic ulcer carried by the presence of only one risk factor is still a matter of debate. Studies on the interaction between the two risk factors yielded conflicting data and no consensus has been reached in the last years. In addition, the interaction between H. pylori infection and low-dose ASA remains even more controversial. In real clinical practice, we can find different clinical scenarios involving these three factors associated with the presence of different gastrointestinal and cardiovascular risk factors. These huge variety of possible combinations greatly hinder the decision making process of physicians. PMID:25071338

Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy.

PubMed

Mena, Guillermo; García-Basteiro, Alberto L; Llupià, Anna; Díez, Consolación; Costa, Josep; Gatell, Josep-María; García, Felipe; Bayas, José-María

2013-08-12

HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired. We analysed the response to vaccination (antiHAV titres ≥20IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression. The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05-0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14-0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3-10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22-5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48-3.63). The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens.

PubMed

Thabit, Abrar K; Crandon, Jared L; Nicolau, David P

2016-11-01

Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log 10 CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log 10 CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

A current review of avian influenza in pigeons and doves (Columbidae).

PubMed

Abolnik, Celia

2014-06-04

Recent reports of the detection of the zoonotic low pathogenic avian influenza (LPAI) H7N9 viruses in healthy pigeons have again put the spotlight on the potential role of pigeons and doves in the transmission of avian influenza between infected poultry and humans. A surge in studies followed the highly pathogenic avian influenza (HPAI) H5N1 epidemic, and this review collates the new data on AIV in pigeons and doves, both from a surveillance perspective, as well as the results of numerous clinical studies. Collectively, results of 32 field studies representing 24 countries across four continents indicate an antibody prevalence of 8.01% in pigeons and doves but only 0.37% of the total was associated with exposure to the same serotype as a highly pathogenic avian influenza (HPAI) outbreak occurring in poultry at the time. Only 1.1% of 6155 columbids sampled tested positive for the virus, and only 9/6155 (0.15%) viruses were detected in regions that were experiencing outbreaks of a notifiable serotype at the time. In 22 experimental infection studies with HPAI and LPAI viruses since 1944, only 26/715 (3.64%) mortalities were reported, and these could usually be associated with excessive doses of inoculum, which would induce fatal inflammatory responses. Since seroconversion and virus detection was demonstrated in many of these studies, albeit without clinical signs in most cases, it is clear that columbids are susceptible to infection, but ineffective propagators and disseminators of the virus, i.e. "dead end" hosts for AIVs, even HPAI. Viruses are shed in minute quantities from both the choana and in the feces for a short duration but titers are below the minimum threshold require to infect other species. Copyright © 2014 Elsevier B.V. All rights reserved.

Safety and tolerability of varenicline tartrate (Champix(®)/Chantix(®)) for smoking cessation in HIV-infected subjects: a pilot open-label study.

PubMed

Cui, Qu; Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix(®), Pfizer, Saint-Laurent, QC, Canada or Chantix(®), Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p = 0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.

Influenza A virus PB1-F2 protein prolongs viral shedding in chickens lengthening the transmission window

PubMed Central

James, Joe; Howard, Wendy; Iqbal, Munir; Nair, Venugopal K.; Barclay, Wendy S.

2016-01-01

Avian influenza is a significant economic burden on the poultry industry in geographical regions where it is enzootic. It also poses a public health concern when avian influenza subtypes infect humans, often with high mortality. Understanding viral genetic factors which positively contribute to influenza A virus (IAV) fitness – infectivity, spread and pathogenesis – is of great importance both for human and livestock health. PB1-F2 is a small accessory protein encoded by IAV and in mammalian hosts has been implicated in a wide range of functions that contribute to increased pathogenesis. In the avian host, the protein has been understudied despite high-level full-length conservation in avian IAV isolates, which is in contrast to the truncations of the PB1-F2 length frequently found in mammalian host isolates. Here we report that the presence of a full-length PB1-F2 protein, from a low pathogenicity H9N2 avian influenza virus, prolongs infectious virus shedding from directly inoculated chickens, thereby enhancing transmission of the virus by lengthening the transmission window to contact birds. As well as extending transmission, the presence of a full-length PB1-F2 suppresses pathogenicity evidenced by an increased minimum lethal dose in embryonated chicken eggs and increasing survival in directly infected birds when compared to a virus lacking an ORF for PB1-F2. We propose that there is a positive pressure to maintain a full-length functional PB1-F2 protein upon infection of avian hosts as it contributes to the effective transmission of IAV in the field. PMID:27558742

Influenza A virus PB1-F2 protein prolongs viral shedding in chickens lengthening the transmission window.

PubMed

James, Joe; Howard, Wendy; Iqbal, Munir; Nair, Venugopal K; Barclay, Wendy S; Shelton, Holly

2016-10-01

Avian influenza is a significant economic burden on the poultry industry in geographical regions where it is enzootic. It also poses a public health concern when avian influenza subtypes infect humans, often with high mortality. Understanding viral genetic factors which positively contribute to influenza A virus (IAV) fitness - infectivity, spread and pathogenesis - is of great importance both for human and livestock health. PB1-F2 is a small accessory protein encoded by IAV and in mammalian hosts has been implicated in a wide range of functions that contribute to increased pathogenesis. In the avian host, the protein has been understudied despite high-level full-length conservation in avian IAV isolates, which is in contrast to the truncations of the PB1-F2 length frequently found in mammalian host isolates. Here we report that the presence of a full-length PB1-F2 protein, from a low pathogenicity H9N2 avian influenza virus, prolongs infectious virus shedding from directly inoculated chickens, thereby enhancing transmission of the virus by lengthening the transmission window to contact birds. As well as extending transmission, the presence of a full-length PB1-F2 suppresses pathogenicity evidenced by an increased minimum lethal dose in embryonated chicken eggs and increasing survival in directly infected birds when compared to a virus lacking an ORF for PB1-F2. We propose that there is a positive pressure to maintain a full-length functional PB1-F2 protein upon infection of avian hosts as it contributes to the effective transmission of IAV in the field.

Safety and Tolerability of Varenicline Tartrate (Champix®/Chantix®) for Smoking Cessation in HIV-Infected Subjects: A Pilot Open-Label Study

PubMed Central

Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

Abstract The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9–12 was 42% (95% confidence interval [CI]: 26–58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline. PMID:22007690

Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital.

PubMed

Patel, Gita Wasan; Duquaine, Susan M; McKinnon, Peggy S

2007-12-01

To compare outcomes and cost for the traditional United States Food and Drug Administration-approved dosing regimen for meropenem versus an alternative dosing regimen providing similar pharmacodynamic exposure with a lower total daily dose. Retrospective cohort study with a cost-minimization analysis. A 417-bed, privately owned community hospital. One hundred patients who received meropenem 1 g every 8 or 12 hours (traditional dosing regimen) between January 1 and September 30, 2004 (historical controls), and 192 patients who received meropenem 500 mg every 6 or 8 hours (alternative dosing regimen) between October 1, 2004, and September 30, 2005. Demographic and clinical data were collected for all patients. Cost-minimization analysis was performed by using the drug acquisition cost for meropenem. Demographics, sources of infection, distributions of organisms, and Charlson Comorbidity Index scores were similar between patients in the traditionally and alternatively dosed groups. Concomitant therapy, duration of therapy, success rates, lengths of stay, and in-hospital mortality rates were also similar between groups. Median time to the resolution of symptoms was 3 days for traditional dosing and 1.5 days for alternative dosing (p<0.0001). A logistic regression model including the dosing strategy showed that only polymicrobial infections and sepsis were associated with increased failure rates. The median cost for antibiotics was $439.05/patient for traditional dosing and $234.08/patient for alternative dosing (p<0.0001). An alternative dosing regimen for meropenem with a lower total daily dose yielded patient outcomes, including success rates and duration of therapy, equivalent to those of the traditional dosing regimen. Alternative dosing decreased total drug exposure, costs for antibiotics, and time to the resolution of infections.

Climate-host mapping of Phytophthora ramorum, causal agent of sudden oak death

Treesearch

Glenn Fowler; Roger Magarey; Manuel Colunga

2006-01-01

Phytophthora ramorum infection was modeled using the NAPPFAST system for the conterminous United States. Parameters used to model P. ramorum infection were: leaf wetness, minimum temperature, optimum temperature and maximum temperature over a specified number of accumulated days. The model was used to create maps showing the...

Climate-Host Mapping of Phytophthora ramorum, causal agent of sudden oak death

Treesearch

Roger Magarey; Glenn Fowler; Manuel Colunga; Bill Smith; Ross Meentemeyer

2008-01-01

We modeled Phytophthora ramorum infection using the North Carolina State University- Animal and Plant Health Inspection Service Plant Pest Forecasting System (NAPPFAST) for the conterminous United States. Our infection model is based on a temperature-moisture response function. The model parameters were: leaf wetness, minimum temperature, optimum...

Combining the Sterile Insect Technique with the Incompatible Insect Technique: III-Robust Mating Competitiveness of Irradiated Triple Wolbachia-Infected Aedes albopictus Males under Semi-Field Conditions.

PubMed

Zhang, Dongjing; Lees, Rosemary Susan; Xi, Zhiyong; Bourtzis, Kostas; Gilles, Jeremie R L

2016-01-01

Combination of the sterile insect technique with the incompatible insect technique is considered to be a safe approach to control Aedes albopictus populations in the absence of an accurate and scalable sex separation system or genetic sexing strain. Our previous study has shown that the triple Wolbachia-infected Ae. albopictus strain (wAlbA, wAlbB and wPip) was suitable for mass rearing and females could be completely sterilized as pupae with a radiation dose of at least 28 Gy. However, whether this radiation dose can influence the mating competitiveness of the triple infected males was still unknown. In this study we aimed to evaluate the effects of irradiation on the male mating competitiveness of the triple infected strain under laboratory and semi-field conditions. The results herein indicate that irradiation with a lower, female-sterilizing dose has no negative impact on the longevity of triple infected males while a reduced lifespan was observed in the wild type males (wAlbA and wAlbB) irradiated with a higher male-sterilizing dose, in small cages. At different sterile: fertile release ratios in small cages, triple-infected males induced 39.8, 81.6 and 87.8% sterility in a wild type female population at 1:1, 5:1 and 10:1 release ratios, respectively, relative to a fertile control population. Similarly, irradiated triple infected males induced 31.3, 70.5 and 89.3% sterility at 1:1, 5:1 and 10:1 release ratios, respectively, again relative to the fertile control. Under semi-field conditions at a 5:1 release ratio, relative to wild type males, the mean male mating competitiveness index of 28 Gy irradiated triple-infected males was significantly higher than 35 Gy irradiated wild type males, while triple infected males showed no difference in mean mating competitiveness to either irradiated triple-infected or irradiated wild type males. An unexpected difference was also observed in the relative male mating competitiveness of the triple infected strain after irradiation at 28 Gy dose in small vs large cages, with a higher male mating competitiveness index calculated from results of experiments in the large cages. Based on these results, we consider that the male mating performance of the triple infected strain after irradiation at 28 Gy, a dose required for complete female sterility and the avoidance of population replacement, is approximately equal to that of the wild type males under semi-field conditions. Though field evaluation is required, this suggests that the triple infected strain is suitable for irradiation and release as part of a combined SIT-IIT approach to Ae. albopictus control.

Combining the Sterile Insect Technique with the Incompatible Insect Technique: III-Robust Mating Competitiveness of Irradiated Triple Wolbachia-Infected Aedes albopictus Males under Semi-Field Conditions

PubMed Central

Zhang, Dongjing; Lees, Rosemary Susan; Xi, Zhiyong; Bourtzis, Kostas; Gilles, Jeremie R. L.

2016-01-01

Combination of the sterile insect technique with the incompatible insect technique is considered to be a safe approach to control Aedes albopictus populations in the absence of an accurate and scalable sex separation system or genetic sexing strain. Our previous study has shown that the triple Wolbachia-infected Ae. albopictus strain (wAlbA, wAlbB and wPip) was suitable for mass rearing and females could be completely sterilized as pupae with a radiation dose of at least 28 Gy. However, whether this radiation dose can influence the mating competitiveness of the triple infected males was still unknown. In this study we aimed to evaluate the effects of irradiation on the male mating competitiveness of the triple infected strain under laboratory and semi-field conditions. The results herein indicate that irradiation with a lower, female-sterilizing dose has no negative impact on the longevity of triple infected males while a reduced lifespan was observed in the wild type males (wAlbA and wAlbB) irradiated with a higher male-sterilizing dose, in small cages. At different sterile: fertile release ratios in small cages, triple-infected males induced 39.8, 81.6 and 87.8% sterility in a wild type female population at 1:1, 5:1 and 10:1 release ratios, respectively, relative to a fertile control population. Similarly, irradiated triple infected males induced 31.3, 70.5 and 89.3% sterility at 1:1, 5:1 and 10:1 release ratios, respectively, again relative to the fertile control. Under semi-field conditions at a 5:1 release ratio, relative to wild type males, the mean male mating competitiveness index of 28 Gy irradiated triple-infected males was significantly higher than 35 Gy irradiated wild type males, while triple infected males showed no difference in mean mating competitiveness to either irradiated triple-infected or irradiated wild type males. An unexpected difference was also observed in the relative male mating competitiveness of the triple infected strain after irradiation at 28 Gy dose in small vs large cages, with a higher male mating competitiveness index calculated from results of experiments in the large cages. Based on these results, we consider that the male mating performance of the triple infected strain after irradiation at 28 Gy, a dose required for complete female sterility and the avoidance of population replacement, is approximately equal to that of the wild type males under semi-field conditions. Though field evaluation is required, this suggests that the triple infected strain is suitable for irradiation and release as part of a combined SIT-IIT approach to Ae. albopictus control. PMID:26990981

Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected children.

PubMed

Hazra, Rohan; Balis, Frank M; Tullio, Antonella N; DeCarlo, Ellen; Worrell, Carol J; Steinberg, Seth M; Flaherty, John F; Yale, Kitty; Poblenz, Marianne; Kearney, Brian P; Zhong, Lijie; Coakley, Dion F; Blanche, Stephane; Bresson, Jean Louis; Zuckerman, Judith A; Zeichner, Steven L

2004-01-01

Tenofovir disoproxil fumarate (DF) is a potent nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV)-infected adults. The single-dose and steady-state pharmacokinetics of tenofovir were evaluated following administration of tenofovir DF in treatment-experienced HIV-infected children requiring a change in antiretroviral therapy. Using increments of tenofovir DF 75-mg tablets, the target dose was 175 mg/m(2); the median administered dose was 208 mg/m(2). Single-dose pharmacokinetics were evaluated in 18 subjects, and the geometric mean area under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) was 2,150 ng. h/ml and the geometric mean maximum concentration (C(max)) was 266 ng/ml. Subsequently, other antiretrovirals were added to each patient's regimen based upon treatment history and baseline viral resistance results. Steady-state pharmacokinetics were evaluated in 16 subjects at week 4. The steady-state, geometric mean AUC for the 24-h dosing interval was 2,920 ng. h/ml and was significantly higher than the AUC(0- infinity ) after the first dose (P = 0.0004). The geometric mean C(max) at steady state was 302 ng/ml. Tenofovir DF was generally very well tolerated. Steady-state tenofovir exposures in children receiving tenofovir DF-containing combination antiretroviral therapy approached values seen in HIV-infected adults (AUC, approximately 3,000 ng. h/ml; C(max), approximately 300 ng/ml) treated with tenofovir DF at 300 mg.

The range of minimum provoking doses in hazelnut-allergic patients as determined by double-blind, placebo-controlled food challenges.

PubMed

Wensing, M; Penninks, A H; Hefle, S L; Akkerdaas, J H; van Ree, R; Koppelman, S J; Bruijnzeel-Koomen, C A F M; Knulst, A C

2002-12-01

The risk for allergic reactions depends on the sensitivity of individuals and the quantities of offending food ingested. The sensitivity varies among allergic individuals, as does the threshold dose of a food allergen capable of inducing an allergic reaction. This study aimed at determining the distribution of minimum provoking doses of hazelnut in a hazelnut-allergic population. Thirty-one patients with a history of hazelnut-related allergic symptoms, a positive skin prick test to hazelnut and/or an elevated specific IgE level, were included. Double-blind, placebo-controlled food challenges (DBPCFC) were performed with seven increasing doses of dried hazelnut (1 mg to 1 g hazelnut protein) randomly interspersed with seven placebo doses. Twenty-nine patients had a positive challenge. Itching of the oral cavity and/or lips was the first symptom in all cases. Additional gastrointestinal symptoms were reported in five patients and difficulty in swallowing in one patient. Lip swelling was observed in two patients, followed by generalized urticaria in one of these. Threshold doses for eliciting subjective reactions varied from a dose of 1 mg up to 100 mg hazelnut protein (equivalent to 6.4-640 mg hazelnut meal). Extrapolation of the dose-response curve showed that 50% of our hazelnut-allergic population will suffer from an allergic reaction after ingestion of 6 mg (95% CI, 2-11 mg) of hazelnut protein. Objective symptoms were observed in two patients after 1 and 1,000 mg, respectively. DBPCFCs demonstrated threshold doses in half of the hazelnut-allergic patients similar to doses previously described to be hidden in consumer products. This stresses the need for careful labelling and strategies to prevent and detect contamination of food products with hazelnut residues.

HPV Vaccination: Evaluation of Reminder Prompts for Doses 2 & 3

ClinicalTrials.gov

2016-05-24

Human Papilloma Virus Infection Type 11; Human Papilloma Virus Infection Type 16; Human Papilloma Virus Infection Type 18; Human Papilloma Virus Infection Type 6; Cervical Cancer; Genital Warts; Oropharyngeal Cancer

Respiratory and intraperitoneal infection of mice with encephalomyocarditis virus: effect of sublethal x-irradiation on host resistance and survival

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

Bogaerts, W.J.C.; Durville-vanderoord, B.J.

1975-01-01

The relationships governing host resistance to viral infection were evaluated in mice following respiratory or peritoneal infection with three strains of encephalomyocarditis (EMC) virus, which were antigenically similar but differed in virulence. Host resistance to each strain was evaluated by determining the mean lethal dose LD50, and the mean infectious dose ID50. The contribution of non-specific resistance to the overall defense of the host was assessed in mice that had received 450 R of x irradiation prior to viral infection. Experimental results indicate that host capacity to resist respiratory infection exceeds that for peritoneal infection for the three EMC strains.more » It is concluded that respiratory inoculation of virus affords better immunization against EMC virus infection than does peritoneal infection. (Author) (GRA)« less

High proportions of regulatory B and T cells are associated with decreased cellular responses to pH1N1 influenza vaccine in HIV-infected children and youth (IMPAACT P1088)

PubMed Central

Weinberg, Adriana; Muresan, Petronella; Fenton, Terence; Richardson, Kelly; Dominguez, Teresa; Bloom, Anthony; Petzold, Elizabeth; Anthony, Patricia; Cunningham, Coleen K.; Spector, Stephen A.; Nachman, Sharon; Siberry, George K.; Handelsman, Edward; Flynn, Patricia M.

2013-01-01

HIV-infected individuals have poor responses to inactivated influenza vaccines. To evaluate the potential role of regulatory T (Treg) and B cells (Breg), we analyzed their correlation with humoral and cell-mediated immune (CMI) responses to pandemic influenza (pH1N1) monovalent vaccine in HIV-infected children and youth. Seventy-four HIV-infected, 4- to 25-y old participants in a 2-dose pH1N1 vaccine study had circulating and pH1N1-stimulated Treg and Breg measured by flow cytometry at baseline, post-dose 1 and post-dose 2. Concomitantly, CMI was measured by ELISPOT and flow cytometry; and antibodies by hemagglutination inhibition (HAI). At baseline, most of the participants had pH1N1-specific IFNγ ELISPOT responses, whose magnitude positively correlated with the baseline pH1N1, but not with seasonal H1N1 HAI titers. pH1N1-specific IFNγ ELISPOT responses did not change post-dose 1 and significantly decreased post-dose 2. In contrast, circulating CD4+CD25+% and CD4+FOXP3+% Treg increased after vaccination. The decrease in IFNγ ELISPOT results was marginally associated with higher pH1N1-specific CD19+FOXP3+ and CD4+TGFβ+% Breg and Treg, respectively. In contrast, increases in HAI titers post-dose 1 were associated with significantly higher circulating CD19+CD25+% post-dose 1, whereas increases in IFNγ ELISPOT results post-dose 1 were associated with higher circulating CD4+/C8+CD25+FOXP3+%. In conclusion, in HIV-infected children and youth, influenza-specific Treg and Breg may contribute to poor responses to vaccination. However, robust humoral and CMI responses to vaccination may result in increased circulating Treg and/or Breg, establishing a feed-back mechanism. PMID:23370281

Pathogenesis of highly pathogenic avian influenza A virus (H7N1) infection in chickens inoculated with three different doses.

PubMed

Chaves, Aida J; Busquets, Nuria; Campos, Naiana; Ramis, Antonio; Dolz, Roser; Rivas, Raquel; Valle, Rosa; Abad, F Xavier; Darji, Ayub; Majo, Natalia

2011-04-01

To study the pathogenesis of a H7N1 highly pathogenic avian influenza virus strain, specific pathogen free chickens were inoculated with decreasing concentrations of virus: 10(5.5) median embryo lethal dose (ELD(50)) (G1), 10(3.5) ELD(50) (G2) and 10(1.5) ELD(50) (G3). Disease progression was monitored over a period of 16 days and sequential necropsies and tissue samples were collected for histological and immunohistochemical examination. Viral RNA loads were also quantified in different tissues, blood, oropharyngeal swabs, and cloacal swabs using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Clinical signs of depression, apathy, listlessness, huddling and ruffled feathers were recorded in G1 and a few G2 birds, whilst neurological signs were only observed in chickens inoculated with the highest dose. Gross lesions of haemorrhages were observed in the unfeathered skin of the comb and legs, and skeletal muscle, lung, pancreas and kidneys of birds inoculated with 10(5.5) ELD(50) and 10(3.5) ELD(50) doses. Microscopic lesions and viral antigen were demonstrated in cells of the nasal cavity, lung, heart, skeletal muscle, brain, spinal cord, gastrointestinal tract, pancreas, liver, bone marrow, thymus, bursa of Fabricius, spleen, kidney, adrenal gland and skin. Viral RNA was detected by RT-qPCR in kidney, lung, intestine, and brain samples of G1 and G2 birds. However, in birds infected with the lowest dose, viral RNA was detected only in brain and lung samples in low amounts at 5 and 7 days post infection. Interestingly, viral shedding was observed in oropharyngeal and cloacal swabs with proportionate decrease with the inoculation dose. We conclude that although an adequate infectious dose is critical in reproducing the clinical infection, chickens exposed to lower doses can be infected and shed virus representing a risk for the dissemination of the viral agent.

THE INFLUENCE OF LOW DOSES OF IONIZING RADIATION ON THE COURSE OF DYSENTERIC INFECTION (in Russian)

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

Dzhikidze, E.K.; Aksenova, A.S.

1959-04-01

Studies of the influence of chronic action of low doses of x rays on the course of latent dysenteric infection are presented. Monkeys, carriers of dysenteric bacteria for a long period of time, were subjected to x irradiation in the dose of 5 to 7 r daily (until their death). The animals died in 7 to 14 months, the total dose being 785 to 2060 r. The cause of the animals' death was due to infectious complications: activization of latent dysentery in macaco, and pneumonia and laryngitis in baboons. Marked r species exhibit specific differences in the sensitivity to dysentericmore » infection. Macaco monkeys perished from dysentery, which developed on the ground of radiation sickness; in baboons no clinical or pathomorphological manitestations of dysentery were observed. (auth)« less

Antifungal activity of amphotericin B and voriconazole against the biofilms and biofilm-dispersed cells of Candida albicans employing a newly developed in vitro pharmacokinetic model.

PubMed

El-Azizi, Mohamed; Farag, Noha; Khardori, Nancy

2015-04-03

Candida albicans is a common cause of a variety of superficial and invasive disseminated infections the majority of which are associated with biofilm growth on implanted devices. The aim of the study is to evaluate the activity of amphotericin B and voriconazole against the biofilm and the biofilm-dispersed cells of Candida albicans using a newly developed in vitro pharmacokinetic model which simulates the clinical situation when the antifungal agents are administered intermittently. RPMI medium containing 1-5 X 10(6) CFU/ml of C. albicans was continuously delivered to the device at 30 ml/h for 2 hours. The planktonic cells were removed and biofilms on the catheter were kept under continuous flow of RPMI medium at 10 ml/h. Five doses of amphotericin B or voriconazole were delivered to 2, 5 and 10 day-old biofilms at initial concentrations (2 and 3 μg/ml respectively) that were exponentially diluted. Dispersed cells in effluents from the device were counted and the adherent cells on the catheter were evaluated after 48 h of the last dose. The minimum inhibitory concentration of voriconazole and amphotericin B against the tested isolate was 0.0325 and 0.25 μg/ml respectively. Amphotericin B significantly reduced the dispersion of C. albicans cells from the biofilm. The log10 reduction in the dispersed cells was 2.54-3.54, 2.30-3.55, and 1.94-2.50 following addition of 5 doses of amphotericin B to 2-, 5- and 10-day old biofilms respectively. The number of the viable cells within the biofilm was reduced by 18 (±7.63), 5 and 4% following addition of the 5 doses of amphotericin B to the biofilms respectively. Voriconazole showed no significant effect on the viability of C. albicans within the biofilm. Both antifungal agents failed to eradicate C. albicans biofilm or stop cell dispersion from them and the resistance progressed with maturation of the biofilm. These findings go along with the need for removal of devices in spite of antifungal therapy in patients with device-related infection. This is the first study which investigates the effects of antifungal agents on the biofilm and biofilm-dispersion of C. albicans in an in vitro pharmacokinetic biofilm model.

Effects of virus dose and extrinsic incubation temperature on vector competence of Culex nigripalpus (Diptera: Culicidae) for St. Louis encephalitis virus.

PubMed

Richards, Stephanie L; Anderson, Sheri L; Lord, Cynthia C; Tabachnick, Walter J

2012-11-01

Culex nigripalpus Theobald is a primary vector of St. Louis encephalitis virus in the southeastern United States. Cx. nigripalpus females were fed blood containing a low (4.0 +/- 0.01 log10 plaque-forming unit equivalents (PFUeq) /ml) or high (4.7 +/- 0.1 log10 PFUeq/ml) St. Louis encephalitis virus dose and maintained at extrinsic incubation temperatures (EIT) of 25 or 28 degrees C for 12 d. Vector competence was measured via quantitative real-time reverse transcriptase polymerase chain reaction to estimate PFUeq using rates of infection, dissemination, and transmission. There were no differences in infection rates between the two EITs at either dose. The low dose had higher infection rates at both EITs. Dissemination rates were significantly higher at 28 degrees C compared with 25 degrees C at both doses. Virus transmission was observed (<7%) only at 28 degrees C for both doses. The virus titer in body tissues was greater at 28 degrees C compared with 25 degrees C at both doses. The difference between the EITs was greater at the low dose, resulting in a higher titer for the low dose than the high dose at 28 degrees C. Virus titers in leg tissues were greater in mosquitoes fed the high versus low dose, but were not influenced by EIT. Further investigations using a variety of environmental and biological factors would be useful in exploring the complexity of vector competence.

Effects of Virus Dose and Extrinsic Incubation Temperature on Vector Competence of Culex nigripalpus (Diptera: Culicidae) for St. Louis Encephalitis Virus

PubMed Central

RICHARDS, STEPHANIE L.; ANDERSON, SHERI L.; LORD, CYNTHIA C.; TABACHNICK, WALTER J.

2013-01-01

Culex nigripalpus Theobald is a primary vector of St. Louis encephalitis virus in the southeastern United States. Cx. nigripalpus females were fed blood containing a low (4.0 ± 0.01 log10 plaque-forming unit equivalents (PFUeq)/ml) or high (4.7 ± 0.1 log10 PFUeq/ml) St. Louis encephalitis virus dose and maintained at extrinsic incubation temperatures (EIT) of 25 or 28°C for 12 d. Vector competence was measured via quantitative real-time reverse transcriptase polymerase chain reaction to estimate PFUeq using rates of infection, dissemination, and transmission. There were no differences in infection rates between the two EITs at either dose. The low dose had higher infection rates at both EITs. Dissemination rates were significantly higher at 28°C compared with 25°C at both doses. Virus transmission was observed (<7%) only at 28°C for both doses. The virus titer in body tissues was greater at 28°C compared with 25°C at both doses. The difference between the EITs was greater at the low dose, resulting in a higher titer for the low dose than the high dose at 28°C. Virus titers in leg tissues were greater in mosquitoes fed the high versus low dose, but were not influenced by EIT. Further investigations using a variety of environmental and biological factors would be useful in exploring the complexity of vector competence. PMID:23270182

Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients

PubMed Central

Sung, Cynthia; Wei, Yuan; Watanabe, Satoru; Lee, How Sung; Khoo, Yok Moi; Fan, Lu; Rathore, Abhay P. S.; Chan, Kitti Wing-Ki; Choy, Milly M.; Kamaraj, Uma S.; Sessions, October M.; Aw, Pauline; de Sessions, Paola F.; Lee, Bernett; Connolly, John E.; Hibberd, Martin L.; Vijaykrishna, Dhanasekaran; Wijaya, Limin; Ooi, Eng Eong; Low, Jenny Guek-Hong

2016-01-01

CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients’ isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir’s potential value for treatment of other flaviruses such as Zika virus should be investigated urgently. Trial Registration: ClinicalTrials.gov NCT01619969 PMID:27509020

[Adequate anti-infective treatment : Importance of individual dosing and application].

PubMed

Brinkmann, A; Röhr, A C; Köberer, A; Fuchs, T; Krüger, W A; König, C; Richter, D; Weigand, M A; Frey, O R

2018-05-15

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (V d ) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beat-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

Passive dosimetry aboard the Mir Orbital Station: external measurements.

PubMed

Benton, E R; Benton, E V; Frank, A L

2002-10-01

This paper reports results from the first measurements made on the exterior of a LEO spacecraft of mean dose equivalent rate and average quality factor as functions of shielding depth for shielding less than 1 g/cm2 Al equivalent. Two sets of measurements were made on the outside of the Mir Orbital Station; one near solar maximum in June 1991 and one near solar minimum in 1997. Absorbed dose was measured using stacks of TLDs. LET spectrum from charged particles of LET infinity H2O > o r= 5keV/micrometers was measured using stacks of CR-39 PNTDs. Results from the TLD and PNTD measurements at a given shielding depth were combined to yield mean total dose rate, mean dose equivalent rate, and average quality factor. Measurements made near solar maximum tend to be greater than those made during solar minimum. Both mean dose rate and mean dose equivalent rate decrease by nearly four orders of magnitude within the first g/cm2 shielding illustrating the attenuation of both trapped electrons and low-energy trapped protons. In order to overcome problems with detector saturation after standard chemical processing, measurement of LET spectrum in the least shielded CR-39 PNTD layer (0.005 g/cm2 Al) was carried out using an atomic force microscope. c2002 Elsevier Science Ltd. All rights reserved.

Passive dosimetry aboard the Mir Orbital Station: external measurements

NASA Technical Reports Server (NTRS)

Benton, E. R.; Benton, E. V.; Frank, A. L.

2002-01-01

This paper reports results from the first measurements made on the exterior of a LEO spacecraft of mean dose equivalent rate and average quality factor as functions of shielding depth for shielding less than 1 g/cm2 Al equivalent. Two sets of measurements were made on the outside of the Mir Orbital Station; one near solar maximum in June 1991 and one near solar minimum in 1997. Absorbed dose was measured using stacks of TLDs. LET spectrum from charged particles of LET infinity H2O > o r= 5keV/micrometers was measured using stacks of CR-39 PNTDs. Results from the TLD and PNTD measurements at a given shielding depth were combined to yield mean total dose rate, mean dose equivalent rate, and average quality factor. Measurements made near solar maximum tend to be greater than those made during solar minimum. Both mean dose rate and mean dose equivalent rate decrease by nearly four orders of magnitude within the first g/cm2 shielding illustrating the attenuation of both trapped electrons and low-energy trapped protons. In order to overcome problems with detector saturation after standard chemical processing, measurement of LET spectrum in the least shielded CR-39 PNTD layer (0.005 g/cm2 Al) was carried out using an atomic force microscope. c2002 Elsevier Science Ltd. All rights reserved.

Hyperglycemia in BALB/c mice after pretreatment with one subdiabetogenic dose of streptozotocin and subsequent infection with a Coxsackie B4 strain.

PubMed

Wegner, U; Kewitsch, A; Madauss, M; Döhner, L; Zühlke, H

1985-01-01

Male BALB/c mice were injected with one subdiabetogenic dose of streptozotocin followed by Coxsackie B4 virus infection 7 days later. The animals developed a transient hyperglycemia after streptozotocin-pretreatment and infection with a human Coxsackie B4 isolate. Frozen sections of pancreata stained with FITC-labeled antibodies showed an intensive infection of the exocrine tissue. Immunofluorescence studies with isolated islets obtained from streptozotocin-treated or untreated animals demonstrated virus antigen in about 20% of the islets 5 days after in vivo virus infection. It is supposed that the hyperglycemia measured in our experiments was caused by a cumulative effect of streptozotocin and virus infection.

Task-Specific Optimization of Mammographic Systems

DTIC Science & Technology

2007-03-01

in Appendix II. 5.3 The results from the previous step will guide the creation for recommendations on the minimum allowable dose for...Degrees Earned Robert Saunders graduated with a doctorate in physics from Duke University in May 2006. Research Opportunities Received based on ...of dose in digital mammography has a measurable but modest impact on diagnostic accuracy.

Evaluation of dosimetry and image of very low-dose computed tomography attenuation correction for pediatric positron emission tomography/computed tomography: phantom study

NASA Astrophysics Data System (ADS)

Bahn, Y. K.; Park, H. H.; Lee, C. H.; Kim, H. S.; Lyu, K. Y.; Dong, K. R.; Chung, W. K.; Cho, J. H.

2014-04-01

In this study, phantom was used to evaluate attenuation correction computed tomography (CT) dose and image in case of pediatric positron emission tomography (PET)/CT scan. Three PET/CT scanners were used along with acryl phantom in the size for infant and ion-chamber dosimeter. The CT image acquisition conditions were changed from 10 to 20, 40, 80, 100 and 160 mA and from 80 to 100, 120 and 140 kVp, which aimed at evaluating penetrate dose and computed tomography dose indexvolume (CTDIvol) value. And NEMA PET Phantom™ was used to obtain PET image under the same CT conditions in order to evaluate each attenuation-corrected PET image based on standard uptake value (SUV) value and signal-to-noise ratio (SNR). In general, the penetrate dose was reduced by around 92% under the minimum CT conditions (80 kVp and 10 mA) with the decrease in CTDIvol value by around 88%, compared with the pediatric abdomen CT conditions (100 kVp and 100 mA). The PET image with its attenuation corrected according to each CT condition showed no change in SUV value and no influence on the SNR. In conclusion, if the minimum dose CT that is properly applied to body of pediatric patient is corrected for attenuation to ensure that the effective dose is reduced by around 90% or more compared with that for adult patient, this will be useful to reduce radiation exposure level.

Management of urinary tract infections in pregnancy: a review with comments on single dose therapy.

PubMed

Zinner, S H

1992-01-01

Most investigators agree that the adverse effects of urinary tract infections in pregnancy can be abrogated by effective early detection and treatment. However, the optimal methods for screening and treatment remain controversial. Although single-dose therapy has not been applied to pregnant women with acute pyelonephritis, most but not all studies which have compared single-dose with longer courses of beta-lactam or other antibiotics in pregnant asymptomatic bacteriuric women have shown no differences in outcome. This paper reviews recent trials of single-dose treatment of bacteriuria in pregnant women.

Postantibiotic effect and postantibiotic sub-minimum inhibitory concentration effect of valnemulin against Staphylococcus aureus isolates from swine and chickens.

PubMed

Zhao, D H; Yu, Y; Zhou, Y F; Shi, W; Deng, H; Liu, Y H

2014-02-01

The postantibiotic effect (PAE) and postantibiotic sub-minimum inhibitory concentration (MIC) effect (PA-SME) of valnemulin against Staphylococcus aureus were investigated in vitro using a spectrophotometric technique and classic viable count method. A standard curve was constructed by regression analysis of the number of colonies and the corresponding optical density (OD) at 630 nm of the inoculum. After exposure to valnemulin at different concentrations for an hour, the antibiotic was removed by centrifuging and washing. The PA-SMEs were measured after initial exposure to valnemulin at 4 × the MIC, and then, valnemulin was added to reach corresponding desired concentrations in the resuspended culture. Samples were collected hourly until the culture became turbid. The results were calculated by converting the OD values into the counts of bacteria in accordance with the curve. The MIC of valnemulin against eight strains was identically 0.125 μg ml(-1) . The mean PAEs were 2.12 h (1 × MIC) and 5.06 h (4 × MIC), and the mean PA-SMEs were 6.85 h (0.1 × MIC), 9.12 h (0.2 × MIC) and 10.8 h (0.3 × MIC). The results showed that the strains with identical MICs exhibited different PAEs and PA-SMEs. Valnemulin produced prolonged PAE and PA-SME periods for Staph. aureus, supporting a longer dosing interval while formulating a daily administration dosage. In this study, valnemulin demonstrated prolonged postantibiotic effects and postantibiotic sub-MIC effects on strains of Staphylococcus aureus. The strains with identical MICs of valnemulin exhibited different PAEs and PA-SMEs. Staphylococcus aureus isolated from different species has little impact on the postantibiotic effect of valnemulin. The result suggests a longer dosing interval while formulating a daily administration dosage, and it may play a valuable role of valnemulin in treating Staph. aureus infections in animals. © 2013 The Society for Applied Microbiology.

Antimicrobial nisin acts against saliva derived multi-species biofilms without cytotoxicity to human oral cells

PubMed Central

Shin, Jae M.; Ateia, Islam; Paulus, Jefrey R.; Liu, Hongrui; Fenno, J. Christopher; Rickard, Alexander H.; Kapila, Yvonne L.

2015-01-01

Objectives: Nisin is a lantibiotic widely used for the preservation of food and beverages. Recently, investigators have reported that nisin may have clinical applications for treating bacterial infections. The aim of this study was to investigate the effects of ultra pure food grade Nisin ZP (>95% purity) on taxonomically diverse bacteria common to the human oral cavity and saliva derived multi-species oral biofilms, and to discern the toxicity of nisin against human cells relevant to the oral cavity. Methods: The minimum inhibitory concentrations and minimum bactericidal concentrations of taxonomically distinct oral bacteria were determined using agar and broth dilution methods. To assess the effects of nisin on biofilms, two model systems were utilized: a static and a controlled flow microfluidic system. Biofilms were inoculated with pooled human saliva and fed filter-sterilized saliva for 20–22 h at 37°C. Nisin effects on cellular apoptosis and proliferation were evaluated using acridine orange/ethidium bromide fluorescent nuclear staining and lactate dehydrogenase activity assays. Results: Nisin inhibited planktonic growth of oral bacteria at low concentrations (2.5–50 μg/ml). Nisin also retarded development of multi-species biofilms at concentrations ≥1 μg/ml. Specifically, under biofilm model conditions, nisin interfered with biofilm development and reduced biofilm biomass and thickness in a dose-dependent manner. The treatment of pre-formed biofilms with nisin resulted in dose- and time-dependent disruption of the biofilm architecture along with decreased bacterial viability. Human cells relevant to the oral cavity were unaffected by the treatment of nisin at anti-biofilm concentrations and showed no signs of apoptotic changes unless treated with much higher concentrations (>200 μg/ml). Conclusion: This work highlights the potential therapeutic value of high purity food grade nisin to inhibit the growth of oral bacteria and the development of biofilms relevant to oral diseases. PMID:26150809

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.

PubMed

Sankaranarayanan, Rengaswamy; Joshi, Smita; Muwonge, Richard; Esmy, Pulikottil Okkuru; Basu, Partha; Prabhu, Priya; Bhatla, Neerja; Nene, Bhagwan M; Shaw, Janmesh; Poli, Usha Rani Reddy; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Tommasino, Massimo; Pawlita, Michael; Gheit, Tarik; Waterboer, Tim; Sehr, Peter; Pillai, Madhavan Radhakrishna

2018-03-15

Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Assessment of radiation exposure from cesium-137 contaminated roads for epidemiological studies in Seoul, Korea

PubMed Central

Lee, Yun-Keun; Ju, Young-Su; Lee, Won Jin; Hwang, Seung Sik; Yim, Sang-Hyuk; Yoo, Sang-Chul; Lee, Jieon; Choi, Kyung-Hwa; Burm, Eunae; Ha, Mina

2015-01-01

Objectives We aimed to assess the radiation exposure for epidemiologic investigation in residents exposed to radiation from roads that were accidentally found to be contaminated with radioactive cesium-137 (137Cs) in Seoul. Methods Using information regarding the frequency and duration of passing via the 137Cs contaminated roads or residing/working near the roads from the questionnaires that were obtained from 8875 residents and the measured radiation doses reported by the Nuclear Safety and Security Commission, we calculated the total cumulative dose of radiation exposure for each person. Results Sixty-three percent of the residents who responded to the questionnaire were considered as ever-exposed and 1% of them had a total cumulative dose of more than 10 mSv. The mean (minimum, maximum) duration of radiation exposure was 4.75 years (0.08, 11.98) and the geometric mean (minimum, maximum) of the total cumulative dose was 0.049 mSv (<0.001, 35.35) in the exposed. Conclusions An individual exposure assessment was performed for an epidemiological study to estimate the health risk among residents living in the vicinity of 137Cs contaminated roads. The average exposure dose in the exposed people was less than 5% of the current guideline. PMID:26184047

Antimicrobial activity of silver nanoparticles synthesized using honey and gamma radiation against silver-resistant bacteria from wounds and burns

NASA Astrophysics Data System (ADS)

Hosny, A. M. S.; Kashef, M. T.; Rasmy, S. A.; Aboul-Magd, D. S.; El-Bazza, Z. E.

2017-12-01

Silver nanoparticles (AgNPs) are promising antimicrobial agents for treatment of wounds and burns. We synthesized AgNPs using honey at different pH values or with different gamma irradiation doses. The resulting nanoparticles were characterized by UV-vis spectroscopy, TEM, DLS and FTIR. Their antimicrobial activity, against standard bacterial strains and silver-resistant clinical isolates from infected wounds and burns, was evaluated in vitro through determination of their minimum inhibitory concentration (MIC). AgNPs prepared using 30 g of honey exposed to 5 kGy gamma radiation had the best physical characters regarding stability and uniformity of particle size and shape. They recorded the lowest MIC values against both the standard and silver-resistant isolates. In conclusion, honey and gamma radiation can be used in synthesis of highly stable pure AgNPs, without affecting the physico-chemical and antimicrobial activity of honey. This offered an advantage in terms of inhibition of silver-resistant bacteria isolates.

Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.

PubMed

Arem, Hannah; Moore, Steven C; Patel, Alpa; Hartge, Patricia; Berrington de Gonzalez, Amy; Visvanathan, Kala; Campbell, Peter T; Freedman, Michal; Weiderpass, Elisabete; Adami, Hans Olov; Linet, Martha S; Lee, I-Min; Matthews, Charles E

2015-06-01

The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. Leisure time moderate- to vigorous-intensity physical activity. The upper limit of mortality benefit from high levels of leisure time physical activity. Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

Urinary tract infection - adults

MedlinePlus

... before taking these drugs. RECURRENT BLADDER INFECTIONS Some women have repeated bladder infections. Your provider may suggest that you: Take a single dose of an antibiotic after sexual contact to ...

Development of the dose-response relationship for human toxoplasma gondii infection associated with meat consumption

USDA-ARS?s Scientific Manuscript database

Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States.A substantial portion of human T. gondii infections may be acquired through the consumption of meats. The dose-response relationship for human exposure...

Antibacterial activity of Artemisia asiatica essential oil against some common respiratory infection causing bacterial strains and its mechanism of action in Haemophilus influenzae.

PubMed

Huang, Jiehui; Qian, Chao; Xu, Hongjie; Huang, Yanjie

2018-01-01

The main objective of the current study was to investigate the chemical composition of the essential oil of Artemisia asiatica together with investigating the antibacterial effects it exerts on several common respiratory infection causing bacteria including Haemophilus influenzae. Its mechanism of action was studied using various state-of-the-art assays like scanning electron microscopy, DNA, RNA and protein leakage assays, growth curve assays etc. The essential oil was extracted from the leaves of A. asiatica by supercritical CO 2 fluid extraction technology. Chemical composition of essential oils was analyzed by gas chromatography-mass-spectrometry (GC-MS). The antibacterial activity was evaluated against 6 bacteria by the paper disc diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericide concentration (MBC) values of the essential oil were estimated by agar dilution method. The antibacterial mechanism was evaluated by growth curve, the integrity of cell membrane and scanning electronmicroscope (SEM). Gas chromatographic analysis of the A. asiatica essential oil led to the identification of 16 chemical constituents accounting for 97.2% of the total oil composition. The major components were found to be Piperitone, (z)-davanone, p-cymene and 1, 8-cineole. The essential oil showed maximum growth inhibition against Haemophilus influenzae with a zone of inhibition of 24.5 mm and MIC/MBC values of 1.9/4.5 mg/mL respectively. Bacteria treated with the essential oil led to a rapid decrease in the number of viable cells. On adding the essential oil of A. asiatica to the bacterial culture, the constituents of the bacterial cell got released into the medium and this cell constituent release increased with increasing doses of the essential oil. SEM showed that the bacterial cells treated with the essential oil showed damaged cell wall, deformed cell morphology and shrunken cells. Copyright © 2017. Published by Elsevier Ltd.

High doses of corticosteroid suppress resistance to Ichthyophonus in starry flounder

USGS Publications Warehouse

Perry, J.A.; Kocan, R.M.; Winton, J.R.; Hershberger, P.K.

2004-01-01

Application of pharmacological doses of the corticosteroid dexamethasone phosphate to starry flounder Platichthys stellatus resulted in a predisposition to clinical ichthyophoniasis and a progression from latent Ichthyophonus infections to patent, histologically identifiable infections. Among Ichthyophonus-challenged starry flounder, the prevalences of clinical infections and histologically identifiable infections were significantly greater in two groups that received dexamethasone (100% and 31%, respectively) than in the respective control groups (8% and 0%). Proliferation of Ichthyophonus infections in corticosteroid-treated groups may have resulted from suppression of the cellular immune response that typically follows corticosteroid application; however, further studies are needed to determine whether these effects occur at lower, physiological concentrations of corticosteroids.

In vitro and in vivo efficacy of fluorodeoxycytidine analogs against highly pathogenic avian influenza H5N1, seasonal, and pandemic H1N1 virus infections

PubMed Central

Kumaki, Yohichi; Day, Craig W.; Smee, Donald F.; Morrey, John D.; Barnard, Dale L.

2011-01-01

Various fluorodeoxyribonucleosides were evaluated for their antiviral activities against influenza virus infections in vitro and in vivo. Among the most potent inhibitors was 2'-deoxy-2'-fluorocytidine (2'-FdC). It inhibited various strains of low and highly pathogenic avian influenza H5N1 viruses, pandemic H1N1 viruses, an oseltamivir-resistant pandemic H1N1 virus, and seasonal influenza viruses (H3N2, H1N1, influenza B) in MDCK cells, with the 90% inhibitory concentrations ranging from 0.13 µM to 4.6 µM, as determined by a virus yield reduction assay. 2'-FdC was then tested for efficacy in BALB/c mice infected with a lethal dose of highly pathogenic influenza A/Vietnam/1203/2004 H5N1 virus. 2’FdC (60 mg/kg/d) administered intraperitoneally (i.p.) twice a day beginning 24 h after virus exposure significantly promoted survival (80% survival) of infected mice (p=0.0001). Equally efficacious were the treatment regimens in which mice were treated with 2'-FdC at 30 or 60 mg/kg/day (bid × 8) beginning 24 h before virus exposure. At these doses, 70–80% of the mice were protected from death due to virus infection (p=0.0005, p=0.0001; respectively). The lungs harvested from treated mice at day four of the infection displayed little surface pathology or histopathology, lung weights were lower, and the 60 mg/kg dose reduced lung virus titers, although not significantly compared to the placebo controls. All doses were well tolerated in uninfected mice. 2'-FdC could also be administered as late as 72 h post virus exposure and still significantly protect 60% mice from the lethal effects of the H5N1 virus infection (p=0.019). Other fluorodeoxyribonucleosides tested in the H5N1 mouse model, 2’-deoxy-5-fluorocytidine and 2'-deoxy-2', 2'-difluorocytidine, were very toxic at higher doses and not inhibitory at lower doses. Finally, 2'-FdC, which was active in the H5N1 mouse model, was also active in a pandemic H1N1 influenza A infection model in mice. When given at 30 mg/kg/d (bid × 5) beginning 24 h before virus exposure), 2’-FdC also significantly enhanced survival of H1N1-infected mice (50%, p=0.038) similar to the results obtained in the H5N1 infection model using a similar dosing regimen (50%, p<0.05). Given the demonstrated in vitro and in vivo inhibition of avian influenza virus replication, 2’FdC may qualify as a lead compound for the development of agents treating influenza virus infections. PMID:21925541

Minimum anesthetic volume in regional anesthesia by using ultrasound-guidance.

PubMed

Di Filippo, Alessandro; Falsini, Silvia; Adembri, Chiara

2016-01-01

The ultrasound guidance in regional anesthesia ensures the visualization of needle placement and the spread of Local Anesthetics. Over the past few years there was a substantial interest in determining the Minimum Effective Anesthetic Volume necessary to accomplish surgical anesthesia. The precise and real-time visualization of Local Anesthetics spread under ultrasound guidance block may represent the best requisite for reducing Local Anesthetics dose and Local Anesthetics-related effects. We will report a series of studies that have demonstrated the efficacy of ultrasound guidance blocks to reduce Local Anesthetics and obtain surgical anesthesia as compared to block performed under blind or electrical nerve stimulation technique. Unfortunately, the results of studies are widely divergent and not seem to indicate a dose considered effective, for each block, in a definitive way; but it is true that, through the use of ultrasound guidance, it is possible to reduce the dose of anesthetic in the performance of anesthetic blocks. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

[Decision process of Notification Value by the Dose Index Registry system in X-ray computed tomography].

PubMed

Shinozaki, Masafumi; Muramatsu, Yoshihisa; Sasaki, Toru

2014-01-01

A new technical standard for X-ray computed tomography (CT) has been published by the National Electrical Manufacturers Association (NEMA) that allows the Alert Value and Notification Value for cumulative dose to be configurable by CT systems operators in conjunction with the XR-25 (Dose check) standard. In this study, a decision method of the Notification Values for reducing the radiation dose was examined using the dose index registry (DIR) system, during 122 continuous days from August 1, 2012 to November 30, 2012. CT images were obtained using the Discovery CT 750HD (GE Healthcare) and the dose index was calculated using the DoseWatch DIR system. The CT dose index-volume (CTDIvol) and dose-length product (DLP) were output from the DIR system in comma-separated value (CSV) file format for each examination protocol. All data were shown as a schematic boxplot using statistical processing software. The CTDIvol of a routine chest examination showed the following values (maximum: 23.84 mGy; minimum: 2.55 mGy; median: 7.60 mGy; 75% tile: 10.01 mGy; 25% tile: 6.54 mGy). DLP showed the following values (maximum: 944.56 mGy·cm; minimum: 97.25 mGy·cm; median: 307.35 mGy·cm; 75% tile: 406.87 mGy·cm; 25% tile: 255.75 mGy·cm). These results indicate that the 75% tile of CTDIvol and DLP as an initial value proved to be safe and efficient for CT examination and operation. We have thus established one way of determining the Notification Value from the output of the DIR system. Transfer back to the protocol of the CT and automated processing each numeric value in the DIR system is desired.

Monitoring exposure to atomic bomb radiation by somatic mutation

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

Akiyama, Mitoshi; Kyoizumi, Seishi; Kusunoki, Yoichiro

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in femalesmore » and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure. 27 refs., 2 figs.« less

High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

PubMed

Takahashi, Hiroyuki; Watanabe, Tomoyuki; Kinoshita, Akitoshi; Yuza, Yuki; Moritake, Hiroshi; Terui, Kiminori; Iwamoto, Shotaro; Nakayama, Hideki; Shimada, Akira; Kudo, Kazuko; Taki, Tomohiko; Yabe, Miharu; Matsushita, Hiromichi; Yamashita, Yuka; Koike, Kazutoshi; Ogawa, Atsushi; Kosaka, Yoshiyuki; Tomizawa, Daisuke; Taga, Takashi; Saito, Akiko M; Horibe, Keizo; Nakahata, Tatsutoshi; Miyachi, Hayato; Tawa, Akio; Adachi, Souichi

2016-08-01

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered. © 2016 John Wiley & Sons Ltd.

The effects of Myxobolus cerebralis, myxospore dose on triactinomyxon production and biology of Tubifex tubifex from two geographic regions

USGS Publications Warehouse

Stevens, Richard; Kerans, B.L.; Lemmon, J. C.; Rasmussen, Charlotte

2001-01-01

The aquatic oligochaete Tubifex tubifex is an obligate host of Myxobolus cerebralis, the causative agent of salmonid whirling disease. Tubifex tubifex can become infected by ingesting myxospores ofM. cerebralis that have been released into sediments upon death and decomposition of infected salmonids. Infected worms release triactinomyxons into the water column that then infect salmonids. How the dose of myxospores ingested by T. tubifex influences parasite proliferation and the worm host are not well understood. Using replicated laboratory experiments, we examined how differing doses of myxospores (50, 500, 1,000 per worm) influenced triactinomyxon production and biomass, abundance, and individual weight of 2 geographically distinct populations of T. tubifex. Worm populations produced differing numbers of triactinomyxons, but, within a population, the production did not differ among myxospore doses. At the lowest myxospore dose, 1 worm population produced 45 times more triactinomyxons than myxospores received, whereas the other produced only 6 times more triactinomyxons than myxospores. Moreover, total T. tubifex biomass, abundance, and individual weight were lower among worms receiving myxospores than in myxospore-free controls. Thus, T. tubifex populations differ in ability to support the replication of M. cerebralis, and infection has measurable consequences on fitness of the worm host. These results suggest that variability in whirling disease severity observed in wild salmonid populations may partially be attributed to differences in T. tubifex populations.

Impact of electronic health record-based, pharmacist-driven valganciclovir dose optimization in solid organ transplant recipients.

PubMed

Hensler, David; Richardson, Chad L; Brown, Joslyn; Tseng, Christine; DeCamp, Phyllis J; Yang, Amy; Pawlowski, Anna; Ho, Bing; Ison, Michael G

2018-04-01

Prophylaxis with valganciclovir reduces the incidence of cytomegalovirus (CMV) infection following solid organ transplant (SOT). Under-dosing of valganciclovir is associated with an increased risk of CMV infection and development of ganciclovir-resistant CMV. An automated electronic health record (EHR)-based, pharmacist-driven program was developed to optimize dosing of valganciclovir in solid organ transplant recipients at a large transplant center. Two cohorts of kidney, pancreas-kidney, and liver transplant recipients from our center pre-implementation (April 2011-March 2012, n = 303) and post-implementation of the optimization program (September 2012-August 2013, n=263) had demographic and key outcomes data collected for 1 year post-transplant. The 1-year incidence of CMV infection dropped from 56 (18.5%) to 32 (12.2%, P = .05) and the incidence of breakthrough infections on prophylaxis was cut in half (61% vs 34%, P = .03) after implementation of the dose optimization program. The hazard ratio of developing CMV was 1.64 (95% CI 1.06-2.60, P = .027) for the pre-implementation group after adjusting for potential confounders. The program also resulted in a numerical reduction in the number of ganciclovir-resistant CMV cases (2 [0.7%] pre-implementation vs 0 post-implementation). An EHR-based, pharmacist-driven valganciclovir dose optimization program was associated with reduction in CMV infections. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Health and productivity of dairy cows fed polychlorinated biphenyls

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

Willett, L.B.; Liu, T.T.; Durst, H.I.

1987-07-01

Holstein cows were studied through a complete lactation, a nonlactating period, and 42 days of a subsequent lactation for overt and subtle responses to a commercial mixture of polychlorinated biphenyls. Dosed cows (n = 4) received consecutive 60-day periods of daily dosing with 10, 100, and 1000 mg of Aroclor 1254. Control cows (n = 6) received daily sham doses. The following were recorded: daily milk production, feed intake, and health observations; weekly body weight, temperature, heart and respiratory rates and rectal palpation; semi-monthly clinical chemistry determinations; and monthly milk fat, microbiological culture of quarter foremilk samples, and composite milkmore » somatic cell counts. Mean daily milk production (22.4 +/- 1.1 vs 24.8 +/- 1.0 kg) and net energy of a complete lactation (1.46 +/- 0.05 vs 1.45 +/- 0.03 Mcal/kg dry matter intake) were not different (p = 0.85) for control and PCB-dosed cows. Milk production during the first 42 days of the subsequent lactation was also similar for control and dosed cows. Occurrences of injuries, dysfunctions, and general infections were not related to polychlorinated biphenyl exposure. Intramammary infections were detected for both lactations with 51 and 32 infections detected in microbiological cultures, respectively, for the control and dosed groups. Environmental pathogens were most frequently isolated from cases of clinically apparent mastitis. The majority of quarter infections detected were due to Corynebacterium bovis. Only one animal (dosed, necropsy revealed left oviduct obstructed) failed to conceive with three to six services required before conception for the other control and dosed cows. Exposure to polychlorinated biphenyls resulting in maximal residues in milk fat, near 100 micrograms/g, had no apparent effect on health and productivity.« less

Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study.

PubMed

Regules, Jason A; Cicatelli, Susan B; Bennett, Jason W; Paolino, Kristopher M; Twomey, Patrick S; Moon, James E; Kathcart, April K; Hauns, Kevin D; Komisar, Jack L; Qabar, Aziz N; Davidson, Silas A; Dutta, Sheetij; Griffith, Matthew E; Magee, Charles D; Wojnarski, Mariusz; Livezey, Jeffrey R; Kress, Adrian T; Waterman, Paige E; Jongert, Erik; Wille-Reece, Ulrike; Volkmuth, Wayne; Emerling, Daniel; Robinson, William H; Lievens, Marc; Morelle, Danielle; Lee, Cynthia K; Yassin-Rajkumar, Bebi; Weltzin, Richard; Cohen, Joe; Paris, Robert M; Waters, Norman C; Birkett, Ashley J; Kaslow, David C; Ballou, W Ripley; Ockenhouse, Christian F; Vekemans, Johan

2016-09-01

Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. NCT01857869. Published by Oxford University Press on behalf of the Infectious Diseases Society of America, 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Median infectious dose (ID₅₀) of porcine reproductive and respiratory syndrome virus isolate MN-184 via aerosol exposure.

PubMed

Cutler, Timothy D; Wang, Chong; Hoff, Steven J; Kittawornrat, Apisit; Zimmerman, Jeffrey J

2011-08-05

The median infectious dose (ID(50)) of porcine reproductive and respiratory syndrome (PRRS) virus isolate MN-184 was determined for aerosol exposure. In 7 replicates, 3-week-old pigs (n=58) respired 10l of airborne PRRS virus from a dynamic aerosol toroid (DAT) maintained at -4°C. Thereafter, pigs were housed in isolation and monitored for evidence of infection. Infection occurred at virus concentrations too low to quantify by microinfectivity assays. Therefore, exposure dose was determined using two indirect methods ("calculated" and "theoretical"). "Calculated" virus dose was derived from the concentration of rhodamine B monitored over the exposure sequence. "Theoretical" virus dose was based on the continuous stirred-tank reactor model. The ID(50) estimate was modeled on the proportion of pigs that became infected using the probit and logit link functions for both "calculated" and "theoretical" exposure doses. Based on "calculated" doses, the probit and logit ID(50) estimates were 1 × 10(-0.13)TCID(50) and 1 × 10(-0.14)TCID(50), respectively. Based on "theoretical" doses, the probit and logit ID(50) were 1 × 10(0.26)TCID(50) and 1 × 10(0.24)TCID(50), respectively. For each point estimate, the 95% confidence interval included the other three point estimates. The results indicated that MN-184 was far more infectious than PRRS virus isolate VR-2332, the only other PRRS virus isolate for which ID(50) has been estimated for airborne exposure. Since aerosol ID(50) estimates are available for only these two isolates, it is uncertain whether one or both of these isolates represent the normal range of PRRS virus infectivity by this route. Copyright © 2011 Elsevier B.V. All rights reserved.

Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets▿

PubMed Central

Decloedt, Eric H.; McIlleron, Helen; Smith, Peter; Merry, Concepta; Orrell, Catherine; Maartens, Gary

2011-01-01

Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C0) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), C0, C12, maximum concentration of drug in serum (Cmax), or half-life (t1/2) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies. PMID:21537021

Pharmacokinetics and Safety of High-Dose and Extended-Interval Regimens of Levofloxacin in Human Immunodeficiency Virus-Infected Patients

PubMed Central

Piscitelli, Stephen C.; Spooner, Katherine; Baird, Barbara; Chow, Andrew T.; Fowler, Cynthia L.; Williams, Rex R.; Natarajan, Jaya; Masur, Henry; Walker, Robert E.

1999-01-01

The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers. PMID:10471591

A comparative study of single-dose treatment of chancroid using thiamphenicol versus Azithromycin.

PubMed

Belda, Walter; Di Chiacchio, Nilton G; Di Chiacchio, Nilton; Romiti, Ricardo; Criado, Paulo R; Velho, Paulo Eduardo N Ferreira

2009-06-01

A study was conducted in São Paulo, Brazil, to compare azithromycin with thiamphenicol for the single-dose treatment of chancroid. In all, 54 men with chancroid were tested. The etiology was determined by clinical characterization and direct bacterioscopy with Gram staining. None of the patients had positive serology or dark-field examination indicating active infection with Treponema pallidum. Genital infections due to Neisseria gonorrhoeae and herpes simplex virus were excluded by polymerase chain reaction testing. For 54 patients with chancroid, cure rates with single-dose treatment were 73% with azithromycin and 89% with thiamphenicol. HIV seropositivity was found to be associated with treatment failure (p=0.001). The treatment failed in all HIV positive patients treated with azithromycin (p=0.002) and this drug should be avoided in these co-infected patients. In the view of the authors, thiamphenicol is the most indicated single-dose regimen for chancroid treatment.

Shedding of Renibacterium salmoninarum by infected chinook salmon Oncorhynchus tschawytscha

USGS Publications Warehouse

McKibben, C.L.; Pascho, R.J.

1999-01-01

Laboratory studies of the transmission and pathogenesis of Renibacterium salmoninarum may describe more accurately what is occurring in the natural environment if test fish are infected by waterborne R. salmoninarum shed from infected fish. To quantify bacterial shedding by chinook salmon Oncorhynchus tschawytscha at 13??C in freshwater, groups of fish were injected intraperitoneally with R. salmoninarum at either 1.3 x 106 colony forming units (CFU) fish-1 (high-dose injection group) or 1.5 x 103 CFU fish-1 (low-dose injection group). R. salmoninarum infection levels were measured in the exposed fish by the enzyme-linked immunosorbent assay (BKD-ELISA). At regular intervals for 30 d, the numbers of R. salmoninarum shed by the injected fish were calculated on the basis of testing water samples by the membrane filtration-fluorescent antibody test (MF-FAT) and bacteriological culture. Mean BKD-ELISA optical densities (ODs) for fish in the low-dose injection group were not different from those of control fish [p > 0.05), and no R. salmoninarum were detected in water samples taken up to 30 d after injection of fish in the low-dose group. By 12 d after injection a proportion of the fish from the high-dose infection group had high (BKD-ELISA OD ??? 1.000) to severe (BKD-ELISA OD ??? 2.000) R. salmoninarum infection levels, and bacteria were detected in the water by both tests. However, measurable levels of R. salmoninarum were not consistently detected in the water until a proportion of the fish maintained high to severe infection levels for an additional 8 d. The concentrations of R salmoninarum in the water samples ranged from undetectable up to 994 cells ml-1 on the basis of the MF-FAT, and up to 1850 CFU ml-1 on the basis of bacteriological culture. The results suggest that chinook salmon infected with R. salmoninarum by injection of approximately 1 x 106 CFU fish-1 can be used as the source of infection in cohabitation challenges beginning 20 darter injection.

Effectiveness of 7-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in HIV-Infected and -Uninfected Children in South Africa: A Matched Case-Control Study

PubMed Central

Cohen, Cheryl; von Mollendorf, Claire; de Gouveia, Linda; Naidoo, Nireshni; Meiring, Susan; Quan, Vanessa; Nokeri, Vusi; Fortuin-de Smit, Melony; Malope-Kgokong, Babatyi; Moore, David; Reubenson, Gary; Moshe, Mamokgethi; Madhi, Shabir A.; Eley, Brian; Hallbauer, Ute; Kularatne, Ranmini; Conklin, Laura; O'Brien, Katherine L.; Zell, Elizabeth R.; Klugman, Keith; Whitney, Cynthia G.; von Gottberg, Anne; Moore, David; Verwey, Charl; Varughese, Sheeba; Archary, Moherndran; Naby, Fathima; Dawood, Khathija; Naidoo, Ramola; Elliott, Gene; Hallbauer, Ute; Eley, Brian; Nuttall, James; Cooke, Louise; Finlayson, Heather; Rabie, Helena; Whitelaw, Andrew; Perez, Dania; Jooste, Pieter; Naidoo, Dhamiran; Kularatne, Ranmini; Reubenson, Gary; Cohen, Cheryl; de Gouveia, Linda; du Plessis, Mignon; Govender, Nevashan; Meiring, Susan; Quan, Vanessa; von Mollendorf, Claire; Fortuin-de Smidt, Melony; Naidoo, Nireshni; Malope-Kgokong, Babatyi; Nokeri, Vusi; Ncha, Relebohile; Lindani, Sonwabo; von Gottberg, Anne; Spies, Barry; Sono, Lino; Maredi, Phasweni; Hamese, Ken; Moshe, Mamokgethi; Nchabeleng, Maphosane; Ngcobo, Ntombenhle; van den Heever, Johann; Madhi, Shabir; Conklin, Laura; Verani, Jennifer; Whitney, Cynthia; Zell, Elizabeth; Loo, Jennifer; Nelson, George; Klugman, Keith; O'Brien, Katherine

2014-01-01

Background. South Africa introduced 7-valent pneumococcal conjugate vaccine (PCV7) in April 2009 using a 2 + 1 schedule (6 and 14 weeks and 9 months). We estimated the effectiveness of ≥2 PCV7 doses against invasive pneumococcal disease (IPD) in human immunodeficiency virus (HIV)–infected and -uninfected children. Methods. IPD (pneumococcus identified from a normally sterile site) cases were identified through national laboratory-based surveillance. Specimens were serotyped by Quellung or polymerase chain reaction. Four controls, matched for age, HIV status, and hospital were sought for each case. Using conditional logistic regression, we calculated vaccine effectiveness (VE) as 1 minus the adjusted odds ratio for vaccination. Results. From March 2010 through November 2012, we enrolled 187 HIV-uninfected (48 [26%] vaccine serotype) and 109 HIV-infected (43 [39%] vaccine serotype) cases and 752 HIV-uninfected and 347 HIV-infected controls aged ≥16 weeks. Effectiveness of ≥2 PCV7 doses against vaccine-serotype IPD was 74% (95% confidence interval [CI], 25%–91%) among HIV-uninfected and −12% (95% CI, −449% to 77%) among HIV-infected children. Effectiveness of ≥3 doses against vaccine-serotype IPD was 90% (95% CI, 14%–99%) among HIV-uninfected and 57% (95% CI, −371% to 96%) among HIV-infected children. Among HIV-exposed but -uninfected children, effectiveness of ≥2 doses was 92% (95% CI, 47%–99%) against vaccine-serotype IPD. Effectiveness of ≥2 doses against all-serotype multidrug-resistant IPD was 96% (95% CI, 62%–100%) among HIV-uninfected children. Conclusions. A 2 + 1 PCV7 schedule was effective in preventing vaccine-serotype IPD in HIV-uninfected and HIV-exposed, uninfected children. This finding supports the World Health Organization recommendation for this schedule as an alternative to a 3-dose primary series among HIV-uninfected individuals. PMID:24917657

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

PubMed

Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

2016-10-01

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

A comparative study of the effects of Escherichia coli and Clostridium perfringens upon boar semen preserved in liquid storage.

PubMed

Pinart, Elisabeth; Domènech, Esther; Bussalleu, Eva; Yeste, Marc; Bonet, Sergi

2017-02-01

The present study compares the sperm quality of boar seminal doses artificially inoculated with Escherichia coli and Clostridium perfringens, and maintained in liquid storage at 15°C for a 9-day period. Seminal doses from 10 sexually mature Piétrain boars were diluted in a Beltsville Thawing Solution (BTS)-based extender and infected either with E. coli or C. perfringens, with bacterial loads ranging from 10 1 to 10 7 cfumL -1 . During storage, the changes in sperm quality were determined by assessing pH, sperm viability, sperm motiliy, sperm morphology, sperm agglutination degree, and sperm-bacteria interaction. The infection of seminal doses led to an alkalinization of the medium, which was of higher extend in doses infected with C. perfringens. The effect of contamination on sperm viability and motility relied on bacterial type and load. Therefore, while E. coli was more harmful than C. perfringens in bacterial loads ranging from 10 1 to 10 6 cfumL -1 , the detrimental impact of C. perfringens was more apparent than that of E. coli at a bacterial load of 10 7 cfumL -1 . Despite sperm morphology not being affected by either bacterial type or load, sperm agglutination and sperm-bacteria interaction were characteristic of doses infected with E. coli, and increased concomintantly with bacterial load and along storage period. In conclusion, the effects of infection by E. coli on sperm quality were dependent of both bacterial load and storage period, whereas the effects of C. perfringens were mainly dependent on the bacterial load, with a threshold at 10 7 cfumL -1 from which the sperm quality of seminal doses was greatly impaired. Copyright © 2016 Elsevier B.V. All rights reserved.

Specific serum protein changes associated with primary and secondary Strongylus vulgaris infections in pony yearlings.

PubMed

Kent, J E

1987-03-01

The concentrations of haptoglobin, immunoglobin (Ig)G(T) and IgG were measured in the serum of four previously parasite-free pony yearlings following a single dose of 700 (Group H) or 200 (Group L) stage three Strongylus vulgaris larvae (L3) and following a reinfection with the same doses 34 weeks later. The results are compared with an uninfected control pony. The haptoglobin concentration increased during Weeks 1 to 6 and 14 to 17 after infection in the serum of the ponies receiving 200 L3, but in only one pony dosed with 700 L3 (during Weeks 1 to 16). The serum haptoglobin also increased during the first seven weeks after the second infection, in three of the four ponies following the second dose of larvae. The serum IgG(T) concentration started to increase from Week 6 or 9 in the ponies given 700 L3, reaching peaks of 44 and 32 g/litre respectively, eight to nine weeks later, compared with a peak of 16 g/litre 20 to 22 weeks after infection in ponies dosed with 200 L3. The IgG(T) concentration increased to a maximum of 25 g/litre in the serum of only one of the four ponies after the reinfection. The serum IgG concentration in all ponies increased nearly twofold during the first eight weeks after both the primary and secondary dose of larvae. It is concluded that the measurement of specific proteins is more reliable and quicker than the electrophoretic separation and quantitation of protein bands, in tracing changes in serum proteins following the artificial infection of ponies with S vulgaris larvae.

Humoral and cell-mediated immune responses after a booster dose of HBV vaccine in HIV-infected children, adolescents and young adults.

PubMed

Giacomet, Vania; Masetti, Michela; Nannini, Pilar; Forlanini, Federica; Clerici, Mario; Zuccotti, Gian Vincenzo; Trabattoni, Daria

2018-01-01

HBV vaccine induces protective antibodies only in 23-56% of HIV-infected children. The aim of our study is to evaluate the immunologic effects of a booster dose of HBV vaccine in HIV-infected youth. 53 young HIV-infected patients in whom HBV vaccination did not elicit protective Ab titers were enrolled. All patients were on ART with optimal immunological and viral response. All patients received a booster dose of HBV vaccine (HBVAXPRO 10 μg i.m.). HBV-specific Ab titer, viral load and CD4+ T cells were measured at baseline (T0), T1, T6 and T12 months. In a subgroup of 16 patients HBV-specific cell mediated immune responses were evaluated at baseline, at T1 and T6. The booster dose induced seroconversion in 51% of patients at T1, 57% at T6, and49% at T12; seroconversion rate was significantly correlated with CD4+T cells at T0 and to the CD4 nadir. The booster dose induced HBV-specific cell mediated immunity at T6 mainly in Responders (Rs): Effector Memory CD8+T cells, HBV-specific TNFα-, IFNγ-, granzyme secreting CD8+ T cells and IL2-secreting CD4+ T cells were significantly increased in Rs compared to T0. In Non Responders (NRs), HBV-specific IL2-secreting CD4+ T cells, Central and Effector Memory CD8+ T cells were the only parameters modified at T6. Seroconversion induced by a booster dose of vaccine correlates with the development of T cell immunological memory in HIV-infected patients who did not respond to the standard immunization. Alternate immunization schedules need to be considered in NRs.

Advantages of Reduced Prophylaxis after Tubularized Incised Plate Repair of Hypospadias.

PubMed

Zeiai, Said; Nordenskjöld, Agneta; Fossum, Magdalena

2016-10-01

Concerns about antibiotic resistance, adverse drug reactions and questionable medical benefits have led to changes in prophylactic antibiotic management in hypospadias repair at our clinic. In March 2010 our guidelines were changed from continuous prophylaxis for 14 days to 1 dose preoperatively and another at removal of the stent. We analyze the effects of this new regimen. We performed a prospective journal cohort study of all our hypospadias operations from June 2008 to December 2011. We collected data from consecutive patients undergoing primary tubularized incised plate repair and postoperative stent. Patients operated on before March 2010 were compared to those operated on later. End points were postoperative infection requiring antibiotics and any complication that required redo surgery. The study included 113 primary tubularized incised plate repairs with postoperative stents. Patient distribution was the same in both groups. Of 58 patients in the group receiving continuous antibiotic prophylaxis 17 had a complication and/or infection, compared to 9 of 55 patients receiving 2-dose prophylaxis. The infection rate was 5% in the continuous prophylaxis group and 4% in the 2-dose group. In contrast to our expectations, a lower complication rate was observed in the group with lower antibiotic dose without an increased risk of infection. There is little documented evidence concerning benefits of antibiotic prophylaxis for postoperative complications, which gives rise to large variations in clinical practice. In our study lower antibiotic dose did not increase the number of infections, but rather decreased complication rates. We advocate antibiotic prophylaxis with only a 2-dose regimen. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Fluoroscopically Guided Interventional Procedures: A Review of Radiation Effects on Patients’ Skin and Hair

DTIC Science & Technology

2010-02-01

subsequent research has yielded additional in- sights. This review is a consensus report of current scien- tifi c data. Expected skin reactions for an...table has been cited and reproduced Essentials The minimum radiation dose n causing a specifi c type of reac- tion in the skin or hair is best...expressed in terms of a range of doses, rather than a single threshold dose. The times of onset and resolution n of specifi c radiation injuries

Breast augmentation, antibiotic prophylaxis, and infection: comparative analysis of 1,628 primary augmentation mammoplasties assessing the role and efficacy of antibiotics prophylaxis duration.

PubMed

Khan, Umar Daraz

2010-02-01

Infections after augmentation mammoplasty are not uncommon, and prophylactic antibiotics are routinely administered to minimize infection. However, there is paucity of information on the relationship between the length of prophylaxis cover and its benefits in primary augmentation mammoplasty. A retrospective analysis of different antibiotic cover regimens, their effectiveness in preventing infections, and the management of infection in established cases is reviewed. A retrospective chart analysis of periprosthetic infections in primary augmentation mammoplasties performed over the past 10 years was conducted. Periprosthetic infection was determined by the presence of pain, swelling, redness, and discharge. Each breast was taken as an individual unit in 1,628 patients, and data for 3,256 breasts were analyzed. The patients had their augmentation in the partial submuscular plane (214 breasts in 107 patients), the subglandular plane (1,548 breasts in 774 patients), and the muscle-splitting biplane (1,494 breasts in 747 patients). All the patients had soft round cohesive gel silicone implants. Of the 3,256 implants, 3,218 were textured, and 38 were smooth surfaced. The patients received antibiotics as a single intravenous dose of cephalosporin (474 breasts in 237 patients), a single intravenous dose plus an oral dose for 24 h (344 breasts in 172 patients), or a single intravenous dose plus an oral course for 5 days (2,438 breasts in 1,219 patients). Infection was recorded as superficial (e.g., wound breakdown, stitch extrusion, stitch abscess) or deep (periprosthetic). The patients with established periprosthetic infections, determined clinically by the presence of pain, discharge, swelling, and redness of the breasts, were managed either conservatively using antibiotics, passive wound drainage, and healing of the wound with secondary intention or by explantation and replacement after 3 to 4 months. In selected cases of periprosthetic infection, the implants were removed after a course of antibiotics and negative swab cultures. The cavity was washed thoroughly with betadine and saline, and new implants were simultaneously reimplanted. The incidence of infection was lowest with a single perioperative dose of intravenous antibiotic compared with a combination of intravenous and oral antibiotics. Superficial infection was seen in 38 breasts (all unilateral), with an incidence of 1.2%, and periprosthetic infection was observed in 17 breasts (13 unilateral and 2 bilateral), giving an infection incidence of 0.52% (p = 0.002). In patients with a single intravenous dose of antibiotic, superficial and periprosthetic infection was seen in four breasts (0.8%) and no breasts, respectively. The difference was not significant (p = 0.13). The patients receiving a single intravenous antibiotic and a 24-h oral antibiotic had superficial and periprosthetic infection rates of 2.3% (8 breasts) and 0.3% (1 breast), respectively, and the difference between the two sub-groups was significantly higher (p = 0.04). The patients receiving an intravenous antibiotic and 5 days of oral antibiotics had superficial and periprosthetic infection rates of 1.1% (26 breasts) and 0.65% (14 breasts), respectively. The difference between the two subgroups was not significant (p = 0.09). Of the 17 periprosthetic infections in 15 patients (13 unilateral and 2 bilateral), 11 breasts (1 bilateral and 9 unilateral) were treated conservatively using antibiotics, passive drainage, and wound healing with secondary intention. Capsular contracture developed in two of the conservatively treated breasts, requiring capsulotomies with change of implants. Of the six periprosthetic infections in six patients, requiring surgical intervention, two implants were treated using explantation with immediate replacement after a course of antibiotics and a negative culture, and two implants were explanted followed by reimplantation later. One patient had both implants removed after unilateral infection, and no reimplantation was performed. One patient had a bilateral infection. In this case, one implant was explanted and the other was treated conservatively. The patient had bilateral reimplantion 6 months later, and bilateral Baker 4 capsular contracture developed in both breasts within 6 months. No other complications were seen in the patients who underwent surgery. A single dose of intravenous antibiotic is adequate for prophylaxis in breast augmentation surgery, and the extra duration of antibiotic cover does not result in reduced superficial or periprosthetic infections. Infection can be managed in more than one way depending on the nature, degree, and extent of infection.

Bladder accumulated dose in image-guided high-dose-rate brachytherapy for locally advanced cervical cancer and its relation to urinary toxicity

NASA Astrophysics Data System (ADS)

Zakariaee, Roja; Hamarneh, Ghassan; Brown, Colin J.; Gaudet, Marc; Aquino-Parsons, Christina; Spadinger, Ingrid

2016-12-01

The purpose of this study was to estimate locally accumulated dose to the bladder in multi-fraction high-dose-date (HDR) image-guided intracavitary brachytherapy (IG-ICBT) for cervical cancer, and study the locally-accumulated dose parameters as predictors of late urinary toxicity. A retrospective study of 60 cervical cancer patients who received five HDR IG-ICBT sessions was performed. The bladder outer and inner surfaces were segmented for all sessions and a bladder-wall contour point-set was created in MATLAB. The bladder-wall point-sets for each patient were registered using a deformable point-set registration toolbox called coherent point drift (CPD), and the fraction doses were accumulated. Various dosimetric and volumetric parameters were calculated using the registered doses, including r{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} (minimum dose to the most exposed n-cm3 volume of bladder wall), r V n Gy (wall volume receiving at least m Gy), and r\\text{EQD}{{2}n \\text{c{{\\text{m}}\\text{3}}}} (minimum equivalent biologically weighted dose to the most exposed n-cm3 of bladder wall), where n  =  1/2/5/10 and m  =  3/5/10. Minimum dose to contiguous 1 and 2 cm3 hot-spot volumes was also calculated. The unregistered dose volume histogram (DVH)-summed equivalent of r{{\\text{D}}n \\text{c{{\\text{m}}3}}} and r\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} parameters (i.e. s{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} and s\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} ) were determined for comparison. Late urinary toxicity was assessed using the LENT-SOMA scale, with toxicity Grade 0-1 categorized as Controls and Grade 2-4 as Cases. A two-sample t-test was used to identify the differences between the means of Control and Case groups for all parameters. A binomial logistic regression was also performed between the registered dose parameters and toxicity grouping. Seventeen patients were in the Case and 43 patients in the Control group. Contiguous values were on average 16 and 18% smaller than parameters for 1 and 2 cm3 volumes, respectively. Contiguous values were on average 26 and 27% smaller than parameters. The only statistically significant finding for Case versus Control based on both methods of analysis was observed for r V3 Gy (p  =  0.01). DVH-summed parameters based on unregistered structure volumes overestimated the bladder dose in our patients, particularly when contiguous high dose volumes were considered. The bladder-wall volume receiving at least 3 Gy of accumulated dose may be a parameter of interest in further investigations of Grade 2+  urinary toxicity.

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

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

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action

PubMed Central

Roy, Ranita; Tiwari, Monalisa; Donelli, Gianfranco; Tiwari, Vishvanath

2018-01-01

ABSTRACT Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. The biofilm matrix surrounding bacteria makes them tolerant to harsh conditions and resistant to antibacterial treatments. Moreover, the biofilms are responsible for causing a broad range of chronic diseases and due to the emergence of antibiotic resistance in bacteria it has really become difficult to treat them with efficacy. Furthermore, the antibiotics available till date are ineffective for treating these biofilm related infections due to their higher values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), which may result in in-vivo toxicity. Hence, it is critically important to design or screen anti-biofilm molecules that can effectively minimize and eradicate biofilm related infections. In the present article, we have highlighted the mechanism of biofilm formation with reference to different models and various methods used for biofilm detection. A major focus has been put on various anti-biofilm molecules discovered or tested till date which may include herbal active compounds, chelating agents, peptide antibiotics, lantibiotics and synthetic chemical compounds along with their structures, mechanism of action and their respective MICs, MBCs, minimum biofilm inhibitory concentrations (MBICs) as well as the half maximal inhibitory concentration (IC50) values available in the literature so far. Different mode of action of anti biofilm molecules addressed here are inhibition via interference in the quorum sensing pathways, adhesion mechanism, disruption of extracellular DNA, protein, lipopolysaccharides, exopolysaccharides and secondary messengers involved in various signaling pathways. From this study, we conclude that the molecules considered here might be used to treat biofilm-associated infections after significant structural modifications, thereby investigating its effective delivery in the host. It should also be ensured that minimum effective concentration of these molecules must be capable of eradicating biofilm infections with maximum potency without posing any adverse side effects on the host. PMID:28362216

Induction of potent local cellular immunity with low dose X4 SHIV{sub SF33A} vaginal exposure

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

Tasca, Silvana; Tsai, Lily; Trunova, Nataliya

2007-10-10

Intravaginal inoculation of rhesus macaques with varying doses of the CXCR4 (X4)-tropic SHIV{sub SF33A} isolate revealed a threshold inoculum for establishment of systemic virus infection and a dose dependency in overall viral burden and CD4+ T cell depletion. While exposure to inoculum size of 1000 or greater 50% tissue infectious dose (TCID{sub 50}) resulted in high viremia and precipitous CD4+ T cell loss, occult infection was observed in seven of eight macaques exposed to 500 TCID{sub 50} of the same virus. The latter was characterized by intermittent detection of low level virus with no evidence of seroconversion or CD4+ Tmore » cell decline, but with signs of an ongoing antiviral T cell immune response. Upon vaginal re-challenge with the same limiting dose 11-12 weeks after the first, classic pathogenic X4 SHIV{sub SF33A} infection was established in four of the seven previously exposed seronegative macaques, implying enhanced susceptibility to systemic infection with prior exposure. Pre-existing peripheral SIV gag-specific CD4+ T cells were more readily demonstrable in macaques that became systemically infected following re-exposure than those that were not. In contrast, early presence of circulating polyfunctional cytokine secreting CD8+ T cells or strong virus-specific proliferative responses in draining lymph nodes and in the gut associated lymphoid tissue (GALT) following the first exposure was associated with protection from systemic re-infection. These studies identify the gut and lymphoid tissues proximal to the genital tract as sites of robust CD8 T lymphocyte responses that contribute to containment of virus spread following vaginal transmission.« less

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

PubMed

Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults.

PubMed

Cooper, Curtis; Thorne, Anona; Klein, Marina; Conway, Brian; Boivin, Guy; Haase, David; Shafran, Stephen; Zubyk, Wendy; Singer, Joel; Halperin, Scott; Walmsley, Sharon

2011-03-25

The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥ 40 =  31-58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. ClinicalTrials.gov NCT00764998.

Tick Saliva Enhances Powassan Virus Transmission to the Host, Influencing Its Dissemination and the Course of Disease

PubMed Central

Hermance, Meghan E.

2015-01-01

ABSTRACT Powassan virus (POWV) is an encephalitic tick-borne flavivirus which can result in serious neuroinvasive disease with up to a 10% case fatality rate. The study objective was to determine whether the salivary gland extract (SGE) from Ixodes scapularis ticks facilitates the transmission and dissemination of POWV in a process known as saliva-activated transmission. Groups of BALB/c mice were footpad inoculated with either a high dose of POWV with and without SGE or a low dose of POWV with and without SGE. Mice from each group were sacrificed daily. Organ viral loads and gene expression profiles were evaluated by quantitative real-time PCR. Both groups of mice infected with high-dose POWV showed severe neurological signs of disease preceding death. The presence of SGE did not affect POWV transmission or disease outcome for mice infected with the high dose of POWV. Neuroinvasion, paralysis, and death occurred for all mice infected with the low dose of POWV plus SGE; however, for mice infected with the low dose of POWV in the absence of SGE, there were no clinical signs of infection and no mice succumbed to disease. Although this group displayed low-level viremias, all mice were completely healthy, and it was the only group in which POWV was cleared from the lymph nodes. We conclude that saliva-activated transmission occurs in mice infected with a low dose of POWV. Our study is the first to demonstrate virus dose-dependent saliva-activated transmission, warranting further investigation of the specific salivary factors responsible for enhancing POWV transmission. IMPORTANCE Powassan virus (POWV) is a tick-borne flavivirus that continues to emerge in the United States, as is evident by the surge in number and expanding geographic range of confirmed cases in the past decade. This neuroinvasive virus is transmitted to humans by infected tick bites. Successful tick feeding is facilitated by a collection of pharmacologically active factors in tick saliva. In a process known as saliva-activated transmission, tick bioactive salivary molecules are thought to modulate the host environment, making it more favorable for the transmission and establishment of a pathogen. This phenomenon has been demonstrated for several tick-borne pathogens; however, a systematic investigation of the role of tick saliva on dissemination and pathogenesis of a tick-borne viral disease has never been attempted before. This study will fill that gap by systematically examining whether the presence of tick saliva contributes to the transmission and dissemination of POWV in mice. PMID:25995246

Tick Saliva Enhances Powassan Virus Transmission to the Host, Influencing Its Dissemination and the Course of Disease.

PubMed

Hermance, Meghan E; Thangamani, Saravanan

2015-08-01

Powassan virus (POWV) is an encephalitic tick-borne flavivirus which can result in serious neuroinvasive disease with up to a 10% case fatality rate. The study objective was to determine whether the salivary gland extract (SGE) from Ixodes scapularis ticks facilitates the transmission and dissemination of POWV in a process known as saliva-activated transmission. Groups of BALB/c mice were footpad inoculated with either a high dose of POWV with and without SGE or a low dose of POWV with and without SGE. Mice from each group were sacrificed daily. Organ viral loads and gene expression profiles were evaluated by quantitative real-time PCR. Both groups of mice infected with high-dose POWV showed severe neurological signs of disease preceding death. The presence of SGE did not affect POWV transmission or disease outcome for mice infected with the high dose of POWV. Neuroinvasion, paralysis, and death occurred for all mice infected with the low dose of POWV plus SGE; however, for mice infected with the low dose of POWV in the absence of SGE, there were no clinical signs of infection and no mice succumbed to disease. Although this group displayed low-level viremias, all mice were completely healthy, and it was the only group in which POWV was cleared from the lymph nodes. We conclude that saliva-activated transmission occurs in mice infected with a low dose of POWV. Our study is the first to demonstrate virus dose-dependent saliva-activated transmission, warranting further investigation of the specific salivary factors responsible for enhancing POWV transmission. Powassan virus (POWV) is a tick-borne flavivirus that continues to emerge in the United States, as is evident by the surge in number and expanding geographic range of confirmed cases in the past decade. This neuroinvasive virus is transmitted to humans by infected tick bites. Successful tick feeding is facilitated by a collection of pharmacologically active factors in tick saliva. In a process known as saliva-activated transmission, tick bioactive salivary molecules are thought to modulate the host environment, making it more favorable for the transmission and establishment of a pathogen. This phenomenon has been demonstrated for several tick-borne pathogens; however, a systematic investigation of the role of tick saliva on dissemination and pathogenesis of a tick-borne viral disease has never been attempted before. This study will fill that gap by systematically examining whether the presence of tick saliva contributes to the transmission and dissemination of POWV in mice. Copyright © 2015, Hermance and Thangamani.

Anticoccidial activity of the methanolic extract of Musa paradisiaca root in chickens.

PubMed

Anosa, George Nnamdi; Okoro, O Josephine

2011-01-01

The study was designed to evaluate the anticoccidial activity of the methanolic extract of Musa paradisiaca root in chickens. The chickens were divided into six groups of 12 chickens each. Each chicken in five groups was infected with 8,000 infective coccidia (Eimeria tenella) oocysts at day 28 of age while one group served as uninfected control. At day 7 post-infection, two chickens remaining in each group were sacrificed for postmortem examination to confirm coccidiosis. Also at day 7 post-infection, each chicken in four infected groups was given graded doses (250, 500 and 1,000 mg/kg b.w.) of the extract or amprolium (conventional drug). Two groups (an infected and uninfected group) did not receive treatment. Parameters used to assess progress of infection and response to treatment included clinical signs typical of coccidiosis, oocyst count per gramme of faeces (OPG) and packed cell volume (PCV). Treatment of previously infected chickens with M. paradisiaca root extract resulted in a progressive decrease in severity of observed clinical signs, marked reductions in OPG and a gradual increase in PCV. In each case, the changes were dose dependent. There was no significant difference in mean OPG and mean PCV of the extract (at 1,000 mg/kg b.w.) and amprolium-treated groups at termination of the study (at day 50 of age). In the acute toxicity study, the extract was found to be non-toxic to the chickens even at the highest dose of 4,000 mg/kg b.w. The results of this study demonstrated that the extract has anticoccidial activity in a dose-dependent manner and at a dosage of 1,000 mg/kg b.w. had similar efficacy with amprolium in the treatment of chicken coccidiosis.

For Single Dosing, Levofloxacin Is Superior to Ciprofloxacin When Combined With an Aminoglycoside in Preventing Severe Infections After Prostate Biopsy.

PubMed

Unnikrishnan, Raman; El-Shafei, Ahmed; Klein, Eric A; Jones, J Stephen; Kartha, Ganesh; Goldman, Howard B

2015-06-01

To investigate whether there is benefit with a longer acting oral fluoroquinolone, we compared the rate of infection after transrectal ultrasound-guided prostate biopsy between 2 prophylactic antibiotic regimens: ciprofloxacin vs levofloxacin, each combined with an aminoglycoside (AG). A retrospective review was performed of all transrectal ultrasound-guided prostate biopsies from September 2011 to January 2013. Initially our regimen entailed 1 dose of 500-mg ciprofloxacin and an AG. In June 2012, we switched to 1 dose of 750-mg levofloxacin and an AG. Infections were categorized as severe if requiring hospital admission, overnight observation, or emergency room treatment for fever or chills. Those treated as an outpatient were defined as mild. Of 1189 total biopsies, the total infection rate was 3.18% (17 of 535) in the ciprofloxacin group and 2.14% (14 of 654) in the levofloxacin group (P = .26). The rate of mild infection was 0.75% (4 of 535) in the ciprofloxacin group and 1.22% (8 of 654) in the levofloxacin group (P = .56). The rate of severe infection was significantly higher in the ciprofloxacin group at 2.43% (13 of 535) compared with that of 0.92% (6 of 654) in the levofloxacin group (P = .04). On multivariate analysis, use of ciprofloxacin rather than levofloxacin was associated with an increased risk of severe infection (odds ratio, 4.59; P = .04). Empiric prophylaxis for prostate biopsies with a single-dose fluoroquinolone augmented with an AG is optimal to reduce infectious complications. We found 750-mg levofloxacin resulted in significantly fewer severe infections compared with 500-mg ciprofloxacin potentially because of its longer half-life. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of oral infection with Kashmir bee virus and Israeli acute paralysis virus on bumblebee (Bombus terrestris) reproductive success.

PubMed

Meeus, Ivan; de Miranda, Joachim R; de Graaf, Dirk C; Wäckers, Felix; Smagghe, Guy

2014-09-01

Israeli acute paralysis virus (IAPV) together with Acute bee paralysis virus (ABPV) and Kashmir bee virus (KBV) constitute a complex of closely related dicistroviruses. They are infamous for their high mortality after injection in honeybees. These viruses have also been reported in non-Apis hymenopteran pollinators such as bumblebees, which got infected with IAPV when placed in the same greenhouse with IAPV infected honeybee hives. Here we orally infected Bombus terrestris workers with different doses of either IAPV or KBV viral particles. The success of the infection was established by analysis of the bumblebees after the impact studies: 50days after infection. Doses of 0.5×10(7) and 1×10(7) virus particles per bee were infectious over this period, for IAPV and KBV respectively, while a dose of 0.5×10(6) IAPV particles per bee was not infectious. The impact of virus infection was studied in micro-colonies consisting of 5 bumblebees, one of which becomes a pseudo-queen which proceeds to lay unfertilized (drone) eggs. The impact parameters studied were: the establishment of a laying pseudo-queen, the timing of egg-laying, the number of drones produced, the weight of these drones and worker mortality. In this setup KBV infection resulted in a significant slower colony startup and offspring production, while only the latter can be reported for IAPV. Neither virus increased worker mortality, at the oral doses used. We recommend further studies on how these viruses transmit between different pollinator species. It is also vital to understand how viral prevalence can affect wild bee populations because disturbance of the natural host-virus association may deteriorate the already critically endangered status of many bumblebee species. Copyright © 2014 Elsevier Inc. All rights reserved.

The Recent Emergence of Clostridium difficile Infection in Romanian Hospitals is Associated with a High Prevalence of Polymerase Chain Reaction Ribotype 027.

PubMed

Popescu, Gabriel Adrian; Serban, Roxana; Pistol, Adriana; Niculcea, Andreea; Preda, Andreea; Lemeni, Daniela; Macovei, Ioana Sabina; Tălăpan, Daniela; Rafila, Alexandru; Florea, Dragoş

2018-03-15

To investigate the epidemiology of Clostridium difficile infection in Romanian hospitals. A survey was conducted at nine hospitals throughout Romania between November 2013 and February 2014. The survey identified 393 patients with Clostridium difficile infection. The median age was 67 years (range: 2-94 years); 56% of patients were aged >65 years. The mean prevalence of Clostridium difficile infection was 5.2 cases per 10.000 patient-days. The highest prevalences were 24.9 and 20 per 10.000 patient-days in hospitals specializing in gastroenterology and infectious diseases, respectively. Clostridium difficile infections were health care-associated in 70.5% patients and community-acquired in 10.2%. The origin was not determined in 19.3%. Clostridium difficile infection was severe in 12.3% of patients, and the in-hospital all-cause mortality was 8.8%. Polymerase chain reaction ribotype 027 had the highest prevalence in all participating hospitals and represented 82.6% of the total ribotyped isolates. The minimum inhibitory concentration of moxifloxacin was >4 μg/mL for 59 of 80 tested isolates (73.8%). Of 59 isolates, 54 were highly resistant to moxifloxacin (minimum inhibitory concentration ≥32 μg/mL), and the majority were polymerase chain reaction ribotype 027 (p<0.0001). The ribotype 027 was the predominant cause of Clostridium difficile infections in Romania. In some specialized hospitals, the prevalence of Clostridium difficile infection was higher than the European mean prevalence, and this demonstrates the need for strict adherence to infection control programs.

[Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation].

PubMed

Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

2016-01-01

Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation.

PubMed

Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

2016-01-01

Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves.

PubMed

Brentnall, C; Cheng, Z; McKellar, Q A; Lees, P

2012-09-15

The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.

[THE USE OF THE MODEL MOUSE ICR--VARIOLA VIRUS FOR EVALUATION OF ANTIVIRAL DRUG EFFICACY].

PubMed

Titova, K A; Sergeev, Al A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Galakhova, D O; Shishkina, L N; Zamedyanskaya, A S; Nesterov, A E; Glotov, A G; Taranov, O S; Omigov, V V; Agafonov, A P; Sergeev, A N

2016-01-01

Mice of the ICR outbred population were infected intranasally (i/n) with the variola virus (VARV, strain Ind-3a). Clinical signs of the disease did not appear even at the maximum possible dose of the virus 5.2 lg PFU/head (plaque-forming units per head). In this case, 50% infective dose (ID50) of VARV estimated by the presence or absence of the virus in the lungs three days after infection (p.i.) was equal to 2.7 ± 0.4 lg PFU/head. Taking into account the 10% application of the virus in the lungs during the intranasal infection of the mice, it was adequate to 1.7 lg PFU/lungs. This indicates a high infectivity of the VARV for mice comparable to its infectivity for humans. After the i/n infection of mice with the VARV at a dose 30 ID50/ head the highest concentration of the virus detected in the lungs (4.9 ± 0.0 lg PFU/ml of homogenate) and in nasal cavity tissues (4.8 ± 0.0 lg PFU/ml) were observed. The pathomorphological changes in the respiratory organs of the mice infected with the VARV appeared at 3-5 days p.i., and the VARV reproduction noted in the epithelial cells and macrophages were noticed. When the preparations ST-246 and NIOCH-14 were administered orally at a dose of 60 μg/g of mouse weight up to one day before infection, after 2 hours, 1 and 2 days p.i., the VARV reproduction in the lungs after 3 days p.i. decreased by an order of magnitude. Thus, outbred ICR mice infected with the VARV can be used as a laboratory model of the smallpox when evaluating the therapeutic and prophylactic efficacy of the antismallpox drugs.

Optimal shield mass distribution for space radiation protection

NASA Technical Reports Server (NTRS)

Billings, M. P.

1972-01-01

Computational methods have been developed and successfully used for determining the optimum distribution of space radiation shielding on geometrically complex space vehicles. These methods have been incorporated in computer program SWORD for dose evaluation in complex geometry, and iteratively calculating the optimum distribution for (minimum) shield mass satisfying multiple acute and protected dose constraints associated with each of several body organs.

Tabulated dose uniformity ratio and minimum dose data: rectangular 60Co source plaques

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

Galanter, L.

1971-01-01

The data tabulated herein extend to rectangular cobalt-60 plaques the information presented for square plaques in BNL 50145 (Revised). The user is referred to BNL 50145 (Revised) and to the other reports listed for a complete discussion of the parameters involved in data generation and for instructions on the use of these data in gamma irradiator design.

Process control and dosimetry in a multipurpose irradiation facility

NASA Astrophysics Data System (ADS)

Cabalfin, E. G.; Lanuza, L. G.; Solomon, H. M.

1999-08-01

Availability of the multipurpose irradiation facility at the Philippine Nuclear Research Institute has encouraged several local industries to use gamma radiation for sterilization or decontamination of various products. Prior to routine processing, dose distribution studies are undertaken for each product and product geometry. During routine irradiation, dosimeters are placed at the minimum and maximum dose positions of a process load.

Challenges and Potential Solutions – Individualised Antibiotic Dosing at the Bedside for Critically Ill Patients: a structured review

PubMed Central

Roberts, Jason A.; Aziz, Mohd Hafiz Abdul; Lipman, Jeffrey; Mouton, Johan W.; Vinks, Alexander A.; Felton, Timothy W.; Hope, William W.; Farkas, Andras; Neely, Michael N.; Schentag, Jerome J.; Drusano, George; Frey, Otto R.; Theuretzbacher, Ursula; Kuti, Joseph L.

2014-01-01

Summary Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in sub-optimal outcomes. In this paper, we review the patient- and pathogen-related challenges that contribute to inadequate antibiotic dosing and discuss how a process for individualised antibiotic therapy, that increases the accuracy of dosing, can be implemented to further optimise care for the critically ill patient. The process for optimised antibiotic dosing firstly requires determination of the physiological derangements in the patient that can alter antibiotic concentrations including altered fluid status, microvascular failure, serum albumin concentrations as well as altered renal and hepatic function. Secondly, knowledge of the susceptibility of the infecting pathogen should be determined through liaison with the microbiology laboratory. The patient and pathogen challenges can then be solved by combining susceptibility data with measured antibiotic concentration data (where possible) into a clinical dosing software. Such software uses pharmacokinetic-pharmacodynamic (PK/PD) models from critically ill patients to accurately predict the dosing requirements for the individual patient with the aim of optimising antibiotic exposure and maximising effectiveness. PMID:24768475

A revised burial dose estimation procedure for optical dating of youngand modern-age sediments

USGS Publications Warehouse

Arnold, L.J.; Roberts, R.G.; Galbraith, R.F.; DeLong, S.B.

2009-01-01

The presence of genuinely zero-age or near-zero-age grains in modern-age and very young samples poses a problem for many existing burial dose estimation procedures used in optical (optically stimulated luminescence, OSL) dating. This difficulty currently necessitates consideration of relatively simplistic and statistically inferior age models. In this study, we investigate the potential for using modified versions of the statistical age models of Galbraith et??al. [Galbraith, R.F., Roberts, R.G., Laslett, G.M., Yoshida, H., Olley, J.M., 1999. Optical dating of single and multiple grains of quartz from Jinmium rock shelter, northern Australia: Part I, experimental design and statistical models. Archaeometry 41, 339-364.] to provide reliable equivalent dose (De) estimates for young and modern-age samples that display negative, zero or near-zero De estimates. For this purpose, we have revised the original versions of the central and minimum age models, which are based on log-transformed De values, so that they can be applied to un-logged De estimates and their associated absolute standard errors. The suitability of these 'un-logged' age models is tested using a series of known-age fluvial samples deposited within two arroyo systems from the American Southwest. The un-logged age models provide accurate burial doses and final OSL ages for roughly three-quarters of the total number of samples considered in this study. Sensitivity tests reveal that the un-logged versions of the central and minimum age models are capable of producing accurate burial dose estimates for modern-age and very young (<350??yr) fluvial samples that contain (i) more than 20% of well-bleached grains in their De distributions, or (ii) smaller sub-populations of well-bleached grains for which the De values are known with high precision. Our results indicate that the original (log-transformed) versions of the central and minimum age models are still preferable for most routine dating applications, since these age models are better suited to the statistical properties of typical single-grain and multi-grain single-aliquot De datasets. However, the unique error properties of modern-age samples, combined with the problems of calculating natural logarithms of negative or zero-Gy De values, mean that the un-logged versions of the central and minimum age models currently offer the most suitable means of deriving accurate burial dose estimates for very young and modern-age samples. ?? 2009 Elsevier Ltd. All rights reserved.

Fluconazole and Pregnancy

MedlinePlus

... It is used in the treatment of vaginal yeast infections when topical creams are not effective. A ... the most commonly used dose to treat vaginal yeast infections. It is also used for fungal infections ...

Thymol kills bacteria, reduces biofilm formation, and protects mice against a fatal infection of Actinobacillus pleuropneumoniae strain L20.

PubMed

Wang, Lei; Zhao, Xueqin; Zhu, Chunling; Xia, Xiaojing; Qin, Wanhai; Li, Mei; Wang, Tongzhao; Chen, Shijun; Xu, Yanzhao; Hang, Bolin; Sun, Yawei; Jiang, Jinqing; Richard, Langford Paul; Lei, Liancheng; Zhang, Gaiping; Hu, Jianhe

2017-05-01

Actinobacillus pleuropneumoniae is the causative agent of the highly contagious and deadly respiratory infection porcine pleuropneumonia, resulting in serious losses to the pig industry worldwide. Alternative to antibiotics are urgently needed due to the serious increase in antimicrobial resistance. Thymol is a monoterpene phenol and efficiently kills a variety of bacteria. This study found that thymol has strong bactericidal effects on the A. pleuropneumoniae 5b serotype strain, an epidemic strain in China. Sterilization occurred rapidly, and the minimum inhibitory concentration (MIC) is 31.25μg/mL; the A. pleuropneumoniae density was reduced 1000 times within 10min following treatment with 1 MIC. Transmission electron microscopy (TEM) analysis revealed that thymol could rapidly disrupt the cell walls and cell membranes of A. pleuropneumoniae, causing leakage of cell contents and cell death. In addition, treatment with thymol at 0.5 MIC significantly reduced the biofilm formation of A. pleuropneumoniae. Quantitative RT-PCR results indicated that thymol treatment significantly increased the expression of the virulence genes purC, tbpB1 and clpP and down-regulated ApxI, ApxII and Apa1 expression in A. pleuropneumoniae. Therapeutic analysis of a murine model showed that thymol (20mg/kg) protected mice from a lethal dose of A. pleuropneumoniae, attenuated lung pathological lesions. This study is the first to report the use of thymol to treat A. pleuropneumoniae infection, establishing a foundation for the development of new antimicrobials. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel prophage lysin Ply5218 with extended lytic activity and stability against Streptococcus suis infection.

PubMed

Zhang, Hang; Zhang, Chuanpeng; Wang, Hengan; Yan, Ya Xian; Sun, Jianhe

2016-09-01

Streptococcus suis (S. suis) is an emerging zoonotic agent that exhibits high level resistance to classic antibiotics and a heavy burden in the swine industry. Therefore alternative antibacterial agents need to be developed. A novel endolysin derived from the S. suis temperate phage phi5218, termed Ply5218, was identified. The minimum inhibitory concentration (MIC) of Ply5218 was 2.5 μg ml(-1) against S. suis strain HA9801, an activity many times greater than the lysins reported previously (MIC of LY7917 and Ply30 against HA9801 were 80 and 64 μg ml(-1), respectively). Ply5218 at 10 μg ml(-1) in vitro exerted broad antibacterial activities against S. suis strains with OD600 ratios decreased from 1 to <0.2 within 1 h. Moreover, Ply5218 showed favorable thermal stability. It was stable at 50°C >30 min, 4°C >30 days, -80°C >7 months, and >60% of the enzyme activity remained after 5 min pre-incubation at 70°C. In vivo, a 0.2 mg dose of Ply5218 protected 90% (9/10) of mice after infection with S. suis HA9801. Finally, Ply5218 maintained high antibacterial activity in some bio-matrices, such as culture media and milk. The data indicate that Ply5218 has all the characteristics to be an effective therapeutic agent against multiple S. suis infections. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antimicrobial and anti-inflammatory potential therapy for opportunistic microorganisms.

PubMed

Assaf, Areej M; Amro, Bassam I; Mashallah, Sundus; Haddadin, Randa N

2016-05-31

Methanolic extracts of six plants (Arbutus andrachne, Chrysanthemum coronarium, Inula viscosa, Origanum syriacum, Punica granatum, and Rosmarinus officinalis) used in traditional medicine for the treatment of bacterial and fungal infections were evaluated. The present study was conducted to evaluate the antimicrobial and anti-inflammatory activity of some medicinal plants in lowering the risk of opportunistic infections of the oral cavity caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. Extracts were evaluated separately and in a mixture. The methanolic plant extracts were tested against three opportunistic microorganisms by determining the minimum inhibitory concentration (MIC). They were also evaluated for their ability to suppress the release of the pro-inflammatory cytokine IL-6 while not suppressing the release of the anti-inflammatory cytokine IL-10 from peripheral blood mononuclear cells using ELISA. All extracts showed both antimicrobial and anti-inflammatory activities. However, O. syriacum exhibited the highest antimicrobial activity for the three microorganisms among all of the tested extracts (MIC S. aureus: 1 mg/mL; P. aeruginosa: 2 mg/mL; and C. albicans: 1 mg/mL). The extracts inhibited the expression of the pro-inflammatory cytokine IL-6 with apparent dose-dependent responses while they attenuated the secretion of the anti-inflammatory cytokine IL-10. The mixture of O. syriacum and R. officinalis showed an anti-inflammatory effect, with a synergistic antimicrobial effect. These findings support the idea that a diet rich in plants and herbs may contribute to the reduction of inflammation and microbial growth and may also be preventive against various infections, including those related to the oral cavity.

Detection and distribution of ostreid herpesvirus 1 in experimentally infected Pacific oyster spat.

PubMed

Segarra, Amélie; Baillon, Laury; Faury, Nicole; Tourbiez, Delphine; Renault, Tristan

2016-01-01

High mortality rates are reported in spat and larvae of Pacific oyster Crassostrea gigas and associated with ostreid herpesvirus 1 (OsHV-1) detection in France. Although the viral infection has been experimentally reproduced in oyster larvae and spat, little knowledge is currently available concerning the viral entry and its distribution in organs and tissues. This study compares OsHV-1 DNA and RNA detection and localization in experimentally infected oysters using two virus doses: a low dose that did not induce any mortality and a high dose inducing high mortality. Real time PCR demonstrated significant differences in terms of viral DNA amounts between the two virus doses. RNA transcripts were detected in oysters receiving the highest dose of viral suspension whereas no transcript was observed in oysters injected with the low dose. This study also allowed observing kinetics of viral DNA and RNA detection in different tissues of oyster spat. Finally, viral detection was significantly different in function of tissues (p<0.005), time (p<0.005) with an interaction between tissues and time (p<0.005) for each probe. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration.

PubMed

Fuster-Lluch, Oscar; Zapater-Hernández, Pedro; Gerónimo-Pardo, Manuel

2017-10-01

The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields serum concentrations below 10 μg/mL due to increased elimination. To reach the 10 μg/mL target, and from a strictly pharmacokinetic point of view, continuous infusion may be more feasible than bolus dosing. Such a change in dosing strategy requires appropriate, pharmacokinetic-pharmacodynamic and specific safety study. © 2017, The American College of Clinical Pharmacology.

Effectiveness of combined chloroquine and primaquine treatment in 14 days versus intermittent single dose regimen, in an open, non-randomized, clinical trial, to eliminate Plasmodium vivax in southern Mexico.

PubMed

Gonzalez-Ceron, Lilia; Rodriguez, Mario H; Sandoval, Marco A; Santillan, Frida; Galindo-Virgen, Sonia; Betanzos, Angel F; Rosales, Angel F; Palomeque, Olga L

2015-10-30

In Mexico, combined chloroquine (CQ) and primaquine (PQ) treatment has been used since the late 1950s to treat Plasmodium vivax infections. Although malaria transmission has declined, current treatment strategies must be evaluated to advance towards malaria elimination. The clinical and parasitological outcome of treating symptomatic P. vivax with the 14-day (T14) treatment or intermittent single dose (ISD) regimen was evaluated in southern Mexico between February 2008 and September 2010. Patients over 12 months old with P. vivax mono-infection and asexual parasitaemia ≥500 parasites/µl were treated under supervision. After diagnosis (day 0), treatment began immediately. T14 patients received CQ for 3 days (10, 10 and 5 mg/kg) and PQ daily for 14 days (0.25 mg/kg), while ISD patients received a single dose of CQ (10 mg/kg) and PQ (0.75 mg/kg) on days 0, 30, 60, 180, 210, and 240. Follow-up was done by observing clinical and laboratory (by microscopy, serology and PCR) outcome, considering two endpoints: primary blood infection clearance and clinical response at ~28 days, and the incidence of recurrent blood infection during 12 months. Parasite genotypes of primary/recurrent blood infections were analysed. During the first 28 days, no differences in parasite clearance or clinical outcome were observed between T14 (86 patients) and ISD (67 patients). On day 3, 95 % of patients in both groups showed no blood parasites, and no recurrences were detected on days 7-28. Contrarily, the therapeutic effectiveness (absence of recurrent parasitaemia) was distinct for T14 versus ISD at 12 months: 83.7 versus 50 %, respectively (p = 0.000). Symptomatic and asymptomatic infections were recorded on days 31-352. Some parasite recurrences were detected by PCR and/or serological testing. T14 was effective for opportune elimination of the primary blood infection and preventing relapse episodes. The first single dose of CQ-PQ eliminated primary blood infection as efficiently as the initial three-dose scheme of T14, but the ISD regimen should be abandoned. A single combined dose administered to symptomatic patients in remote areas while awaiting parasitological diagnosis may contribute to halting P. vivax transmission. Alternatives for meeting the challenge of T14 supervision are discussed. NIH-USA, ClinicalTrial.gov Identifier: NCT02394197.

A missing dimension in measures of vaccination impacts

USGS Publications Warehouse

Gomes, M. Gabriela M.; Lipsitch, Marc; Wargo, Andrew R.; Kurath, Gael; Rebelo, Carlota; Medley, Graham F.; Coutinho, Antonio

2013-01-01

Immunological protection, acquired from either natural infection or vaccination, varies among hosts, reflecting underlying biological variation and affecting population-level protection. Owing to the nature of resistance mechanisms, distributions of susceptibility and protection entangle with pathogen dose in a way that can be decoupled by adequately representing the dose dimension. Any infectious processes must depend in some fashion on dose, and empirical evidence exists for an effect of exposure dose on the probability of transmission to mumps-vaccinated hosts [1], the case-fatality ratio of measles [2], and the probability of infection and, given infection, of symptoms in cholera [3]. Extreme distributions of vaccine protection have been termed leaky (partially protects all hosts) and all-or-nothing (totally protects a proportion of hosts) [4]. These distributions can be distinguished in vaccine field trials from the time dependence of infections [5]. Frailty mixing models have also been proposed to estimate the distribution of protection from time to event data [6], [7], although the results are not comparable across regions unless there is explicit control for baseline transmission [8]. Distributions of host susceptibility and acquired protection can be estimated from dose-response data generated under controlled experimental conditions [9]–[11] and natural settings [12], [13]. These distributions can guide research on mechanisms of protection, as well as enable model validity across the entire range of transmission intensities. We argue for a shift to a dose-dimension paradigm in infectious disease science and community health.

Vaccinations for Adults with HIV Infection

MedlinePlus

... doses are given 8 weeks apart, followed by booster doses every 5 years. Meningococcal B Maybe. You ... each pregnancy. After that, you need a Td booster dose every 10 years. Consult your healthcare provider ...

Potential antimalarial activity of Methyl Jasmonate and its effect on lipid profiles in Plasmodium Berghei infected mice.

PubMed

Oyinloye, Oladapo E; Kosoko, Ayokulehin M; Emikpe, Benjamin; Falade, Catherine O; Ademowo, Olusegun G

2015-09-01

The antimalarial activity and lipid profiles of Methyl Jasmonate (MJ) were investigated against established malaria infection in vivo using BALB/c mice. Arteether (AE) and chloroquine (CQ) were used as reference drugs while ethanol was used as the vehicle for drug delivery for MJ. Mice treated with 10 and 25 mg/kg MJ showed a remarkable reduction in percentage parasitemia by 68.3% and 78.2% on day 10(post treatment) respectively while 45.4% and 87.2% reduction in percentage parasitemia were observed in the group treated with 50 mg/kg on day 3 and 10 (post treatment) respectively. The highest mean survival time was observed in CQ followed by AE and MJ in dose-dependent manner. A progressive decrease in packed cell volume (PCV) was observed in infected untreated mice which led to the death of all the mice by day 9 (post treatment). Infected mice treated with MJ showed reduced level of HDL and LDL compared with infected untreated group. As the dose of MJ increased in infected mice cholesterol levels increased while there was reduction in triglyceride. Overall there was marked decrease in parasitemia in Plasmodium berghei infected mice treated with graded doses of MJ but appears to have reduced antimalarial activity compared with CQ and AE.

Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum1

PubMed Central

Schmidt, L. H.; Vaughan, Dennis; Mueller, Donna; Crosby, Ruth; Hamilton, Rebecca

1977-01-01

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine. PMID:406829

Efficacy of favipiravir (T-705) in nonhuman primates infected with Ebola virus or Marburg virus.

PubMed

Bixler, Sandra L; Bocan, Thomas M; Wells, Jay; Wetzel, Kelly S; Van Tongeren, Sean A; Dong, Lian; Garza, Nicole L; Donnelly, Ginger; Cazares, Lisa H; Nuss, Jonathan; Soloveva, Veronica; Koistinen, Keith A; Welch, Lisa; Epstein, Carol; Liang, Li-Fang; Giesing, Dennis; Lenk, Robert; Bavari, Sina; Warren, Travis K

2018-03-01

Favipiravir is a broad-spectrum antiviral agent that has demonstrated efficacy against Ebola virus (EBOV) in rodents. However, there are no published reports of favipiravir efficacy for filovirus infection of nonhuman primates (NHPs). Here we evaluated the pharmacokinetic profile of favipiravir in NHPs, as well as in vivo efficacy against two filoviruses, EBOV and Marburg virus (MARV). While no survival benefit was observed in two studies employing once- or twice-daily oral dosing of favipiravir during EBOV infection of NHPs, an antiviral effect was observed in terms of extended time-to-death and reduced levels of viral RNA. However, oral dosing in biosafety level-4 (BSL-4) presents logistical and technical challenges, and repeated anesthesia events may potentially worsen survival outcome in animals. For the third study of treatment of MARV infection, we therefore made use of catheters, jackets, and tethers for intravenous (IV) dosing and blood collection, which minimized the requirement for repeated anesthesia events. When MARV infection was treated with IV favipiravir, five of six animals (83%) survived infection, while all untreated NHPs succumbed. An accompanying report presents the results of favipiravir treatment of EBOV infection in mice. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Solar Modulation of Inner Trapped Belt Radiation Flux as a Function of Atmospheric Density

NASA Technical Reports Server (NTRS)

Lodhi, M. A. K.

2005-01-01

No simple algorithm seems to exist for calculating proton fluxes and lifetimes in the Earth's inner, trapped radiation belt throughout the solar cycle. Most models of the inner trapped belt in use depend upon AP8 which only describes the radiation environment at solar maximum and solar minimum in Cycle 20. One exception is NOAAPRO which incorporates flight data from the TIROS/NOAA polar orbiting spacecraft. The present study discloses yet another, simple formulation for approximating proton fluxes at any time in a given solar cycle, in particular between solar maximum and solar minimum. It is derived from AP8 using a regression algorithm technique from nuclear physics. From flux and its time integral fluence, one can then approximate dose rate and its time integral dose.

The role of single-shot metronidazole in the prevention of Clostridium difficile infection following ileostomy reversal surgery.

PubMed

Fernandes, Roland; Robinson, Paul; Rangarajan, Karan; Scott, Sophie; Angco, Laura

2017-05-01

Symptomatic infection with Clostridium difficile is strongly linked to antibiotic use and rates are higher for colorectal surgery. In February 2015, trust policy for antibiotic prophylaxis of ileostomy reversal surgery was changed from three doses of metronidazole plus cefuroxime to single-dose metronidazole, in a bid to reduce rates of Clostridium difficile infection. A retrospective cohort study was conducted at a single, large hospital trust between February 2014 and February 2016, before and after change in antimicrobial policy. Theatre data, clinical notes and pathology results were all reviewed. Outcome data, patient age, gender, length of operation and hospital stay were extracted. One hundred three patients underwent ileostomy reversal surgery between February 2014 and February 2015. All received cefuroxime together with metronidazole at induction of anaesthesia followed by two further post-operative doses as operative prophylaxis. Ninety-six patients underwent ileostomy reversal surgery between February 2015 and February 2016. All received single-dose metronidazole at induction as prophylaxis. Post-operative diarrhoea was significantly reduced in patients given single-dose metronidazole compared with patients managed with multiple dose, dual antibiotic therapy (32 vs 12.5%, P 0.001). Rates of CDI were also significantly reduced in patients given single-dose metronidazole (6.8 vs 1%, P 0.038). Single-dose, pre-operative metronidazole is effective at reducing post-operative diarrhoea and CDI in ileostomy reversal surgery compared with multiple-dose cefuroxime plus metronidazole. Metronidazole may be effective as a prophylactic antibiotic against CDI in colonic surgery.

Time and dose-dependence evaluation of nitroheterocyclic drugs for improving efficacy following Trypanosoma cruzi infection: A pre-clinical study.

PubMed

Mazzeti, Ana Lia; Diniz, Lívia de F; Gonçalves, Karolina R; Nascimento, Alvaro F S; Spósito, Pollyanna A F; Mosqueira, Vanessa C F; Machado-Coelho, George L L; Ribeiro, Isabela; Bahia, Maria T

2018-02-01

Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3-10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Method of predicting the mean lung dose based on a patient's anatomy and dose-volume histograms

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

Zawadzka, Anna, E-mail: a.zawadzka@zfm.coi.pl; Nesteruk, Marta; Department of Radiation Oncology, University Hospital Zurich and University of Zurich, Zurich

The aim of this study was to propose a method to predict the minimum achievable mean lung dose (MLD) and corresponding dosimetric parameters for organs-at-risk (OAR) based on individual patient anatomy. For each patient, the dose for 36 equidistant individual multileaf collimator shaped fields in the treatment planning system (TPS) was calculated. Based on these dose matrices, the MLD for each patient was predicted by the homemade DosePredictor software in which the solution of linear equations was implemented. The software prediction results were validated based on 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) plans previously prepared formore » 16 patients with stage III non–small-cell lung cancer (NSCLC). For each patient, dosimetric parameters derived from plans and the results calculated by DosePredictor were compared. The MLD, the maximum dose to the spinal cord (D{sub max} {sub cord}) and the mean esophageal dose (MED) were analyzed. There was a strong correlation between the MLD calculated by the DosePredictor and those obtained in treatment plans regardless of the technique used. The correlation coefficient was 0.96 for both 3D-CRT and VMAT techniques. In a similar manner, MED correlations of 0.98 and 0.96 were obtained for 3D-CRT and VMAT plans, respectively. The maximum dose to the spinal cord was not predicted very well. The correlation coefficient was 0.30 and 0.61 for 3D-CRT and VMAT, respectively. The presented method allows us to predict the minimum MLD and corresponding dosimetric parameters to OARs without the necessity of plan preparation. The method can serve as a guide during the treatment planning process, for example, as initial constraints in VMAT optimization. It allows the probability of lung pneumonitis to be predicted.« less

The Timing of Hepatitis B Virus (HBV) Immunization Relative to Human Immunodeficiency Virus (HIV) Diagnosis and the Risk of HBV Infection Following HIV Diagnosis

PubMed Central

Landrum, Michael L.; Hullsiek, Katherine Huppler; Chun, Helen M.; Crum-Cianflone, Nancy F.; Ganesan, Anuradha; Weintrob, Amy C.; Barthel, R. Vincent; O'Connell, Robert J.; Agan, Brian K.

2011-01-01

To assess associations between the timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and vaccine effectiveness, US Military HIV Natural History Study cohort participants without HBV infection at the time of HIV diagnosis were grouped by vaccination status, retrospectively followed from HIV diagnosis for incident HBV infection, and compared using Cox proportional hazards models. A positive vaccine response was defined as hepatitis B surface antibody level ≥10 IU/L. Of 1,877 participants enrolled between 1989 and 2008, 441 (23%) were vaccinated prior to HIV diagnosis. Eighty percent of those who received vaccine doses only before HIV diagnosis had a positive vaccine response, compared with 66% of those who received doses both before and after HIV and 41% of those who received doses only after HIV (P < 0.01 for both compared with persons vaccinated before HIV only). Compared with the unvaccinated, persons vaccinated only before HIV had reduced risk of HBV infection after HIV diagnosis (hazard ratio = 0.38, 95% confidence interval: 0.20, 0.75). No reduction in HBV infection risk was observed for other vaccination groups. These data suggest that completion of the vaccine series prior to HIV infection may be the optimal strategy for preventing this significant comorbid infection in HIV-infected persons. PMID:21051446

The timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and the risk of HBV infection following HIV diagnosis.

PubMed

Landrum, Michael L; Hullsiek, Katherine Huppler; Chun, Helen M; Crum-Cianflone, Nancy F; Ganesan, Anuradha; Weintrob, Amy C; Barthel, R Vincent; O'Connell, Robert J; Agan, Brian K

2011-01-01

To assess associations between the timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and vaccine effectiveness, US Military HIV Natural History Study cohort participants without HBV infection at the time of HIV diagnosis were grouped by vaccination status, retrospectively followed from HIV diagnosis for incident HBV infection, and compared using Cox proportional hazards models. A positive vaccine response was defined as hepatitis B surface antibody level ≥ 10 IU/L. Of 1,877 participants enrolled between 1989 and 2008, 441 (23%) were vaccinated prior to HIV diagnosis. Eighty percent of those who received vaccine doses only before HIV diagnosis had a positive vaccine response, compared with 66% of those who received doses both before and after HIV and 41% of those who received doses only after HIV (P < 0.01 for both compared with persons vaccinated before HIV only). Compared with the unvaccinated, persons vaccinated only before HIV had reduced risk of HBV infection after HIV diagnosis (hazard ratio = 0.38, 95% confidence interval: 0.20, 0.75). No reduction in HBV infection risk was observed for other vaccination groups. These data suggest that completion of the vaccine series prior to HIV infection may be the optimal strategy for preventing this significant comorbid infection in HIV-infected persons.

Vaccine Poliovirus Shedding and Immune Response to Oral Polio Vaccine in HIV-Infected and -Uninfected Zimbabwean Infants

PubMed Central

Troy, Stephanie B.; Musingwini, Georgina; Halpern, Meira S.; Huang, ChunHong; Stranix-Chibanda, Lynda; Kouiavskaia, Diana; Shetty, Avinash K.; Chumakov, Konstantin; Nathoo, Kusum; Maldonado, Yvonne A.

2013-01-01

Background. With prolonged replication, attenuated polioviruses used in oral polio vaccine (OPV) can mutate into vaccine-derived poliovirus (VDPV) and cause poliomyelitis outbreaks. Individuals with primary humoral immunodeficiencies can become chronically infected with vaccine poliovirus, allowing it to mutate into immunodeficiency-associated VDPV (iVDPV). It is unclear if children perinatally infected with the human immunodeficiency virus (HIV), who have humoral as well as cellular immunodeficiencies, might be sources of iVDPV. Methods. We conducted a prospective study collecting stool and blood samples at multiple time points from Zimbabwean infants receiving OPV according to the national schedule. Nucleic acid extracted from stool was analyzed by real-time polymerase chain reaction for OPV serotypes. Results. We analyzed 825 stool samples: 285 samples from 92 HIV-infected children and 540 from 251 HIV-uninfected children. Poliovirus shedding was similar after 0–2 OPV doses but significantly higher in the HIV-infected versus uninfected children after ≥3 OPV doses, particularly within 42 days of an OPV dose, independent of seroconversion status. HIV infection was not associated with prolonged or persistent poliovirus shedding. HIV infection was associated with significantly lower polio seroconversion rates. Conclusions. HIV infection is associated with decreased mucosal and humoral immune responses to OPV but not the prolonged viral shedding required to form iVDPV. PMID:23661792

[An investigation of ionizing radiation dose in a manufacturing enterprise of ion-absorbing type rare earth ore].

PubMed

Zhang, W F; Tang, S H; Tan, Q; Liu, Y M

2016-08-20

Objective: To investigate radioactive source term dose monitoring and estimation results in a manufacturing enterprise of ion-absorbing type rare earth ore and the possible ionizing radiation dose received by its workers. Methods: Ionizing radiation monitoring data of the posts in the control area and supervised area of workplace were collected, and the annual average effective dose directly estimated or estimated using formulas was evaluated and analyzed. Results: In the control area and supervised area of the workplace for this rare earth ore, α surface contamination activity had a maximum value of 0.35 Bq/cm 2 and a minimum value of 0.01 Bq/cm 2 ; β radioactive surface contamination activity had a maximum value of 18.8 Bq/cm 2 and a minimum value of 0.22 Bq/cm 2 . In 14 monitoring points in the workplace, the maximum value of the annual average effective dose of occupational exposure was 1.641 mSv/a, which did not exceed the authorized limit for workers (5 mSv/a) , but exceeded the authorized limit for general personnel (0.25 mSv/a) . The radionuclide specific activity of ionic mixed rare earth oxides was determined to be 0.9. Conclusion: The annual average effective dose of occupational exposure in this enterprise does not exceed the authorized limit for workers, but it exceeds the authorized limit for general personnel. We should pay attention to the focus of the radiation process, especially for public works radiation.

Hemodialysis patients receiving a greater Kt dose than recommended have reduced mortality and hospitalization risk.

PubMed

Maduell, Francisco; Ramos, Rosa; Varas, Javier; Martin-Malo, Alejandro; Molina, Manuel; Pérez-Garcia, Rafael; Marcelli, Daniele; Moreso, Francesc; Aljama, Pedro; Merello, Jose Ignacio

2016-12-01

Achieving an adequate dialysis dose is one of the key goals for dialysis treatments. Here we assessed whether patients receiving the current cleared plasma volume (Kt), individualized for body surface area per recommendations, had improved survival and reduced hospitalizations at 2 years of follow-up. Additionally, we assessed whether patients receiving a greater dose gained more benefit. This prospective, observational, multicenter study included 6129 patients in 65 Fresenius Medical Care Spanish facilities. Patients were classified monthly into 1 of 10 risk groups based on the difference between achieved and target Kt. Patient groups with a more negative relationship were significantly older with a higher percentage of diabetes mellitus and catheter access. Treatment dialysis time, effective blood flow, and percentage of on-line hemodiafiltration were significantly higher in groups with a higher dose. The mortality risk profile showed a progressive increase when achieved minus target Kt became more negative but was significantly lower in the group with 1 to 3 L clearance above target Kt and in groups with greater increases above target Kt. Additionally, hospitalization risk appeared significantly reduced in groups receiving 9 L or more above the minimum target. Thus, prescribing an additional 3 L or more above the minimum Kt dose could potentially reduce mortality risk, and 9 L or more reduce hospitalization risk. As such, future prospective studies are required to confirm these dose effect findings. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Vertical and venereal transmission of Chandipura virus (Rhabdoviridae) by Aedes aegypti (Diptera: Culicidae).

PubMed

Mavale, M S; Geevarghese, G; Ghodke, Y S; Fulmali, P V; Singh, Anand; Mishra, A C

2005-09-01

Experiments in the laboratory documented vertical and venereal transmission of Chandipura virus (CHPV) in Aedes aegypti (L.). The minimum filial infection rate among the progeny of infected females was 1.2%; the rate among male and female progeny was 0.9 and 1.4%, respectively. The venereal infection rate of CHPV among inseminated females was 32.7%. Our study indicates the possible occurrence of vertical and venereal transmission of CHPV in insect vectors.

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.

PubMed

Hewitt, Ellen; Pitcher, Thomas; Rizoska, Biljana; Tunblad, Karin; Henderson, Ian; Sahlberg, Britt-Louise; Grabowska, Urszula; Classon, Björn; Edenius, Charlotte; Malcangio, Marzia; Lindström, Erik

2016-09-01

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Monte Carlo simulations of the secondary neutron ambient and effective dose equivalent rates from surface to suborbital altitudes and low Earth orbit

NASA Astrophysics Data System (ADS)

El-Jaby, Samy; Richardson, Richard B.

2015-07-01

Occupational exposures from ionizing radiation are currently regulated for airline travel (<20 km) and for missions to low-Earth orbit (∼300-400 km). Aircrew typically receive between 1 and 6 mSv of occupational dose annually, while aboard the International Space Station, the area radiation dose equivalent measured over just 168 days was 106 mSv at solar minimum conditions. It is anticipated that space tourism vehicles will reach suborbital altitudes of approximately 100 km and, therefore, the annual occupational dose to flight crew during repeated transits is expected to fall somewhere between those observed for aircrew and astronauts. Unfortunately, measurements of the radiation environment at the high altitudes reached by suborbital vehicles are sparse, and modelling efforts have been similarly limited. In this paper, preliminary MCNPX radiation transport code simulations are developed of the secondary neutron flux profile in air from surface altitudes up to low Earth orbit at solar minimum conditions and excluding the effects of spacecraft shielding. These secondary neutrons are produced by galactic cosmic radiation interacting with Earth's atmosphere and are among the sources of radiation that can pose a health risk. Associated estimates of the operational neutron ambient dose equivalent, used for radiation protection purposes, and the neutron effective dose equivalent that is typically used for estimates of stochastic health risks, are provided in air. Simulations show that the neutron radiation dose rates received at suborbital altitudes are comparable to those experienced by aircrew flying at 7 to 14 km. We also show that the total neutron dose rate tails off beyond the Pfotzer maximum on ascension from surface up to low Earth orbit.

Monte Carlo simulations of the secondary neutron ambient and effective dose equivalent rates from surface to suborbital altitudes and low Earth orbit.

PubMed

El-Jaby, Samy; Richardson, Richard B

2015-07-01

Occupational exposures from ionizing radiation are currently regulated for airline travel (<20 km) and for missions to low-Earth orbit (∼300-400 km). Aircrew typically receive between 1 and 6 mSv of occupational dose annually, while aboard the International Space Station, the area radiation dose equivalent measured over just 168 days was 106 mSv at solar minimum conditions. It is anticipated that space tourism vehicles will reach suborbital altitudes of approximately 100 km and, therefore, the annual occupational dose to flight crew during repeated transits is expected to fall somewhere between those observed for aircrew and astronauts. Unfortunately, measurements of the radiation environment at the high altitudes reached by suborbital vehicles are sparse, and modelling efforts have been similarly limited. In this paper, preliminary MCNPX radiation transport code simulations are developed of the secondary neutron flux profile in air from surface altitudes up to low Earth orbit at solar minimum conditions and excluding the effects of spacecraft shielding. These secondary neutrons are produced by galactic cosmic radiation interacting with Earth's atmosphere and are among the sources of radiation that can pose a health risk. Associated estimates of the operational neutron ambient dose equivalent, used for radiation protection purposes, and the neutron effective dose equivalent that is typically used for estimates of stochastic health risks, are provided in air. Simulations show that the neutron radiation dose rates received at suborbital altitudes are comparable to those experienced by aircrew flying at 7 to 14 km. We also show that the total neutron dose rate tails off beyond the Pfotzer maximum on ascension from surface up to low Earth orbit. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography.

PubMed

Gerritsen, M G; Willemink, M J; Pompe, E; van der Bruggen, T; van Rhenen, A; Lammers, J W J; Wessels, F; Sprengers, R W; de Jong, P A; Minnema, M C

2017-01-01

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography

PubMed Central

Pompe, E.; van der Bruggen, T.; van Rhenen, A.; Lammers, J. W. J.; Wessels, F.; Sprengers, R. W.; de Jong, P. A.; Minnema, M. C.

2017-01-01

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose. PMID:28235014

Accumulated Delivered Dose Response of Stereotactic Body Radiation Therapy for Liver Metastases

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

Swaminath, Anand; Massey, Christine; Brierley, James D.

2015-11-01

Purpose: To determine whether the accumulated dose using image guided radiation therapy is a stronger predictor of clinical outcomes than the planned dose in stereotactic body radiation therapy (SBRT) for liver metastases. Methods and Materials: From 2003 to 2009, 81 patients with 142 metastases were treated in institutional review board–approved SBRT studies (5-10 fractions). Patients were treated during free breathing (with or without abdominal compression) or with controlled exhale breath-holding. SBRT was planned on a static exhale computed tomography (CT) scan, and the minimum planning target volume dose to 0.5 cm{sup 3} (minPTV) was recorded. The accumulated minimum dose to themore » 0.5 cm{sup 3} gross tumor volume (accGTV) was calculated after performing dose accumulation from exported image guided radiation therapy data sets registered to the planning CT using rigid (2-dimensional MV/kV orthogonal) or deformable (3-dimensional/4-dimensional cone beam CT) image registration. Univariate and multivariate Cox regression models assessed the factors influencing the time to local progression (TTLP). Hazard ratios for accGTV and minPTV were compared using model goodness-of-fit and bootstrapping. Results: Overall, the accGTV dose exceeded the minPTV dose in 98% of the lesions. For 5 to 6 fractions, accGTV doses of >45 Gy were associated with 1-year local control of 86%. On univariate analysis, the cancer subtype (breast), smaller tumor volume, and increased dose were significant predictors for improved TTLP. The dose and volume were uncorrelated; the accGTV dose and minPTV dose were correlated and were tested separately on multivariate models. Breast cancer subtype, accGTV dose (P<.001), and minPTV dose (P=.02) retained significance in the multivariate models. The univariate hazard ratio for TTLP for 5-Gy increases in accGTV versus minPTV was 0.67 versus 0.74 (all patients; 95% confidence interval of difference 0.03-0.14). Goodness-of-fit testing confirmed the accGTV dose as a stronger dose–response predictor than the minPTV dose. Conclusions: The accGTV dose is a better predictor of TTLP than the minPTV dose for liver metastasis SBRT. The use of modern image guided radiation therapy in future analyses of dose–response outcomes should increase the concordance between the planned and delivered doses.« less

An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model.

PubMed

Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S; Evers, Taylor J; Enkirch, Theresa; Reddy, G Prabhakar; Sun, Aiming; Saindane, Manohar T; Arrendale, Richard F; Painter, George; Liotta, Dennis C; Natchus, Michael G; von Messling, Veronika; Plemper, Richard K

2014-04-16

Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

Challenge Pools of Hepatitis C Virus Genotypes 1–6 Prototype Strains: Replication Fitness and Pathogenicity in Chimpanzees and Human Liver–Chimeric Mouse Models

PubMed Central

Bukh, Jens; Meuleman, Philip; Tellier, Raymond; Engle, Ronald E.; Feinstone, Stephen M.; Eder, Gerald; Satterfield, William C.; Govindarajan, Sugantha; Krawczynski, Krzysztof; Miller, Roger H.; Leroux-Roels, Geert; Purcell, Robert H.

2010-01-01

Chimpanzees represent the only animal model for studies of the natural history of hepatitis C virus (HCV). To generate virus stocks of important HCV variants, we infected chimpanzees with HCV strains of genotypes 1–6 and determined the infectivity titer of acute-phase plasma pools in additional animals. The courses of first- and second-passage infections were similar, with early appearance of viremia, HCV RNA titers of >104.7 IU/mL, and development of acute hepatitis; the chronicity rate was 56%. The challenge pools had titers of 103–105 chimpanzee infectious doses/mL. Human liver–chimeric mice developed high-titer infections after inoculation with the challenge viruses of genotypes 1–6. Inoculation studies with different doses of the genotype 1b pool suggested that a relatively high virus dose is required to consistently infect chimeric mice. The challenge pools represent a unique resource for studies of HCV molecular virology and for studies of pathogenesis, protective immunity, and vaccine efficacy in vivo. PMID:20353362

Leisure-time physical activity dose-response effects on obesity among US adults: results from the 1999-2006 National Health and Nutrition Examination Survey.

PubMed

Seo, Dong-Chul; Li, Kaigang

2010-05-01

It is not well established whether total volume of leisure-time physical activity (LTPA) has dose-response effects on obesity. The dose-response relationship was examined using 12 227 non-institutionalised individuals, aged 20-64 years, drawn from the 8 years (1999-2006) of the continuous National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. The age-adjusted prevalence of women's obesity was 41.4% for those with no LTPA in the past month; 39.1% for those who engaged in LTPA but fell short of the recommended minimum amount of LTPA (ie, <450 metabolic equivalent minutes per week (MET min/week)); 31.0% for those who met the recommended minimum guideline (ie, 450 to < 750); 28.0% for those whose LTPA exceeded the minimum guideline but less than the first quartile among the overachievers (ie, 750 to <1260); 23.4% for the overachievers between the first and third quartile (ie, 1260 to <3556); and 19.5% for the overachievers at or above the third quartile (ie, 3556 MET min/week or above). This association was maintained even after occupational physical activity (OPA) was controlled. However, this pattern was not observed for Mexican and black adults and showed a floor effect as LTPA increased. There is a crude graded inverse dose-response relationship between total volume of LTPA and obesity in US adult women, but not in men. Gender and racial/ethnic differences exist in the relationship of accumulated LTPA with obesity due, in part, to differential ratios of LTPA to OPA.

Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review

PubMed Central

Lin, Kuan-Yin; Chen, Guan-Jhou; Lee, Yu-Lin; Huang, Yi-Chia; Cheng, Aristine; Sun, Hsin-Yun; Chang, Sui-Yuan; Liu, Chun-Eng; Hung, Chien-Ching

2017-01-01

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. The virus is known to be transmitted fecal-orally, resulting in symptoms ranging from asymptomatic infection to fulminant hepatitis. HAV can also be transmitted through oral-anal sex. Residents from regions of low endemicity for HAV infection often remain susceptible in their adulthood. Therefore, clustered HAV infections or outbreaks of acute hepatitis A among men who have sex with men and injecting drug users have been reported in countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in human immunodeficiency virus (HIV)-positive individuals compared to HIV-negative individuals with acute hepatitis A. Current guidelines recommend HAV vaccination for individuals with increased risks of exposure to HAV (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis). The seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) are lower among HIV-positive individuals compared to HIV-negative individuals. While the response rates may be augmented by adding a booster dose at week 4 sandwiched between the first dose and the 6-mo dose, the need of booster vaccination remain less clear among HIV-positive individuals who have lost anti-HAV antibodies. PMID:28611512

Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review.

PubMed

Lin, Kuan-Yin; Chen, Guan-Jhou; Lee, Yu-Lin; Huang, Yi-Chia; Cheng, Aristine; Sun, Hsin-Yun; Chang, Sui-Yuan; Liu, Chun-Eng; Hung, Chien-Ching

2017-05-28

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. The virus is known to be transmitted fecal-orally, resulting in symptoms ranging from asymptomatic infection to fulminant hepatitis. HAV can also be transmitted through oral-anal sex. Residents from regions of low endemicity for HAV infection often remain susceptible in their adulthood. Therefore, clustered HAV infections or outbreaks of acute hepatitis A among men who have sex with men and injecting drug users have been reported in countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in human immunodeficiency virus (HIV)-positive individuals compared to HIV-negative individuals with acute hepatitis A. Current guidelines recommend HAV vaccination for individuals with increased risks of exposure to HAV (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis). The seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) are lower among HIV-positive individuals compared to HIV-negative individuals. While the response rates may be augmented by adding a booster dose at week 4 sandwiched between the first dose and the 6-mo dose, the need of booster vaccination remain less clear among HIV-positive individuals who have lost anti-HAV antibodies.

Protection of dogs against canine heartworm infection 28 days after four monthly treatments with Advantage Multi® for Dogs.

PubMed

Bowman, Dwight D; Grazette, Alyssa R; Basel, Chris; Wang, Yingying; Hostetler, Joseph A

2016-01-08

Monthly heartworm preventives are designed to protect dogs by killing heartworms acquired the month prior to their administration, and after treatment with most products, the drug levels rapidly dissipate to very low levels. Work with Advantage Multi® for Dogs (imidacloprid + moxidectin) topical solution showed protection against hookworm infection throughout the month after administration of several monthly doses suggesting that similar protection might occur with heartworms. This study assessed the amount of protection afforded to dogs by the administration of four monthly doses of Advantage Multi for Dogs prior to infection with third-stage heartworm larvae (Dirofilaria immitis) 28 days after the last (fourth) treatment. There were 16 purpose-bred mongrel dogs in the study that were divided into two groups, 8 control and 8 treated dogs. Dogs were housed in a manner preventing contact between animals and groups, and personal protective gear worn by staff minimised the chance spread of the topically applied product between runs. The dogs in the treated group received monthly applications of Advantage Multi for Dogs as per label instructions on Study Days 0, 28, 56, and 84. On Study Day 112, all 16 dogs received 50 third-stage larvae of D. immitis ("Missouri" isolate) via subcutaneous inoculation in the inguinal region. The study was terminated on Day 264, and the number of heartworms per dog was determined at necropsy. Moxidectin levels after 4 treatments 28 days apart were near steady state on Study Day 112 when the dogs were inoculated with D. immitis third-stage larvae. At necropsy, 152 days after infection, all the control dogs had adult worms in their pulmonary arteries (geometric mean = 33.9; range 25-41), and none of the dogs treated four times prior to infection, with the last treatment 30 days prior to infection, harbored worms at necropsy. The efficacy of prevention was 100% when the dogs were infected 28 days after the last monthly treatment. When dogs receive consecutive doses of Advantage Multi for Dogs as prescribed, heartworm infections will be prevented throughout the monthly dosing interval after administration of several monthly doses.

Bursal immunopathology responses of specific-pathogen-free chickens and red jungle fowl infected with very virulent infectious bursal disease virus.

PubMed

Farhanah, Mohd Isa; Yasmin, Abdul Rahaman; Khanh, Nguyen Phuc; Yeap, Swee Keong; Hair-Bejo, Mohd; Omar, Abdul Rahman

2018-04-06

Very virulent infectious bursal disease virus (vvIBDV) targets B lymphocytes in the bursa of Fabricius (BF), causing immunosuppression and increased mortality rates in young birds. There have been few studies on the host immune response following vvIBDV infection at different inoculum doses in chickens with different genetic backgrounds. In this study, we characterized the immune responses of specific-pathogen-free (SPF) chickens and Malaysian red jungle fowl following infection with vvIBDV strain UPM0081 at 10 3.8 and 10 6.8 times the 50% embryo infectious dose (EID 50 ). The viral burden, histopathological changes, immune cell populations, and expression of immune-related genes were measured and compared between infected and uninfected bursa at specific intervals. The populations of KUL1 + , CD3 + CD4 + and CD3 + CD8 + cells were significantly increased in both types of chickens at 3 dpi, and there was significant early depletion of IgM + B cells at 1 dpi in the red jungle fowl. vvIBDV infection also induced differential expression of genes that are involved in Th1 and pro-inflammatory responses, with groups receiving the higher dose (10 6.8 EID 50 ) showing earlier expression of IFNG, IL12B, IL15, IL6, CXCLi2, IL28B, and TLR3 at 1 dpi. Although both chicken types showed equal susceptibility to infection, the red jungle fowl were clinically healthier than the SPF chickens despite showing more depletion of IgM + B cells and failure to induce IFNB activation. In conclusion, high-dose vvIBDV infection caused an intense early host immune response in the infected bursa, with depletion of IgM + B cells, bursal lesions, and cytokine expression as a response to mitigate the severity of the infection.

A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection.

PubMed

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-04-29

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus).A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1-3 days after onset of symptoms, even when very low infectious viral doses of 5x10(2) pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed.We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID(50) (minimal monkey infectious dose 50%) of 8.3x10(2) pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis.

A Novel Highly Reproducible and Lethal Nonhuman Primate Model for Orthopox Virus Infection

PubMed Central

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-01-01

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus). A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1–3 days after onset of symptoms, even when very low infectious viral doses of 5×102 pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed. We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID50 (minimal monkey infectious dose 50%) of 8.3×102 pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis. PMID:20454688

Comparative minimum inhibitory and mutant prevention drug concentrations of enrofloxacin, ceftiofur, florfenicol, tilmicosin and tulathromycin against bovine clinical isolates of Mannheimia haemolytica.

PubMed

Blondeau, J M; Borsos, S; Blondeau, L D; Blondeau, B J J; Hesje, C E

2012-11-09

Mannheimia haemolytica is the most prevalent cause of bovine respiratory disease (BRD) and this disease accounts for 75% of morbidity, 50-70% of feedlot deaths and is estimated to cost up to $1 billion dollars annually in the USA. Antimicrobial therapy is essential for reducing morbidity, mortality and impacting on the financial burden of this disease. Due to the concern of increasing antimicrobial resistance, investigation of antibacterial agents for their potential for selecting for resistance is of paramount importance. A novel in vitro measurement called the mutant prevention concentration (MPC) defines the antimicrobial drug concentration necessary to block the growth of the least susceptible cells present in high density (≥10(7) colony forming units/ml) bacterial populations such as those seen in acute infection. We compared the minimum inhibitory concentration (MIC) and MPC values for 5 antimicrobial agents (ceftiofur, enrofloxacin, florfenicol, tilmicosin, tulathromycin) against 285 M. haemolytica clinical isolates. The MIC(90)/MPC(90) values for each agent respectively were as follows: 0.016/2, 0.125/1, 2/≥16, 8/≥32, 2/8. Dosing to achieve MPC concentrations (where possible) may serve to reduce the selection of bacterial subpopulations with reduced antimicrobial susceptibility. The rank order of potency based on MIC(90) values was ceftiofur > enrofloxacin > florfenicol = tulathromycin > tilmicosin. The rank order of potency based on MPC(90) values was enrofloxacin > ceftiofur > tulathromycin > florfenicol ≥ tilmicosin. Copyright © 2012 Elsevier B.V. All rights reserved.

Invitro Anti-mycotic Activity of Hydro Alcoholic Extracts of Some Indian Medicinal Plants against Fluconazole Resistant Candida albicans.

PubMed

Varadarajan, Saranya; Narasimhan, Malathi; Malaisamy, Malaiyandi; Duraipandian, Chamundeeswari

2015-08-01

Candidiasis is one of the most common opportunistic infections caused by Candida albicans. Fluconazole is the drug of choice for prevention and management of this condition. However, the emergence of fluconazole resistant candidal strains has become a major concern. Many herbs like fenugreek, cinnamon, papaya, oregano, garlic are rich in phytochemical constituents known to express antimycotic activity. With the available information, the present research study was carried out to assess the invitro anti-mycotic activity of hydro alcoholic extracts of Trigonella foenum-graecum seeds, Cinnamomum verum bark and Carica papaya leaves and seeds against fluconazole resistant Candida albicans. Hydro alcoholic extracts of Trigonella foenum-graecum (seeds), Cinnamomum verum (bark), Carica papaya CO.2 strain (male and female leaves) and Carica papaya CO.2 strain (seeds) were prepared by maceration. The anti-mycotic activity of the prepared extracts against Candida albicans was assessed by agar well diffusion method. Three independent experiments were performed in triplicates and the mean and standard deviation were calculated. Minimum inhibitory concentration was determined. The results of the present study revealed that all the extracts exhibited anti-mycotic activity in a dose dependent manner and minimum inhibitory concentration of all the extracts was found to be 15.62 μg/ml. The results of the present study shed light on the fact that plant extracts could be used not only as an alternate drug for management of fluconazole resistant candidiasis but also explored further for oral cancer prevention as a therapeutic adjunct.

RADIATION STERILIZATION OF COCOA POWDERS. Report No. 2 (Progress) for May 17, 1959-August 17, 1959

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

McComb, C.

1961-10-31

A study was made of the effects of O.l, 0.3, and 0.6 megarad of gamma radiation on microflora, flavor, and vitamin content of chocolate syrup. A dose of 0.3 was found to be the minimum useful dose bacteriologically. Vitamin content was not reduced, and no off-flavor was reported. (T.R.H.)

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-03-08

In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Single line source with and without vaginal loading and the impact on target coverage and organ at risk doses for cervix cancer Stages IB, II, and IIIB: treatment planning simulation in patients treated with MRI-guided adaptive brachytherapy in a multicentre study (EMBRACE).

PubMed

Nkiwane, Karen S; Pötter, Richard; Tanderup, Kari; Federico, Mario; Lindegaard, Jacob C; Kirisits, Christian

2013-01-01

Three-dimensional evaluation and comparison of target and organs at risk (OARs) doses from two traditional standard source loading patterns in the frame of MRI-guided cervical cancer brachytherapy for various clinical scenarios based on patient data collected in a multicenter trial setting. Two nonoptimized three-dimensional MRI-based treatment plans, Plan 1 (tandem and vaginal loading) and Plan 2 (tandem loading only), were generated for 134 patients from seven centers participating in the EMBRACE study. Both plans were normalized to point A (Pt. A). Target and OAR doses were evaluated in terms of minimum dose to 90% of the high-risk clinical target volume (HRCTV D90) grouped by tumor stage and minimum dose to the most exposed 2cm³ of the OARs volume. An HRCTV D90 ≥ Pt. A was achieved in 82% and 44% of the patients with Plans 1 and 2, respectively. Median HRCTV D90 with Plans 1 and 2 was 120% and 90% of Pt. A dose, respectively. Both plans had optimal dose coverage in 88% of Stage IB tumors; however, the tandem-only plan resulted in about 50% of dose reduction to the vagina and rectum. For Stages IIB and IIIB, Plan 1 had on average 35% better target coverage but with significant doses to OARs. Standard tandem loading alone results in good target coverage in most Stage IB tumors without violating OAR dose constraints. For Stage IIB tumors, standard vaginal loading improves the therapeutic window, however needs optimization to fulfill the dose prescription for target and OAR. In Stage IIIB, even optimized vaginal loading often does not fulfill the needs for dose prescription. The significant dose variation across various clinical scenarios for both target and OARs indicates the need for image-guided brachytherapy for optimal dose adaptation both for limited and advanced diseases. Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

The Effect of Dose-Volume Parameters and Interfraction Interval on Cosmetic Outcome and Toxicity After 3-Dimensional Conformal Accelerated Partial Breast Irradiation

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

Leonard, Kara Lynne, E-mail: karalynne.kerr@gmail.com; Hepel, Jaroslaw T.; Department of Radiation Oncology, Rhode Island Hospital, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island

2013-03-01

Purpose: To evaluate dose-volume parameters and the interfraction interval (IFI) as they relate to cosmetic outcome and normal tissue effects of 3-dimensional conformal radiation therapy (3D-CRT) for accelerated partial breast irradiation (APBI). Methods and Materials: Eighty patients were treated by the use of 3D-CRT to deliver APBI at our institutions from 2003-2010 in strict accordance with the specified dose-volume constraints outlined in the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group 0413 (NSABP-B39/RTOG 0413) protocol. The prescribed dose was 38.5 Gy in 10 fractions delivered twice daily. Patients underwent follow-up with assessment for recurrence, late toxicity, andmore » overall cosmetic outcome. Tests for association between toxicity endpoints and dosimetric parameters were performed with the chi-square test. Univariate logistic regression was used to evaluate the association of interfraction interval (IFI) with these outcomes. Results: At a median follow-up time of 32 months, grade 2-4 and grade 3-4 subcutaneous fibrosis occurred in 31% and 7.5% of patients, respectively. Subcutaneous fibrosis improved in 5 patients (6%) with extended follow-up. Fat necrosis developed in 11% of women, and cosmetic outcome was fair/poor in 19%. The relative volume of breast tissue receiving 5%, 20%, 50%, 80%, and 100% (V5-V100) of the prescribed dose was associated with risk of subcutaneous fibrosis, and the volume receiving 50%, 80%, and 100% (V50-V100) was associated with fair/poor cosmesis. The mean IFI was 6.9 hours, and the minimum IFI was 6.2 hours. The mean and minimum IFI values were not significantly associated with late toxicity. Conclusions: The incidence of moderate to severe late toxicity, particularly subcutaneous fibrosis and fat necrosis and resulting fair/poor cosmesis, remains high with continued follow-up. These toxicity endpoints are associated with several dose-volume parameters. Minimum and mean IFI values were not associated with late toxicity.« less

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model▿

PubMed Central

Moore, Brioni R.; Page-Sharp, Madhu; Stoney, Jillian R.; Ilett, Kenneth F.; Jago, Jeffrey D.; Batty, Kevin T.

2011-01-01

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5- to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t1/2), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL = 3.86 × W0.56, V = 230 × W0.94, and t1/2 = 123 × W0.2) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations. PMID:21646487

Comparative Effectiveness of Two Oil Adjuvant-Inactivated Avian Influenza H9N2 Vaccines.

PubMed

Kilany, Walid H; Bazid, Abdel-Hamid I; Ali, Ahmed; El-Deeb, Ayman H; El-Abideen, Mohamed A Zain; Sayed, Magdy El; El-Kady, Magdy F

2016-05-01

Low pathogenic avian influenza H9N2 virus infection has been an important risk to the Egyptian poultry industry since 2011. Economic losses have occurred from early infection and co-infection with other pathogens. Therefore, H9N2 vaccination of broiler chicks as young as 7 days old was recommended. The current inactivated H9N2 vaccines (0.5 ml/bird) administered at a reduced dose (0.25 ml/bird) do not guarantee the delivery of an effective dose for broilers. In this study, the efficacy of the reduced-dose volume (0.3 ml/bird), compared with the regular vaccine dose (0.5 ml/bird) of inactivated H9N2 vaccines using two different commercially available adjuvants, was investigated. The vaccines were prepared from the local H9N2 virus (Ck/EG/114940v/NLQP/11) using the same antigen content: 300 hemagglutinating units. Postvaccination (PV) immune response was monitored using the hemagglutination inhibition test. At 4 wk PV, both vaccinated groups were challenged using the homologous H9N2 strain at a 50% egg infective dose (EID50) of 10(6) EID50/bird via the intranasal route. Clinical signs, mortality, and virus shedding in oropharyngeal swabs were monitored at 2, 4, 6, and 10 days postchallenge (DPC). The reduced-dose volume of vaccine induced a significantly faster and higher immune response than the regular volume of vaccine at 2 and 3 wk PV. No significant difference in virus shedding between the two vaccine formulas was found (P ≥ 0.05), and both vaccines were able to stop virus shedding by 6 DPC. The reduced-dose volume of vaccine using a suitable oil adjuvant and proper antigen content can be used effectively for early immunization of broiler chicks.

Dose estimates for the local inhabitants from 210Po ingestion via dietary sources at a proposed uranium mining site in India.

PubMed

Giri, Soma; Jha, V N; Singh, Gurdeep; Tripathi, R M

2012-07-01

To study the distribution of (210)Po activity in food in Bagjata in East Singhbhum, India. (210)Po were analyzed in the food samples of plant origin such as cereals, pulses, fruits, vegetables and food of animal origin such fish, chicken, egg, etc., in and around Bagjata uranium mining area as a part of baseline study after acid digestion. The intake and ingestion dose of the radionuclide was estimated. The general range of (210)Po activity in all the dietary components ranged widely from <0.2-36 Bqkg(-1)(fresh). In the food of plant origin, the minimum activity of (210)Po was estimated in vegetables while maximum in pulses. In food of animal origin, the observed minimum activity of (210)Po was in eggs and the maximum observed was in chicken samples. The intake of (210)Po considering all dietary components was found to be 464 Bq.Y(-1) while the ingestion dose was calculated to be 557 μSv.Y(-1), respectively. The estimated doses are reflecting the natural background dose via the route of ingestion, which is much below the 1 mSv limit set in the International Commission on Radiological Protection (ICRP) recommendations. The study confirms that current levels of (210)Po do not pose a significant radiological risk to the local inhabitants.

Influence of vehicles used for oral dosing of test molecules on the progression of Mycobacterium tuberculosis infection in mice.

PubMed

Singh, Shubhra; Dwivedi, Richa; Chaturvedi, Vinita

2012-11-01

Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both sets of parameters, whereas the other vehicles affected only physical parameters.

Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice

PubMed Central

Singh, Shubhra; Dwivedi, Richa

2012-01-01

Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both sets of parameters, whereas the other vehicles affected only physical parameters. PMID:22926571

Evaluation of the antibacterial potential of Petroselinum crispum and Rosmarinus officinalis against bacteria that cause urinary tract infections

PubMed Central

Petrolini, Fernanda Villas Boas; Lucarini, Rodrigo; de Souza, Maria Gorete Mendes; Pires, Regina Helena; Cunha, Wilson Roberto; Martins, Carlos Henrique Gomes

2013-01-01

In this study we evaluated the antibacterial activity of the crude hydroalcoholic extracts, fractions, and compounds of two plant species, namely Rosmarinus officinalis and Petroselinum crispum, against the bacteria that cause urinary tract infection. The microdilution method was used for determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The crude hydroalcoholic extract of R. officinalis displayed in vitro activity against Gram-positive bacteria, with satisfactory MBC for the clinical isolate S. saprophyticus. The fractions and the pure compound rosmarinic acid did not furnish promising results for Gram-negative bacteria, whereas fractions 2, 3, and 4 gave encouraging results for Gram-positive bacteria and acted as bactericide against S. epidermidis as well as E. faecalis (ATCC 29212) and its clinical isolate. R. officinalis led to promising results in the case of Gram-positive bacteria, resulting in a considerable interest in the development of reliable alternatives for the treatment of urinary infections. PMID:24516424

Evaluation of the antibacterial potential of Petroselinum crispum and Rosmarinus officinalis against bacteria that cause urinary tract infections.

PubMed

Petrolini, Fernanda Villas Boas; Lucarini, Rodrigo; de Souza, Maria Gorete Mendes; Pires, Regina Helena; Cunha, Wilson Roberto; Martins, Carlos Henrique Gomes

2013-01-01

In this study we evaluated the antibacterial activity of the crude hydroalcoholic extracts, fractions, and compounds of two plant species, namely Rosmarinus officinalis and Petroselinum crispum, against the bacteria that cause urinary tract infection. The microdilution method was used for determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The crude hydroalcoholic extract of R. officinalis displayed in vitro activity against Gram-positive bacteria, with satisfactory MBC for the clinical isolate S. saprophyticus. The fractions and the pure compound rosmarinic acid did not furnish promising results for Gram-negative bacteria, whereas fractions 2, 3, and 4 gave encouraging results for Gram-positive bacteria and acted as bactericide against S. epidermidis as well as E. faecalis (ATCC 29212) and its clinical isolate. R. officinalis led to promising results in the case of Gram-positive bacteria, resulting in a considerable interest in the development of reliable alternatives for the treatment of urinary infections.

Microbiological etiology and susceptibility of bacterial conjunctivitis isolates from clinical trials with ophthalmic, twice-daily besifloxacin.

PubMed

Haas, Wolfgang; Gearinger, Lynne S; Hesje, Christine K; Sanfilippo, Christine M; Morris, Timothy W

2012-05-01

Bacterial conjunctivitis is a contagious infection of the surface of the eye usually treated empirically with topical antibiotics. Since the etiologic agent is rarely identified, it is important to monitor which bacteria cause conjunctivitis and determine their antibacterial resistance profiles. A total of 496 bacterial samples were isolated during a randomized, double-masked, vehicle-controlled, parallel-group study conducted in the United States with besifloxacin ophthalmic suspension 0.6% dosed twice daily. Species were determined by standard biochemical and/or molecular identification methods. Minimum inhibitory concentrations were determined according to Clinical and Laboratory Standards Institute standards. The most prevalent species was Haemophilus influenzae, followed by Staphylococcus epidermidis, Staphylococcus aureus, the Streptococcus mitis group, and Streptococcus pneumoniae. One species identified in this study, which was not previously noted as a common cause of bacterial conjunctivitis, was Dolosigranulum pigrum. Ampicillin resistance was common among H. influenzae isolates, while macrolide resistance was high among S. pneumoniae, S. epidermidis, and S. aureus. The latter two species also included a number of isolates resistant to methicillin and ciprofloxacin. Antibiotic resistance among isolates remains a concern and the appearance of an emerging ocular pathogen, D. pigrum, suggests the need for continued observation. The topical ophthalmic fluoroquinolones continue to provide a good balance of low to moderate (i.e., manageable) levels of resistance plus broad-spectrum coverage for empiric treatment of ocular infections.

Incidence of gonorrhoea due to penicillinase producing Neisseria gonorrhoeae in Japan 1981-3 and treatment using a new antibiotic combination, BRL25000 (amoxycillin and clavulanic acid).

PubMed Central

Osato, K; Tsugami, H; Harada, K; Maruyama, J

1986-01-01

During the three years 1981-3, 134 (9.1%) of 1473 patients presenting at our clinics were found to be infected with penicillinase producing strains of Neisseria gonorrhoeae (PPNG). Minimum inhibitory concentrations (MICs) of benzylpenicillin and ampicillin against these PPNG strains were 8 mg/l or more, whereas against non-PPNG strains they were consistently 4 mg/l or less. In contrast, the MIC of BRL25000 (two parts amoxycillin and one part clavulanic acid, the beta lactamase inhibitor) was 4 mg/l or less even against PPNG strains. MICs of a number of other drugs commonly used to treat gonorrhoea, such as cephaloridine, cefoxitin, tetracycline, doxycycline, minocycline, kanamycin, and spectinomycin, showed no appreciable differences between non-PPNG and PPNG strains and the MIC of cephaloridine in particular was relatively high. BRL25000 proved to be very effective in the treatment of PPNG infection and cured all of 121 patients treated. A daily dose of 2.25g, cured 105 patients in two days, 11 patients in three days, four patients in four days, and one patient in five days. A new rapid diagnostic method for detecting PPNG strains, capable of application at an outpatient clinic and providing a result on the following day, is described. Images PMID:3089905

Amoxicillin/clavulanate potassium extended release tablets: a new antimicrobial for the treatment of acute bacterial sinusitis and community-acquired pneumonia.

PubMed

Benninger, Michael S

2003-10-01

Community-acquired bacterial respiratory tract infections are among the most common health disorders requiring medical care and are associated with substantial morbidity, mortality, and direct and indirect costs. Recent increases in the prevalence of antimicrobial resistance have resulted in reduced susceptibility of the most common respiratory tract bacterial pathogens to a number of antimicrobials. Amoxicillin/clavulanate potassium extended release (ER) tablets (Augmentin XR, GlaxoSmithKline) is a new formulation of amoxicillin/clavulanate that retains activity against betalactamase-producing organisms whilst increasing the activity against Streptococcus pneumoniae through elevated and sustained plasma amoxicillin concentrations. The bilayer tablet provides immediate release of clavulanate and both immediate and sustained release of amoxicillin to maintain therapeutic concentrations of amoxicillin over longer periods of the dosing interval. In clinical trials of acute bacterial sinusitis (ABS) and community-acquired pneumonia (CAP), amoxicillin/clavulanate ER was shown to have excellent bacteriological and clinical success rates, even in patients infected with antimicrobial-resistant pathogens, and was found to be generally well tolerated. Amoxicillin/clavulanate ER is approved in the US for the treatment of patients with ABS or CAP caused by beta-lactamase-producing pathogens (ie, Haemophilus influenzae, Moraxella catarrhalis, Haemophilus parainfluenzae, Klebsiella pneumoniae, or methicillin-susceptible Staphylococcus aureus) and S. pneumoniae with reduced susceptibility to penicillin (penicillin minimum inhibitory concentration = 2.0 microg/ml).

Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial.

PubMed

Gulati, Ashima; Sinha, Aditi; Sreenivas, Vishnubhatla; Math, Aparna; Hari, Pankaj; Bagga, Arvind

2011-01-01

Relapses of nephrotic syndrome often follow minor infections, commonly of the upper respiratory tract. Daily administration of maintenance prednisolone during intercurrent infections was examined to determine whether the treatment reduces relapse rates in children with frequently relapsing nephrotic syndrome. In a randomized controlled trial (nonblind, parallel group, tertiary-care hospital), 100 patients with idiopathic, frequently relapsing nephrotic syndrome eligible for therapy with prolonged low-dose, alternate-day prednisolone with or without levamisole were randomized to either receive their usual dose of alternate-day prednisolone daily for 7 days during intercurrent infections (intervention group) or continue alternate-day prednisolone (controls). Primary outcome was assessed by comparing the rates of infection-associated relapses at 12-month follow-up. Secondary outcomes were the frequency of infections and the cumulative amount of prednisolone received in both groups. Patients in the intervention group showed significantly lower infection-associated (rate difference, 0.7 episodes/patient per year; 95% confidence intervals [CI] 0.3, 1.1) and lower total relapse rates (0.9 episodes/patient per year, 95% CI 0.4, 1.4) without increase in steroid toxicity. Poisson regression, adjusted for occurrence of infections, showed that daily administration of prednisolone during infections independently resulted in 59% reduction in frequency of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). For every six patients receiving this intervention, one showed a reduction of relapse frequency to less than three per year. Daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduces relapse rates and the proportion of children with frequently relapsing nephrotic syndrome.

Lung development and the host response to influenza A virus are altered by different doses of neonatal oxygen in mice

PubMed Central

Buczynski, Bradley W.; Yee, Min; Paige Lawrence, B.

2012-01-01

Oxygen exposure in preterm infants has been associated with altered lung development and increased risk for respiratory viral infections later in life. Although the dose of oxygen sufficient to exert these changes in humans remains unknown, adult mice exposed to 100% oxygen between postnatal days 1–4 exhibit alveolar simplification and increased sensitivity to influenza virus infection. Additionally, two nonlinear thresholds of neonatal oxygen exposures were previously identified that promote modest (between 40% and 60% oxygen) and severe (between 80% and 100% oxygen) changes in lung development. Here, we investigate whether these two thresholds correlate with the severity of lung disease following respiratory viral infection. Adult mice exposed to 100% oxygen at birth, and to a lesser extent 80% oxygen, demonstrated enhanced body weight loss, persistent inflammation, and fibrosis following infection compared with infected siblings exposed to room air at birth. In contrast, the host response to infection was indistinguishable between mice exposed to room air and 40% or 60% oxygen. Interestingly, levels of monocyte chemoattractant protein (MCP)-1 were equivalently elevated in infected mice that had been exposed to 80% or 100% oxygen as neonates. However, reducing levels of MCP-1 using heterozygous Mcp-1 mice did not affect oxygen-dependent changes in the response to infection. Thus lung development and the host response to respiratory viral infection are disrupted by different doses of oxygen. Our findings suggest that measuring lung function alone may not be sufficient to identify individuals born prematurely who have increased risk for respiratory viral infection. PMID:22408042

Distinct immune responses and virus shedding in pigs following aerosol, intra-nasal and contact infection with pandemic swine influenza A virus, A(H1N1)09.

PubMed

Hemmink, Johanneke D; Morgan, Sophie B; Aramouni, Mario; Everett, Helen; Salguero, Francisco J; Canini, Laetitia; Porter, Emily; Chase-Topping, Margo; Beck, Katy; Loughlin, Ronan Mac; Carr, B Veronica; Brown, Ian H; Bailey, Mick; Woolhouse, Mark; Brookes, Sharon M; Charleston, Bryan; Tchilian, Elma

2016-10-20

Influenza virus infection in pigs is a major farming problem, causing considerable economic loss and posing a zoonotic threat. In addition the pig is an excellent model for understanding immunity to influenza viruses as this is a natural host pathogen system. Experimentally, influenza virus is delivered to pigs intra-nasally, by intra-tracheal instillation or by aerosol, but there is little data comparing the outcome of different methods. We evaluated the shedding pattern, cytokine responses in nasal swabs and immune responses following delivery of low or high dose swine influenza pdmH1N1 virus to the respiratory tract of pigs intra-nasally or by aerosol and compared them to those induced in naturally infected contact pigs. Our data shows that natural infection by contact induces remarkably high innate and adaptive immune response, although the animals were exposed to a very low virus dose. In contacts, the kinetics of virus shedding were slow and prolonged and more similar to the low dose directly infected animals. In contrast the cytokine profile in nasal swabs, antibody and cellular immune responses of contacts more closely resemble immune responses in high dose directly inoculated animals. Consideration of these differences is important for studies of disease pathogenesis and assessment of vaccine protective efficacy.

Evaluation of the Antibacterial Activity of Green Propolis Extract and Meadowsweet Extract Against Staphylococcus aureus Bacteria: Importance in Would Care Compounding Preparations.

PubMed

Lupatini, Nogueira Rodrigo José; Danopoulos, Panagiota; Swikidisa, Rosita; Alves, Pinheiro Vanessa

2016-01-01

The use of natural products in compounded wound care formulas is an exciting avenue to pursue for compounding pharmacists since these natural products may contain compounds that promote healing on their own. The use of these natural extracts as an alternative therapy for wound care may also provide several benefits, such as decreased inflammation, infection, side effects, and treatment costs. Thus far, several studies have demonstrated antimicrobial activity for various natural product extracts, including green propolis and meadowsweet. The antimicrobial properties of these extracts make them particularly interesting for wound care because the healing process is significantly delayed by bacterial infection and colonization at the site of injury. Therefore, to further investigate the antimicrobial properties of green propolis and meadowsweet extracts, we performed minimum inhibitory concentration and minimum bactericidal concentration assays against Staphylococcus aureus, a microorganism known to cause wound infections. The antimicrobial activity of green propolis and meadowsweet extracts was tested in vitro against a standard strain of Staphylococcus aureus in brain heart infusion broth and Mueller-Hinton agar plates. Green propolis extract demonstrated antimicrobial activity against Staphylococcus aureus with a minimum inhibitory concentration of 1.25 mg/mL and a minimum bactericidal concentration of 1.25 mg/mL. In contrast, meadowsweet extract failed to inhibit Staphylococcus aureus growth at the highest concentration tested (30 mg/mL). Green propolis was more effective than meadowsweet extract at inhibiting the growth of Staphylococcus aureus, suggesting that the addition of green propolis extract in wound care formulas might be more beneficial for the treatment of wounds. Therefore, we propose that green propolis extract is a promising natural product for wound care formulations. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Daptomycin: rationale and role in the management of skin and soft tissue infections.

PubMed

Seaton, R A

2008-11-01

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide tolerance in S. aureus has underlined the importance of the newer anti-MRSA agents, particularly in the management of complicated skin and soft tissue infections (cSSTIs). The novel cyclic lipopeptide antibiotic daptomycin shows marked in vitro cidality against MRSA compared with both vancomycin and linezolid. Although comparative studies in cSSTIs have demonstrated non-inferiority with vancomycin and semi-synthetic penicillins, data from both clinical trials and observational studies suggest in vivo cidality as evidenced by rapid resolution of clinical signs of local inflammation and reduced duration of therapy. Overall success in SSTI post-marketing studies is >90%, and >88% in MRSA-infected patients, with no difference in the outcome observed between those with complicated versus uncomplicated infections. When used at licensed doses (4-6 mg/kg), daptomycin is safe and effective in SSTIs with significant muscle toxicity occurring in only 0.4% to 2.5% of patients. Clinical failure in daptomycin-treated SSTIs is associated with severity of infection (creatinine clearance <30 mL/min, intensive care unit stay and sepsis syndrome). Higher dosing at 6 mg/kg (with increased dosing interval in renal failure) should be considered in such patients as well as those at risk of bacteraemia, osteomyelitis, diabetic foot infection and in situations where there is more rapid drug clearance, such as infections complicating intravenous drug use and thermal burns. Once-daily dosing allows ease of use in both hospital and outpatient settings and may facilitate early discharge or avoided admission in some patient groups with SSTIs. Clinical experience to date suggests potential economic advantages associated with earlier hospital discharge and shorter duration of therapy, although further detailed cost-effectiveness comparisons are required to validate these observations in different healthcare settings.

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

PubMed Central

Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. Trial Registration www.controlled-trials.com ISRCTN47375023 PMID:21980373

Challenges in assessing nursing home residents with advanced dementia for suspected urinary tract infections.

PubMed

D'Agata, Erika; Loeb, Mark B; Mitchell, Susan L

2013-01-01

To describe the presentation of suspected urinary tract infections (UTIs) in nursing home (NH) residents with advanced dementia and how they align with minimum criteria to justify antimicrobial initiation. Twelve-month prospective study. Twenty-five NHs. Two hundred sixty-six NH residents with advanced dementia. Charts were abstracted monthly for documentation of suspected UTI episodes to determine whether episodes met minimum criteria to initiate antimicrobial therapy according to consensus guidelines. Seventy-two residents experienced 131 suspected UTI episodes. Presenting symptoms and signs for these episodes are mental status change (44.3%), fever (20.6%), hematuria (6.9%), dysuria (3.8%), costovertebral tenderness (2.3%), urinary frequency (1.5%), rigor (1.5%), urgency (0%), and suprapubic pain (0%). Only 21 (16.0%) episodes met minimal criteria to initiate antimicrobial therapy based on signs and symptoms. Of the 110 episodes that lacked minimum criteria to justify antimicrobial initiation, 82 (74.5%) were treated with antimicrobial therapy. Urinalyses and urine culture results were available for 101 episodes, of which 80 (79.2%) had positive results on both tests. The proportion of episodes with a positive urinalysis and culture was similar for those that met (83.3%) and did not meet (78.3%) minimum criteria (P = .06). The symptoms and signs necessary to meet minimum criteria to support antimicrobial initiation for UTIs are frequently absent in NH residents with advanced dementia. Antimicrobial therapy is prescribed for the majority of suspected UTIs that do not meet these minimum criteria. Urine specimens are frequently positive regardless of symptoms. These observations underscore the need to reconsider the diagnosis and the initiation of treatment for suspected UTIs in advanced dementia. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

Bolus-dependent dosimetric effect of positioning errors for tangential scalp radiotherapy with helical tomotherapy

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

Lobb, Eric, E-mail: eclobb2@gmail.com

2014-04-01

The dosimetric effect of errors in patient position is studied on-phantom as a function of simulated bolus thickness to assess the need for bolus utilization in scalp radiotherapy with tomotherapy. A treatment plan is generated on a cylindrical phantom, mimicking a radiotherapy technique for the scalp utilizing primarily tangential beamlets. A planning target volume with embedded scalplike clinical target volumes (CTVs) is planned to a uniform dose of 200 cGy. Translational errors in phantom position are introduced in 1-mm increments and dose is recomputed from the original sinogram. For each error the maximum dose, minimum dose, clinical target dose homogeneitymore » index (HI), and dose-volume histogram (DVH) are presented for simulated bolus thicknesses from 0 to 10 mm. Baseline HI values for all bolus thicknesses were in the 5.5 to 7.0 range, increasing to a maximum of 18.0 to 30.5 for the largest positioning errors when 0 to 2 mm of bolus is used. Utilizing 5 mm of bolus resulted in a maximum HI value of 9.5 for the largest positioning errors. Using 0 to 2 mm of bolus resulted in minimum and maximum dose values of 85% to 94% and 118% to 125% of the prescription dose, respectively. When using 5 mm of bolus these values were 98.5% and 109.5%. DVHs showed minimal changes in CTV dose coverage when using 5 mm of bolus, even for the largest positioning errors. CTV dose homogeneity becomes increasingly sensitive to errors in patient position as bolus thickness decreases when treating the scalp with primarily tangential beamlets. Performing a radial expansion of the scalp CTV into 5 mm of bolus material minimizes dosimetric sensitivity to errors in patient position as large as 5 mm and is therefore recommended.« less

NAIRAS aircraft radiation model development, dose climatology, and initial validation.

PubMed

Mertens, Christopher J; Meier, Matthias M; Brown, Steven; Norman, Ryan B; Xu, Xiaojing

2013-10-01

[1] The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway.

NAIRAS aircraft radiation model development, dose climatology, and initial validation

NASA Astrophysics Data System (ADS)

Mertens, Christopher J.; Meier, Matthias M.; Brown, Steven; Norman, Ryan B.; Xu, Xiaojing

2013-10-01

The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway.

NAIRAS aircraft radiation model development, dose climatology, and initial validation

PubMed Central

Mertens, Christopher J; Meier, Matthias M; Brown, Steven; Norman, Ryan B; Xu, Xiaojing

2013-01-01

[1] The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway. PMID:26213513

SU-E-T-580: Comparison of Cervical Carcinoma IMRT Plans From Four Commercial Treatment Planning Systems (TPS)

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

Cao, Y; Li, R; Chi, Z

2014-06-01

Purpose: Different treatment planning systems (TPS) use different treatment optimization and leaf sequencing algorithms. This work compares cervical carcinoma IMRT plans optimized with four commercial TPSs to investigate the plan quality in terms of target conformity and delivery efficiency. Methods: Five cervical carcinoma cases were planned with the Corvus, Monaco, Pinnacle and Xio TPSs by experienced planners using appropriate optimization parameters and dose constraints to meet the clinical acceptance criteria. Plans were normalized for at least 95% of PTV to receive the prescription dose (Dp). Dose-volume histograms and isodose distributions were compared. Other quantities such as Dmin(the minimum dose receivedmore » by 99% of GTV/PTV), Dmax(the maximum dose received by 1% of GTV/PTV), D100, D95, D90, V110%, V105%, V100% (the volume of GTV/PTV receiving 110%, 105%, 100% of Dp), conformity index(CI), homogeneity index (HI), the volume of receiving 40Gy and 50 Gy to rectum (V40,V50) ; the volume of receiving 30Gy and 50 Gy to bladder (V30,V50) were evaluated. Total segments and MUs were also compared. Results: While all plans meet target dose specifications and normal tissue constraints, the maximum GTVCI of Pinnacle plans was up to 0.74 and the minimum of Corvus plans was only 0.21, these four TPSs PTVCI had significant difference. The GTVHI and PTVHI of Pinnacle plans are all very low and show a very good dose distribution. Corvus plans received the higer dose of normal tissue. The Monaco plans require significantly less segments and MUs to deliver than the other plans. Conclusion: To deliver on a Varian linear-accelerator, the Pinnacle plans show a very good dose distribution. Corvus plans received the higer dose of normal tissue. The Monaco plans have faster beam delivery.« less

Dose mapping using MCNP code and experiment for SVST-Co-60/B irradiator in Vietnam.

PubMed

Tran, Van Hung; Tran, Khac An

2010-06-01

By using MCNP code and ethanol-chlorobenzene (ECB) dosimeters the simulations and measurements of absorbed dose distribution in a tote-box of the Cobalt-60 irradiator, SVST-Co60/B at VINAGAMMA have been done. Based on the results Dose Uniformity Ratios (DUR), positions and values of minimum and maximum dose extremes in a tote-box, and efficiency of the irradiator for the different dummy densities have been gained. There is a good agreement between simulation and experimental results in comparison and they have valuable meanings for operation of the irradiator. Copyright 2010 Elsevier Ltd. All rights reserved.

Studies on the resistance/reactivation of Giardia muris cysts and Cryptosporidium parvum oocysts exposed to medium-pressure ultraviolet radiation.

PubMed

Belosevic, M; Craik, S A; Stafford, J L; Neumann, N F; Kruithof, J; Smith, D W

2001-10-16

The ex vivo and in vivo reactivation of Giardia muris cysts and Cryptosporidium parvum oocysts after exposure to different doses of ultraviolet (UV) radiation was determined using animal infectivity. The infectivity of UV-treated parasites stored for 1-4 days (G. muris) or 1-17 days (C. parvum) at room temperature in the dark was similar to that of organisms administered immediately after UV treatment, indicating that the parasites did not reactivate ex vivo. In contrast, we observed in vivo reactivation of G. muris in three of seven independent animal infectivity experiments, when parasites were treated with relatively low doses of medium-pressure UV (<25 mJ/cm(2)). Our observations indicate that G. muris cysts and C. parvum oocysts exposed to medium-pressure UV doses of 60 mJ/cm(2) or higher did not exhibit resistance to and/or reactivation following treatment. This suggests that when appropriate doses of UV are used, significant and permanent inactivation of these parasites may be achieved.

Safety and immunogenicity of a monovalent MF59®-adjuvanted A/H1N1 vaccine in HIV-infected children and young adults.

PubMed

Palma, Paolo; Romiti, Maria Luisa; Bernardi, Stefania; Pontrelli, Giuseppe; Mora, Nadia; Santilli, Veronica; Tchidjou, Hyppolite Kuekou; Aquilani, Angela; Cotugno, Nicola; Alghisi, Federico; Lucidi, Vincenzina; Rossi, Paolo; Douagi, Iyadh

2012-03-01

This Phase IV study evaluated the safety and immunogenicity of a two-dose, MF59®-adjuvanted (Novartis Vaccines, Marburg, Germany), monovalent, A/H1N1 pandemic influenza vaccination schedule in Human Immunodeficiency Virus (HIV) positive children and young adults. A total of 83 children infected with HIV-1, and 37 non-immunocompromised, age-matched controls were enrolled. All participants received two vaccine doses administered three weeks apart. Antibody responses were assessed by haemagglutination assay at baseline, three weeks after each vaccine dose, and six months after immunization. Vaccines were evaluated according to European influenza vaccine licensure criteria. The investigational vaccine was well tolerated. After the first vaccine dose, seroconversion rates were significantly lower in HIV-positive patients (60%) than controls (82%), with GMTs of 419 and 600, respectively. No significant differences in seroconversion rates were observed between the two study groups in response to the second vaccine dose. Persisting antibody titers were similar for both HIV-positive and non-infected controls, six months after immunization. One dose of MF59-adjuvanted vaccine was sufficient to provide adequate levels of seroprotection against A/H1N1 influenza disease in HIV-positive children. However, a two-dose vaccination schedule may be optimal for this population. Copyright © 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Reduced Rift Valley fever virus infection rates in mosquitoes associated with pledget feedings.

PubMed

Turell, M J

1988-12-01

Infection rates were compared in Culex pipiens and Aedes taeniorhynchus after they fed on Rift Valley fever (RVF) viremic hamsters or ingested similar doses of RVF virus from blood-soaked pledgets. Infection rates were significantly lower for mosquitoes that ingested virus from a pledget than for those that ingested similar doses from viremic hamsters. The method used to prevent normal clot formation for the pledget feedings (i.e., defibrination by shaking with glass beads or addition of heparin) did not affect subsequent infection rates. Both inhibition of normal clot formation and freezing of virus after it had last been propagated were associated with significantly reduced infection rates with the pledget feedings. Laboratory studies using artificial feeding techniques may not give reliable estimates of the vector competence of mosquitoes for arboviruses.

Dose-response relationships for environmentally mediated infectious disease transmission models

PubMed Central

Eisenberg, Joseph N. S.

2017-01-01

Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose–response relationship. Much of the work characterizing the functional forms of dose–response relationships has used statistical fit to experimental data. However, there has been little research examining the consequences of the choice of functional form in the context of transmission dynamics. To this end, we identify four properties of dose–response functions that should be considered when selecting a functional form: low-dose linearity, scalability, concavity, and whether it is a single-hit model. We find that i) middle- and high-dose data do not constrain the low-dose response, and different dose–response forms that are equally plausible given the data can lead to significant differences in simulated outbreak dynamics; ii) the choice of how to aggregate continuous exposure into discrete doses can impact the modeled force of infection; iii) low-dose linear, concave functions allow the basic reproduction number to control global dynamics; and iv) identifiability analysis offers a way to manage multiple sources of uncertainty and leverage environmental monitoring to make inference about infectivity. By applying an environmentally mediated infectious disease model to the 1993 Milwaukee Cryptosporidium outbreak, we demonstrate that environmental monitoring allows for inference regarding the infectivity of the pathogen and thus improves our ability to identify outbreak characteristics such as pathogen strain. PMID:28388665

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

Elliott, T.B.; Madonna, G.S.; Ledney, G.D.

Increased susceptibility to bacterial infection, probably by translocation from the intestinal flora, can be a lethal complication for 2-3 weeks after exposure to ionizing radiation. Antibiotics alone do not provide adequate therapy for induced infections in neutropenic mice. Because some substances that are derived from bacterial cell walls activate macrophages and stimulate nonspecific resistance to infection, such agents might be used to prevent or treat postirradiation infections. In this study, a cell-wall glycolipid, trehalose dimycolate (TDM), was evaluated together with a third-generation cephalosporin, ceftriaxone, for their separate and combined effects on survival of B6D2F1 female mice that were exposed tomore » the sublethal dose of 7.0 Gy Co radiation and challenged s.c. with lethal doses of Klebsiella pneumoniae. A single injection of TDM inoculated i.p. 1 hr postirradiation increased 30-day survival to 80% after a lethal challenge by K. pneumoniae 4 days later. When the challenge dose of K. pneumoniae was increased to 5000 Ld 50/30 on Day 4, all mice died.« less

Experimental infection of cliff swallows (Petrochelidon pyrrhonota) with varying doses of West Nile virus

USGS Publications Warehouse

Oesterle, P.T.; Nemeth, N.M.; VanDalen, Kaci K.; Sullivan, H.; Bentler, K.T.; Young, G.R.; McLean, R.G.; Clark, L.; Smeraski, C.; Hall, Jeffrey S.

2009-01-01

Cliff swallows (Petrochelidon pyrrhonota) were inoculated with differing doses of West Nile virus (WNV) to evaluate their potential role as reservoir hosts in nature. Swallows often nest in large colonies in habitats and months associated with high mosquito abundance and early WNV transmission in North America. Additionally, cliff swallow diet consists of insects, including mosquitoes, leading to an additional potential route of WNV infection. The average peak viremia titer among infected cliff swallows was 106.3 plaque-forming units (PFU)/mL serum and the reservoir competence index was 0.34. There was no correlation between dose and probability of becoming infected or viremia peak and duration. Oral shedding was detected from 2 to 14 days post-inoculation with an average peak titer of 1044 PFU/swab. These results suggest that cliff swallows are competent reservoir hosts of WNV and therefore, they may play a role in early seasonal amplification and maintenance of WNV. Copyright ?? 2009 by The American Society of Tropical Medicine and Hygiene.

[Efficacy of vaccination against hepatitis B in adult with HIV infection].

PubMed

Kalinowska-Nowak, Anna; Bociaga-Jasik, Monika; Garlicki, Aleksander; Mach, Tomasz

2007-01-01

The aim of the study was to evaluate the efficacy of vaccination against hepatitis B in HIV infected individuals and the influence of the stage of HIV infection and antiretroviral therapy (HAART). Response for additional doses of hepatitis B vaccine among the patients who do not develop protective anti-HBs level after routine vaccination schedule was analysed. Fifty-four HIV infected individuals, 20 women (37%) and 34 men (63%), 20 to 64 years old (mean age 32 years) were analysed. 32 patients (59.6%), 22 men and 10 women were treated with antiretroviral drugs. Stage of HIV infection was assessed on the basis of data derived from medical records (lowest CD4 cells count, highest viral load), and immunological status at the moment of introduction of vaccination (CD4 cells count, viral load). Efficacy of vaccination was compared with control group, which consisted of 56 healthy volunteers. In both groups hepatitis B virus infection was excluded by serologic tests. HBvaxPro vaccine produced by Merck Sharp & Dohme Company, dose registered for adults (10 ug) was injected at month 0-1-6. Patients with anti-HBs <10 IU/l have received booster doses of vaccine month intervals, no more then three. Protective level of antibodies was found in 52 (92.9%) persons from control group and 32 (63%) HIV infected individuals. Anti-HBs > 100 IU/l was twice more common in control group (80%) than in investigated group (46.3%) (p < 0.001). Protective level of anti-HBs had 14.3% patients with CD4 below 200 cells/pl, none of them had anti-HBs > 100 IU/l. Patients with higher CD4 cell count had better response for vaccination (p = 0.015). Differences between patients with high and low viral load were not statistically significant (p = 0.015). Patients with viral load below 10,000 copies/ml had slightly better response then those with higher viral load. Efficacy of vaccination was also associated with the level of distraction of immunological system before introduction of HAART. Patients with CD4 < 200 cells/microl or HIV-RNA > 50,000 copies/ml had worst immunological response for vaccination. After the fist additional dose of vaccine anti-HBs >10 IU/l had 79.7% patients, 87.1% after the second dose and 90.7% after the third dose. Anti-HBs >100 IU/l had subsequently 57.4%, 66.7%, 79.6% patients. We concluded that efficacy of the routine vaccination schedule was lower among HIV individuals in comparison with healthy volunteers. Influence of the progression of HIV infection on the response for vaccination was detected. Additional vaccine's doses have improved efficacy of immunisation which was comparable with general population.

Nonparametric estimation of benchmark doses in environmental risk assessment

PubMed Central

Piegorsch, Walter W.; Xiong, Hui; Bhattacharya, Rabi N.; Lin, Lizhen

2013-01-01

Summary An important statistical objective in environmental risk analysis is estimation of minimum exposure levels, called benchmark doses (BMDs), that induce a pre-specified benchmark response in a dose-response experiment. In such settings, representations of the risk are traditionally based on a parametric dose-response model. It is a well-known concern, however, that if the chosen parametric form is misspecified, inaccurate and possibly unsafe low-dose inferences can result. We apply a nonparametric approach for calculating benchmark doses, based on an isotonic regression method for dose-response estimation with quantal-response data (Bhattacharya and Kong, 2007). We determine the large-sample properties of the estimator, develop bootstrap-based confidence limits on the BMDs, and explore the confidence limits’ small-sample properties via a short simulation study. An example from cancer risk assessment illustrates the calculations. PMID:23914133

Environment in relation to white pine blister rust infection

Treesearch

E.P. Van Arsdel

1972-01-01

Pine trees can be free of blister rust infection either because they are growing in a climate unfavorable to rust or because they are genetically resistant to the rust. The climatic escape is hundreds of times more common than genetic resistance in the American white pines. The minimum time and temperature required for penetration by an isolate of the rice blast fungus...

The Safety, Effectiveness and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-Based Antitubercular Therapy

PubMed Central

Decloedt, Eric H.; Maartens, Gary; Smith, Peter; Merry, Concepta; Bango, Funeka; McIlleron, Helen

2012-01-01

Objective Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment. Methods Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month. Results 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1–9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable. Conclusion Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate. PMID:22412856

A RANDOMIZED TREATMENT TRIAL: SINGLE VERSUS 7 DAY DOSE OF METRONIDAZOLE FOR THE TREATMENT OF TRICHOMONAS VAGINALIS AMONG HIV-INFECTED WOMEN

PubMed Central

Kissinger, Patricia; Mena, Leandro; Levison, Judy; Clark, Rebecca A.; Gatski, Megan; Henderson, Harold; Schmidt, Norine; Rosenthal, Susan; Myers, Leann; Martin, David H.

2010-01-01

Objective To determine if the metronidazole (MTZ) 2 gm single dose (recommended) is as effective as the 7 day 500 mg BID dose (alternative) for treatment of Trichomonas vaginalis (TV) among HIV+ women. Methods Phase IV randomized clinical trial; HIV+ women with culture confirmed TV were randomized to treatment arm: MTZ 2 gm single dose or MTZ 500 mg BID 7 day dose. All women were given 2 gm MTZ doses to deliver to their sex partners. Women were re-cultured for TV at a test-of-cure (TOC) visit occurring 6-12 days after treatment completion. TV-negative women at TOC were again re-cultured at a 3 month visit. Repeat TV infection rates were compared between arms. Results 270 HIV+/TV+ women were enrolled (mean age = 40 years, ± 9.4; 92.2% African-American). Treatment arms were similar with respect to age, race, CD4 count, viral load, ART status, site, and loss-to-follow up. Women in the 7 day arm had: lower repeat TV infection rates at TOC [8.5% (11/130) versus 16.8% (21/125) (R.R. 0.50, 95% CI=0.25, 1.00; P<0.05)], and at 3 months [11.0% (8/73) versus 24.1% (19/79) (R.R. 0.46, 95% CI=0.21, 0.98; P=0.03)] compared to the single dose arm. Conclusions The 7 day MTZ dose was more effective than the single dose for the treatment of TV among HIV+ women. PMID:21423852

A nonlethal young domesticated ferret (Mustela putorius furo) model for studying pandemic influenza virus A/California/04/2009 (H1N1).

PubMed

Lednicky, John A; Croutch, Claire R; Lawrence, Sandra J; Hamilton, Sara B; Daniels, Deirdre E; Astroff, Barry

2010-10-01

Recent events have heightened the need for the rapid development of vaccines directed against pandemic influenza H1N1 viruses circulating during 2009 to 2010. The current study was conducted to establish a virus challenge dose for a subsequent CA/04 vaccine efficacy study in 3-mo-old domesticated ferrets. An additional consideration in using CA/04 in ferrets is the selection of endpoints on which to base the challenge dose, given the potential nonlethality of this particular model. Four doses ranging from 10(4) to 10(7) TCID(50) units of CA/04 per animal were administered by intranasal instillation to groups of male and female ferrets, and virus titers in nasal washes obtained 1, 3, and 5 d thereafter were determined in MDCK cells. Dosed ferrets developed clinically mild infections. Peak virus titers occurred on day 3 after instillation regardless of dose. Virus-treated ferrets had less weight gain than did untreated ferrets. In conclusion, 3-mo-old ferrets can be infected with doses as low as 10(4) TCID(50) units of CA/04, and virus titers in nasal washes and decreased body weight gain can be used to assess the course of nonlethal infection of 3-mo-old ferrets by CA/04.

Nosema ceranae Can Infect Honey Bee Larvae and Reduces Subsequent Adult Longevity.

PubMed

Eiri, Daren M; Suwannapong, Guntima; Endler, Matthew; Nieh, James C

2015-01-01

Nosema ceranae causes a widespread disease that reduces honey bee health but is only thought to infect adult honey bees, not larvae, a critical life stage. We reared honey bee (Apis mellifera) larvae in vitro and provide the first demonstration that N. ceranae can infect larvae and decrease subsequent adult longevity. We exposed three-day-old larvae to a single dose of 40,000 (40K), 10,000 (10K), zero (control), or 40K autoclaved (control) N. ceranae spores in larval food. Spores developed intracellularly in midgut cells at the pre-pupal stage (8 days after egg hatching) of 41% of bees exposed as larvae. We counted the number of N. ceranae spores in dissected bee midguts of pre-pupae and, in a separate group, upon adult death. Pre-pupae exposed to the 10K or 40K spore treatments as larvae had significantly elevated spore counts as compared to controls. Adults exposed as larvae had significantly elevated spore counts as compared to controls. Larval spore exposure decreased longevity: a 40K treatment decreased the age by which 75% of adult bees died by 28%. Unexpectedly, the low dose (10K) led to significantly greater infection (1.3 fold more spores and 1.5 fold more infected bees) than the high dose (40K) upon adult death. Differential immune activation may be involved if the higher dose triggered a stronger larval immune response that resulted in fewer adult spores but imposed a cost, reducing lifespan. The impact of N. ceranae on honey bee larval development and the larvae of naturally infected colonies therefore deserve further study.

MORTALITY IN DIOXIN-EXPOSED MICE INFECTED WITH INFLUENZA: MITOCHONDRIAL TOXICITY (REYES-LIKE SYNDROME) VERSUS ENHANCED INFLAMMATION AS THE MODE OF ACTION

EPA Science Inventory

Abstract
Increased mortality following influenza A infection was reported in B6C3F1 mice exposed to a low (0.01 g/kg) dose of dioxin. However, mortality was not associated with increased viral load and antibody titers to the virus were not decreased at doses of TCDD 10 g/k...

Glibenclamide, a Blocker of K+ATP Channels, Shows Antileishmanial Activity in Experimental Murine Cutaneous Leishmaniasis▿

PubMed Central

Serrano-Martín, Xenón; Payares, Gilberto; Mendoza-León, Alexis

2006-01-01

Glibenclamide reduced the rate of lesion growth in BALB/c mice infected with Leishmania (Leishmania) mexicana, the effect was dose dependent, and the highest dose proved more effective than glucantime. Cross-resistance to glucantime was found in animals infected with a glibenclamide-resistant line, but combined therapy reduced lesion progression even in the glibenclamide-resistant strain. PMID:17015627

[Antimicrobial treatment in complicated intraabdominal infections--current situation].

PubMed

Vyhnánek, F

2009-04-01

Compared to other infections, intraabdominal infections include wide spectrum of infections of various severity, have different ethiology, which is frequently polymicrobial, show different microbiological results, which are difficult to interpret. The role of surgical intervention is essential. Intraabdominal infections are common causes of morbidity and mortality. Their prognosis is significantly improved with early and exact diagnosis, appropriate surgical or radiological intervention and timely effective antimicrobial therapy. Practitioners may choose between older or more modern antibiotics, between monotherapy or combination therapy, however, they should also consider clinical condition of the patient, the antibiotic's spectrum of activity, the treatment timing and its duration, the dose and dosing scheme of the particular antimicrobials. Furthermore, antimicrobial therapy should be used with caution, with the aim to prevent development of antimicrobial resistence. Inappropriate choice of antimicrobials in initial empiric therapy results in relapsing infections, surgical intervention and prolongation of hospitalization, and even death rates reflect adequate and timely empiric therapy.

Simulation of Earth-Moon-Mars Environments for the Assessment of Organ Doses

NASA Astrophysics Data System (ADS)

Kim, M. Y.; Schwadron, N. A.; Townsend, L.; Cucinotta, F. A.

2010-12-01

Space radiation environments for historically large solar particle events (SPE) and galactic cosmic rays (GCR) at solar minimum and solar maximum are simulated in order to characterize exposures to radio-sensitive organs for missions to low-Earth orbit (LEO), moon, and Mars. Primary and secondary particles for SPE and GCR are transported through the respective atmosphere of Earth or Mars, space vehicle, and astronaut’s body tissues using the HZETRN/QMSFRG computer code. In LEO, exposures are reduced compared to deep space because particles are deflected by the Earth’s magnetic field and absorbed by the solid body of the Earth. Geomagnetic transmission function as a function of altitude was applied for the particle flux of charged particles, and the shift of the organ exposures to higher velocity or lower stopping powers compared to those in deep space was analyzed. In the transport through Mars atmosphere, a vertical distribution of atmospheric thickness was calculated from the temperature and pressure data of Mars Global Surveyor, and the directional cosine distribution was implemented to describe the spherically distributed atmospheric distance along the slant path at each altitude. The resultant directional shielding by Mars atmosphere at solar minimum and solar maximum was used for the particle flux simulation at various altitudes on the Martian surface. Finally, atmospheric shielding was coupled with vehicle and body shielding for organ dose estimates. We made predictions of radiation dose equivalents and evaluated acute symptoms at LEO, moon, and Mars at solar minimum and solar maximum.

Pi meson radiotherapy for advanced head and neck neoplasms: preliminary results.

PubMed

Khan, K M; Bush, S; Herzon, F; Klingerman, M M

1981-01-01

Under the auspices of the University of New Mexico Cancer Research and Treatment Center, trials are under way at the Los Alamos Meson Physics Facility to evaluate the effects of pi meson irradiation on locally advanced human tumors. This paper summarizes the preliminary results in patients with locally advanced head and neck tumors treated under Phase 1 and Phase II studies. A total of 26 patients were treated between June 1977 and May 1979 with a minimum follow-up of 9 months and a maximum follow-up of 33 months. Sites of disease included the oropharynx in 10 cases (base of tongue in 7, tonsil in 2, and pharyngoepiglottic fold in 1), the supraglottic larynx in 4, the nasopharynx in 5, the oral cavity in 4, the hypopharynx in 2, and the sublingual salivary gland in 1. Twelve of the 26 patients are alive, and 10 survive with no evidence of disease. Doses employed ranged from a minimum of 1,000 peak pion rad in 7 fractions over 9 days to a maximum of 5,4000 peak pion rad in 51 fractions of 89 days. The minimum dose employed for any patients treated with peak pions alone was 3,000 rad. These data are analyzed according to dose, sit, histology, tumor response, local control, and survival. Results from these cases form the basis of the Phase III randomized trials for advanced squamous-cell carcinomas of the head and neck, which are currently in progress.

Booster dose vaccination for preventing hepatitis B.

PubMed

Poorolajal, Jalal; Hooshmand, Elham

2016-06-07

Antibodies against hepatitis B surface antigen (HBsAg) wane over time following hepatitis B immunisation; hence, it is unclear whether people vaccinated in three-dose or four-dose schedules of the hepatitis B vaccine are still immune when the hepatitis B surface antibody (anti-HBs) level in their body is undetectable, or lower than the level usually considered protective. This question may potentially be answered indirectly by measuring the anamnestic immune response to a booster dose of vaccine. The term 'booster' (or revaccination) refers to an additional dose of hepatitis B vaccine (HBV) given some time post-primary vaccination to induce immune memory and improve protection against hepatitis B virus (HBV) infection. To assess the benefits and harms of booster dose hepatitis B vaccination, more than five years after the primary vaccination, for preventing HBV infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, conference databases, and reference lists of articles to January 2016. We also contacted authors of articles. In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (May 2016). Randomised clinical trials addressing anamnestic immune response to a booster dose of hepatitis B vaccine, more than five years after the primary vaccination, in apparently healthy participants, vaccinated in a three-dose or four-dose schedule of the hepatitis B vaccine during the primary vaccination, without receiving an additional dose or immunoglobulin. Both review authors decided if the identified studies met the inclusion criteria or not. Primary outcomes included the proportion of participants with anamnestic immune response in non-protected participants and signs of HBV infection. Secondary outcomes were the proportion of participants that developed local and systemic adverse events following a booster dose injection. We planned to report the weighted proportion with 95% confidence intervals (CIs). There were no eligible randomised clinical trials fulfilling the inclusion criteria of this review. We were unable to include any randomised clinical trials on the topic; only randomised clinical trials will be able to provide an answer as to whether a booster dose vaccination is able to protect against hepatitis B infection.

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte-macrophage colony-stimulating factor in experimental pulmonary tuberculosis.

PubMed

Francisco-Cruz, A; Mata-Espinosa, D; Estrada-Parra, S; Xing, Z; Hernández-Pando, R

2013-03-01

BALB/c mice with pulmonary tuberculosis (TB) develop a T helper cell type 1 that temporarily controls bacterial growth. Bacterial proliferation increases, accompanied by decreasing expression of interferon (IFN)-γ, tumour necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). Activation of dendritic cells (DCs) is delayed. Intratracheal administration of only one dose of recombinant adenoviruses encoding granulocyte-macrophage colony-stimulating factor (AdGM-CSF) 1 day before Mycobacterium tuberculosis (Mtb) infection produced a significant decrease of pulmonary bacterial loads, higher activated DCs and increased expression of TNF-α, IFN-γ and iNOS. When AdGM-CSF was given in female mice B6D2F1 (C57BL/6J X DBA/2J) infected with a low Mtb dose to induce chronic infection similar to latent infection and corticosterone was used to induce reactivation, a very low bacilli burden in lungs was detected, and the same effect was observed in healthy mice co-housed with mice infected with mild and highly virulent bacteria in a model of transmissibility. Thus, GM-CSF is a significant cytokine in the immune protection against Mtb and gene therapy with AdGM-CSF increased protective immunity when administered in a single dose 1 day before Mtb infection in a model of progressive disease, and when used to prevent reactivation of latent infection or transmission. © 2012 British Society for Immunology.

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte–macrophage colony-stimulating factor in experimental pulmonary tuberculosis

PubMed Central

Francisco-Cruz, A.; Mata-Espinosa, D.; Estrada-Parra, S.; Xing, Z.; Hernández-Pando, R.

2013-01-01

Summary BALB/c mice with pulmonary tuberculosis (TB) develop a T helper cell type 1 that temporarily controls bacterial growth. Bacterial proliferation increases, accompanied by decreasing expression of interferon (IFN)-γ, tumour necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). Activation of dendritic cells (DCs) is delayed. Intratracheal administration of only one dose of recombinant adenoviruses encoding granulocyte–macrophage colony-stimulating factor (AdGM-CSF) 1 day before Mycobacterium tuberculosis (Mtb) infection produced a significant decrease of pulmonary bacterial loads, higher activated DCs and increased expression of TNF-α, IFN-γ and iNOS. When AdGM-CSF was given in female mice B6D2F1 (C57BL/6J X DBA/2J) infected with a low Mtb dose to induce chronic infection similar to latent infection and corticosterone was used to induce reactivation, a very low bacilli burden in lungs was detected, and the same effect was observed in healthy mice co-housed with mice infected with mild and highly virulent bacteria in a model of transmissibility. Thus, GM-CSF is a significant cytokine in the immune protection against Mtb and gene therapy with AdGM-CSF increased protective immunity when administered in a single dose 1 day before Mtb infection in a model of progressive disease, and when used to prevent reactivation of latent infection or transmission. PMID:23379435

Modification of Enrofloxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance▿

PubMed Central

Randall, Luke P.; Cooles, Sue W.; Coldham, Nick C.; Stapleton, Ken S.; Piddock, Laura J. V.; Woodward, Martin J.

2006-01-01

We hypothesized that higher doses of fluoroquinolones for a shorter duration could maintain efficacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enrofloxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 μg/ml enrofloxacin correlated with increased activity. In vivo, the efficacy of the 1-day treatment was significantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efficacy similar to that of the 5-day treatment in all but one repeat treatment group and significantly (P < 0.01) reduced the Salmonella counts. Dosing at 2.5× the recommended dose and pulsed dosing both increased the peak antibiotic concentrations in cecal contents, liver, lung, and sera as determined by high-pressure liquid chromatography. There was limited evidence that shorter treatment regimens (in particular the 1-day regimen) selected for fewer strains with reduced susceptibility. In conclusion, the 2-day treatment would overall require a shorter withholding time than the 5-day treatment and, in view of the increased peak antibiotic concentrations, may give rise to improved efficacy, in particular for treating respiratory and systemic infections. However, it would be necessary to validate the 2-day regimen in a field situation and in particular against respiratory and systemic infections to validate or refute this hypothesis. PMID:17030564

In vivo screening of four phytochemicals/extracts and a fungal immunomodulatory protein against an Eimeria acervulina infection in broilers.

PubMed

Peek, H W; Halkes, S B A; Mes, J J; Landman, W J M

2013-01-01

Besides the anticoccidial drug resistance problem, increasing consumer concerns about food safety and residues have propelled the quest for alternative prevention and control strategies amongst which phytotherapy has gained appeal due to a renewed interest in natural medicine. The objective was in vivo screening of four phytochemicals/extracts and a fungal immunomodulatory protein (FIP) against an Eimeria acervulina infection in broilers. Four phytochemicals/extracts (extract from Echinacea purpurea, betaine (Betain™), curcumin, carvacrol (two different doses)), and a recombinant FIP from Ganoderma lucidum cloned and expressed in Escherichia coli were investigated for their anticoccidial potential. The experiment was conducted in a battery cage trial with 54 cages of eight birds each. Broilers infected with E. acervulina (a low and high infection dose of 10(4) and 10(5) sporulated oocysts, respectively) and treated with the phytochemicals/extracts or the FIP were compared with broilers treated with the anticoccidial salinomycin sodium (Sacox®) and with an untreated uninfected and an untreated infected control group. Coccidiosis lesion scores, body weight gains and oocyst shedding were used as parameters. The results showed a coccidiosis infection dose effect on the mean coccidiosis lesion scores. The phytochemicals/extracts and the FIP failed to reduce coccidiosis lesion scores and oocyst shedding, while salinomycin efficiently controlled the E. acervulina infection and enabled significantly higher body weight gains. In conclusion, the selected phytochemicals/extracts and the FIP did not reduce the lesions of an experimentally induced E. acervulina infection.

Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors.

PubMed

Dobard, Charles; Sharma, Sunita; Parikh, Urvi M; West, Rolieria; Taylor, Andrew; Martin, Amy; Pau, Chou-Pong; Hanson, Debra L; Lipscomb, Jonathan; Smith, James; Novembre, Francis; Hazuda, Daria; Garcia-Lerma, J Gerardo; Heneine, Walid

2014-03-12

Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P < 0.05, Fisher's exact test). Breakthrough infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.

The expression and evolution of virulence in multiple infections: the role of specificity, relative virulence and relative dose

PubMed Central

2013-01-01

Background Multiple infections of the same host by different strains of the same microparasite species are believed to play a crucial role during the evolution of parasite virulence. We investigated the role of specificity, relative virulence and relative dose in determining the competitive outcome of multiple infections in the Daphnia magna-Pasteuria ramosa host-parasite system. Results We found that infections by P. ramosa clones (single genotype) were less virulent and produced more spores than infections by P. ramosa isolates (possibly containing multiple genotypes). We also found that two similarly virulent isolates of P. ramosa differed considerably in their within-host competitiveness and their effects on host offspring production when faced with coinfecting P. ramosa isolates and clones. Although the relative virulence of a P. ramosa isolate/clone appears to be a good indicator of its competitiveness during multiple infections, the relative dose may alter the competitive outcome. Moreover, spore counts on day 20 post-infection indicate that the competitive outcome is largely decided early in the parasite’s growth phase, possibly mediated by direct interference or apparent competition. Conclusions Our results emphasize the importance of epidemiology as well as of various parasite traits in determining the outcome of within-host competition. Incorporating realistic epidemiological and ecological conditions when testing theoretical models of multiple infections, as well as using a wider range of host and parasite genotypes, will enable us to better understand the course of virulence evolution. PMID:23641899

The expression and evolution of virulence in multiple infections: the role of specificity, relative virulence and relative dose.

PubMed

Ben-Ami, Frida; Routtu, Jarkko

2013-05-03

Multiple infections of the same host by different strains of the same microparasite species are believed to play a crucial role during the evolution of parasite virulence. We investigated the role of specificity, relative virulence and relative dose in determining the competitive outcome of multiple infections in the Daphnia magna-Pasteuria ramosa host-parasite system. We found that infections by P. ramosa clones (single genotype) were less virulent and produced more spores than infections by P. ramosa isolates (possibly containing multiple genotypes). We also found that two similarly virulent isolates of P. ramosa differed considerably in their within-host competitiveness and their effects on host offspring production when faced with coinfecting P. ramosa isolates and clones. Although the relative virulence of a P. ramosa isolate/clone appears to be a good indicator of its competitiveness during multiple infections, the relative dose may alter the competitive outcome. Moreover, spore counts on day 20 post-infection indicate that the competitive outcome is largely decided early in the parasite's growth phase, possibly mediated by direct interference or apparent competition. Our results emphasize the importance of epidemiology as well as of various parasite traits in determining the outcome of within-host competition. Incorporating realistic epidemiological and ecological conditions when testing theoretical models of multiple infections, as well as using a wider range of host and parasite genotypes, will enable us to better understand the course of virulence evolution.

Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica Vaccine Trial.

PubMed

Safaeian, Mahboobeh; Porras, Carolina; Pan, Yuanji; Kreimer, Aimee; Schiller, John T; Gonzalez, Paula; Lowy, Douglas R; Wacholder, Sholom; Schiffman, Mark; Rodriguez, Ana C; Herrero, Rolando; Kemp, Troy; Shelton, Gloriana; Quint, Wim; van Doorn, Leen-Jan; Hildesheim, Allan; Pinto, Ligia A

2013-11-01

The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. ©2013 AACR.

Does Zika virus infection affect mosquito response to repellents?

PubMed Central

Leal, Walter S.; Barbosa, Rosângela M. R.; Zeng, Fangfang; Faierstein, Gabriel B.; Tan, Kaiming; Paiva, Marcelo H. S.; Guedes, Duschinka R. D.; Crespo, Mônica M.; Ayres, Constância F. J.

2017-01-01

The World Health Organization (WHO) recommends that people travelling to or living in areas with Zika virus (ZIKV) outbreaks or epidemics adopt prophylactic measures to reduce or eliminate mosquito bites, including the use of insect repellents. It is, however, unknown whether repellents are effective against ZIKV-infected mosquitoes, in part because of the ethical concerns related to exposing a human subject’s arm to infected mosquitoes in the standard arm-in-cage assay. We used a previously developed, human subject-free behavioural assay, which mimics a human subject to evaluate the top two recommended insect repellents. Our measurements showed that DEET provided significantly higher protection than picaridin provided against noninfected, host-seeking females of the southern house mosquito, Culex quinquefasciatus, and the yellow fever mosquito, Aedes aegypti. When tested at lower doses, we observed a significant reduction in DEET-elicited protection against ZIKV-infected yellow fever mosquitoes from old and recent laboratory colonies. The reduction in protection is more likely associated with aging than the virus infection and could be compensated by applying a 5x higher dose of DEET. A substantial protection against ZIKV-infected and old noninfected mosquitoes was achieved with 5% DEET, which corresponds approximately to a 30% dose in the conventional arm-in-cage assays. PMID:28205633

Results from the first five years of radiation exposure monitoring aboard the ISS

NASA Astrophysics Data System (ADS)

Golightly, M.; Semones, E.; Shelfer, T.; Johnson, S.; Zapp, N.; Weyland, M.

NASA uses a variety of radiation monitoring devices aboard the International Space Station as part of its space flight radiation health program. This operational monitoring system consists of passive dosimeters, internal and external charged particle telescopes, and a tissue equivalent proportional counter (TEPC). Sixteen passive dosimeters, each consisting of TLD-100, TLD-300, TLD-600, and TLD-700 chips in a small acrylic holder, are placed throughout the habitable volume of the ISS. The TEPC and internal charged particle telescopes are portable and can be relocated to multiple locations in the Lab Module or Service Module. The external charged particle telescopes are mounted to a fixed boom attached to the starboard truss. Passive dosimeters were used in eleven monitoring periods over the period 20 May 1999 to 04 May 2003. Over this period exposure rates from TLD-100 measurements ranged from 0.120-0.300 mGy/d. Exposure rates inside the habitable volume are non-uniform: exposures vary by a factor of ˜ 1.7 from minimum to maximum, with the greatest non-uniformity occurring in the Lab Module. Highest daily exposure rates are near the window in the Lab Module, inside the Joint Airlock, and the sleep stations inside the Service Module, while the lowest rates occur inside the polyethylene-lined Temporary Sleep Station in the Lab Module, adjacent to the port ``arm'' of Node 1, and the aft end of the Service Module. The minimum exposure rates as measured by the passive dosimeters occurred in the spring of 2002, very close to the solar F10.7 emission maximum (Feb 2002), and two years after the sunspot maximum (Apr 2000). Exposure rates have since gradually increased as the sun's activity transitions towards solar minimum conditions. Since 01 Jun 2002, dose rates measured by the IV-CPDS, estimated from the count rate in first detector of the telescope's stack, ranged from ˜ 0.170-0.390 mGy/d. The maximum measured dose rate occurred 28 Oct 2003 during the ``Halloween'' space weather event. Interestingly, the minimum dose rate occurred 31 Oct 2003, near the end of the same remarkable space weather event, when the Earth was experiencing a significant Forbush decrease. The average IV-CPDS-measured dose rate increased from 0.194 to 0.234 mGy/d since 01 Jun 2002--an increase of ˜ 21% and a further indication that the low-Earth radiation environment is transitioning from solar maximum conditions towards solar minimum.

Particle effects on ultraviolet disinfection of coliform bacteria in recycled water.

PubMed

Jolis, D; Lam, C; Pitt, P

2001-01-01

Pilot- and bench-scale coliform inactivation tests with UV irradiation were used to show how suspended solids remaining in filtered secondary effluent affect the efficiency of the UV disinfection process. Observed kinetic inactivation rates decreased with increasing suspended particle sizes of 7 microm or larger present in tertiary effluent. First-order inactivation rates estimated from collimated beam dose-response curves for discrete ranges of UV doses were substantially different, which should caution researchers not to compare inactivation data obtained with largely dissimilar UV doses or suspended particle distributions. A dose of approximately 800 J/m2 was identified as the minimum dose that will consistently meet the California wastewater reclamation coliform criterion when applied to in-line filtration effluent.

Changes in the vascular tissue of fresh Hass avocados treated with cobalt 60

NASA Astrophysics Data System (ADS)

Arevalo, Lourdes; Bustos, Ma. Emilia; Saucedo, Cresenciano

2002-03-01

This research was based on fresh avocado fruit treated with gamma rays at quarantine doses and stored at room temperature. The effects of irradiation were analyzed and measured by three different types of studies: histological, biochemical and physiological. Histological studies were focused on the effect of Cobalt 60 gamma rays in the mesocarp of avocado irradiated at three different doses; 150, 250, and 350 Gy. Damage was observed principally in the parenchyma tissue where the cell membrane was plazmolized and a red color was observed due to the development of phenol compounds. Another important effect was an increase in the size of xylem and phloem cells in the vascular tissue even at the minimum dose of 150 Gy. The biochemical and the physiological studies were done on avocado fruit irradiated at 100 and 150 Gy. An increase in L-phenilalanine ammonialyase activity was observed and therefore, an increase in the concentration of phenol compounds. These changes were not perceived by panelists in a sensorial test. Irradiated fruits were accepted by panelists as well as control fruit as regards parameters of taste, internal color and external color. These results demonstrate the feasibility of using irradiation to disinfest avocado fruit using a minimum dose of 100 Gy.

Estimates of galactic cosmic ray shielding requirements during solar minimum

NASA Technical Reports Server (NTRS)

Townsend, Lawrence W.; Nealy, John E.; Wilson, John W.; Simonsen, Lisa C.

1990-01-01

Estimates of radiation risk from galactic cosmic rays are presented for manned interplanetary missions. The calculations use the Naval Research Laboratory cosmic ray spectrum model as input into the Langley Research Center galactic cosmic ray transport code. This transport code, which transports both heavy ions and nucleons, can be used with any number of layers of target material, consisting of up to five different arbitrary constituents per layer. Calculated galactic cosmic ray fluxes, dose and dose equivalents behind various thicknesses of aluminum, water and liquid hydrogen shielding are presented for the solar minimum period. Estimates of risk to the skin and the blood-forming organs (BFO) are made using 0-cm and 5-cm depth dose/dose equivalent values, respectively, for water. These results indicate that at least 3.5 g/sq cm (3.5 cm) of water, or 6.5 g/sq cm (2.4 cm) of aluminum, or 1.0 g/sq cm (14 cm) of liquid hydrogen shielding is required to reduce the annual exposure below the currently recommended BFO limit of 0.5 Sv. Because of large uncertainties in fragmentation parameters and the input cosmic ray spectrum, these exposure estimates may be uncertain by as much as a factor of 2 or more. The effects of these potential exposure uncertainties or shield thickness requirements are analyzed.

Safety, Pharmacokinetic, and Efficacy Studies of Oral DB868 in a First Stage Vervet Monkey Model of Human African Trypanosomiasis

PubMed Central

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Liu, Qiang; Mutuku, James N.; Chen, Yao; Bridges, Arlene S.; Mdachi, Raymond E.; Ismail, Mohamed A.; Ching, Shelley; Boykin, David W.; Hall, James Edwin; Tidwell, Richard R.; Paine, Mary F.; Brun, Reto; Wang, Michael Zhuo

2013-01-01

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median Cmax (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5–7 days), oral regimen for first stage HAT. PMID:23755309

Effective immunosuppression with dexamethasone phosphate in the Galleria mellonella larva infection model resulting in enhanced virulence of Escherichia coli and Klebsiella pneumoniae.

PubMed

Torres, Miquel Perez; Entwistle, Frances; Coote, Peter J

2016-08-01

The aim was to evaluate whether immunosuppression with dexamethasone 21-phosphate could be applied to the Galleria mellonella in vivo infection model. Characterised clinical isolates of Escherichia coli or Klebsiella pneumoniae were employed, and G. mellonella larvae were infected with increasing doses of each strain to investigate virulence in vivo. Virulence was then compared with larvae exposed to increasing doses of dexamethasone 21-phosphate. The effect of dexamethasone 21-phosphate on larval haemocyte phagocytosis in vitro was determined via fluorescence microscopy and a burden assay measured the growth of infecting bacteria inside the larvae. Finally, the effect of dexamethasone 21-phosphate treatment on the efficacy of ceftazidime after infection was also noted. The pathogenicity of K. pneumoniae or E. coli in G. mellonella larvae was dependent on high inoculum numbers such that virulence could not be attributed specifically to infection by live bacteria but also to factors associated with dead cells. Thus, for these strains, G. mellonella larvae do not constitute an ideal infection model. Treatment of larvae with dexamethasone 21-phosphate enhanced the lethality induced by infection with E. coli or K. pneumoniae in a dose- and inoculum size-dependent manner. This correlated with proliferation of bacteria in the larvae that could be attributed to dexamethasone inhibiting haemocyte phagocytosis and acting as an immunosuppressant. Notably, prior exposure to dexamethasone 21-phosphate reduced the efficacy of ceftazidime in vivo. In conclusion, demonstration of an effective immunosuppressant regimen can improve the specificity and broaden the applications of the G. mellonella model to address key questions regarding infection.

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

PubMed Central

Archin, Nancie M.; Kirchherr, Jennifer L.; Sung, Julia A.M.; Clutton, Genevieve; Sholtis, Katherine; Xu, Yinyan; Allard, Brigitte; Stuelke, Erin; Kashuba, Angela D.; Kuruc, Joann D.; Gay, Cynthia L.; Goonetilleke, Nilu

2017-01-01

BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS. In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell–associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals. RESULTS. Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells. CONCLUSIONS. These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed. TRIAL REGISTRATION. Clinicaltrials.gov NCT01319383. FUNDING. NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109. PMID:28714868

Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model.

PubMed

Julander, Justin G; Ennis, Jane; Turner, Jeffrey; Morrey, John D

2011-05-01

Interferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5×10(7) PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model.

Reduction of Zika virus infectivity in platelet concentrates after treatment with ultraviolet C light and in plasma after treatment with methylene blue and visible light.

PubMed

Fryk, Jesse J; Marks, Denese C; Hobson-Peters, Jody; Watterson, Daniel; Hall, Roy A; Young, Paul R; Reichenberg, Stefan; Tolksdorf, Frank; Sumian, Chryslain; Gravemann, Ute; Seltsam, Axel; Faddy, Helen M

2017-11-01

Zika virus (ZIKV) has emerged as a potential threat to transfusion safety worldwide. Pathogen inactivation is one approach to manage this risk. In this study, the efficacy of the THERAFLEX UV-Platelets system and THERAFLEX MB-Plasma system to inactivate ZIKV in platelet concentrates (PCs) and plasma was investigated. PCs spiked with ZIKV were treated with the THERAFLEX UV-Platelets system at 0.05, 0.10, 0.15, and 0.20 J/cm 2 UVC. Plasma spiked with ZIKV was treated with the THERAFLEX MB-Plasma system at 20, 40, 60, and 120 J/cm 2 light at 630 nm with at least 0.8 µmol/L methylene blue (MB). Samples were taken before the first and after each illumination dose and tested for residual virus. For each system the level of viral reduction was determined. Treatment of PCs with THERAFLEX UV-Platelets system resulted in a mean of 5 log reduction in ZIKV infectivity at the standard UVC dose (0.20 J/cm 2 ), with dose dependency observed with increasing UVC dose. For plasma treated with MB and visible light, ZIKV infectivity was reduced by a mean of at least 5.68 log, with residual viral infectivity reaching the detection limit of the assay at 40 J/cm 2 (one-third the standard dose). Our study demonstrates that the THERAFLEX UV-Platelets system and THERAFLEX MB-Plasma system can reduce ZIKV infectivity in PCs and pooled plasma to the detection limit of the assays used. These findings suggest both systems have the capacity to be an effective option to manage potential ZIKV transfusion transmission risk. © 2017 AABB.

Testing Dose-Dependent Effects of the Nectar Alkaloid Anabasine on Trypanosome Parasite Loads in Adult Bumble Bees.

PubMed

Anthony, Winston E; Palmer-Young, Evan C; Leonard, Anne S; Irwin, Rebecca E; Adler, Lynn S

2015-01-01

The impact of consuming biologically active compounds is often dose-dependent, where small quantities can be medicinal while larger doses are toxic. The consumption of plant secondary compounds can be toxic to herbivores in large doses, but can also improve survival in parasitized herbivores. In addition, recent studies have found that consuming nectar secondary compounds may decrease parasite loads in pollinators. However, the effect of compound dose on bee survival and parasite loads has not been assessed. To determine how secondary compound consumption affects survival and pathogen load in Bombus impatiens, we manipulated the presence of a common gut parasite, Crithidia bombi, and dietary concentration of anabasine, a nectar alkaloid produced by Nicotiana spp. using four concentrations naturally observed in floral nectar. We hypothesized that increased consumption of secondary compounds at concentrations found in nature would decrease survival of uninfected bees, but improve survival and ameliorate parasite loads in infected bees. We found medicinal effects of anabasine in infected bees; the high-anabasine diet decreased parasite loads and increased the probability of clearing the infection entirely. However, survival time was not affected by any level of anabasine concentration, or by interactive effects of anabasine concentration and infection. Crithidia infection reduced survival time by more than two days, but this effect was not significant. Our results support a medicinal role for anabasine at the highest concentration; moreover, we found no evidence for a survival-related cost of anabasine consumption across the concentration range found in nectar. Our results suggest that consuming anabasine at the higher levels of the natural range could reduce or clear pathogen loads without incurring costs for healthy bees.

Shuttle radiation dose measurements in the International Space Station orbits

NASA Technical Reports Server (NTRS)

Badhwar, Gautam D.

2002-01-01

The International Space Station (ISS) is now a reality with the start of a permanent human presence on board. Radiation presents a serious risk to the health and safety of the astronauts, and there is a clear requirement for estimating their exposures prior to and after flights. Predictions of the dose rate at times other than solar minimum or solar maximum have not been possible, because there has been no method to calculate the trapped-particle spectrum at intermediate times. Over the last few years, a tissue-equivalent proportional counter (TEPC) has been flown at a fixed mid-deck location on board the Space Shuttle in 51.65 degrees inclination flights. These flights have provided data that cover the expected changes in the dose rates due to changes in altitude and changes in solar activity from the solar minimum to the solar maximum of the current 23rd solar cycle. Based on these data, a simple function of the solar deceleration potential has been derived that can be used to predict the galactic cosmic radiation (GCR) dose rates to within +/-10%. For altitudes to be covered by the ISS, the dose rate due to the trapped particles is found to be a power-law function, rho(-2/3), of the atmospheric density, rho. This relationship can be used to predict trapped dose rates inside these spacecraft to +/-10% throughout the solar cycle. Thus, given the shielding distribution for a location inside the Space Shuttle or inside an ISS module, this approach can be used to predict the combined GCR + trapped dose rate to better than +/-15% for quiet solar conditions.

DOSIMETRIC CONSEQUENCES OF USING CONTRAST-ENHANCED COMPUTED TOMOGRAPHIC IMAGES FOR INTENSITY-MODULATED STEREOTACTIC BODY RADIOTHERAPY PLANNING.

PubMed

Yoshikawa, Hiroto; Roback, Donald M; Larue, Susan M; Nolan, Michael W

2015-01-01

Potential benefits of planning radiation therapy on a contrast-enhanced computed tomography scan (ceCT) should be weighed against the possibility that this practice may be associated with an inadvertent risk of overdosing nearby normal tissues. This study investigated the influence of ceCT on intensity-modulated stereotactic body radiotherapy (IM-SBRT) planning. Dogs with head and neck, pelvic, or appendicular tumors were included in this retrospective cross-sectional study. All IM-SBRT plans were constructed on a pre- or ceCT. Contours for tumor and organs at risk (OAR) were manually constructed and copied onto both CT's; IM-SBRT plans were calculated on each CT in a manner that resulted in equal radiation fluence. The maximum and mean doses for OAR, and minimum, maximum, and mean doses for targets were compared. Data were collected from 40 dogs per anatomic site (head and neck, pelvis, and limbs). The average dose difference between minimum, maximum, and mean doses as calculated on pre- and ceCT plans for the gross tumor volume was less than 1% for all anatomic sites. Similarly, the differences between mean and maximum doses for OAR were less than 1%. The difference in dose distribution between plans made on CTs with and without contrast enhancement was tolerable at all treatment sites. Therefore, although caution would be recommended when planning IM-SBRT for tumors near "reservoirs" for contrast media (such as the heart and urinary bladder), findings supported the use of ceCT with this dose calculation algorithm for both target delineation and IM-SBRT treatment planning. © 2015 American College of Veterinary Radiology.

Anti-infective and cytotoxic properties of Bupleurum marginatum

PubMed Central

2014-01-01

Background Bupleurum marginatum Wall. ex DC (Apiaceae) is a perennial herb widely used in traditional Chinese and Kampo medicine for the treatment of various infectious diseases. The biological activities of B. marginatum have not been fully investigated. This study aims to investigate the antitrypanosomal, antimicrobial and antiviral activities of methanol (ME) and dichloromethane (DCM) extracts of B. marginatum aerial parts and the ability of both extracts to inhibit the growth of different cancer cell lines. Methods Phytochemical characterization of the extracts was performed by LC-MS profiling. The antitrypanosomal activity was evaluated using the resazurin method. The antimicrobial activity was assessed using agar diffusion and microdilution methods, and the minimum inhibitory concentration (MIC) values were determined. The antiviral activity was determined for 6.25, 12.5, and 50 μg/mL doses using a plaque reduction assay. Cytotoxicity was investigated in eight cancer cell lines (Caco-2, CCL-81, CCRF-CEM, COS-7, HL-60, MIA PaCa-2, MCF-7, and PANC-1) using the MTT assay and the caspase 3/7 activity was determined over the range of 62.5–1000 μg/mL. Results Phytochemical analyses resulted in the characterization of 15 components, mainly flavonoids and lignans. The DCM extract showed significant antitrypanosomal activity (IC50: 36.21 μg/mL) and moderate activity against Streptococcus pyogenes (MIC value: 0.25 mg/mL). At a dose of 12.5 μg/mL, the DCM extract inhibited 73.6% of the plaque production by hepatitis A virus. CCRF-CEM cells were the most sensitive to both extracts (IC50: 12.5–22.7 μg/mL). The cytotoxicity was mediated by induction of apoptosis (19-fold increase in the cellular caspase 3/7 level after treatment with the DCM extract at 1 mg/mL). Conclusions ME and DCM extract of B. marginatum showed anti-infective and antiproliferative effects. PMID:24438177

Assessment of Anthelmintic Efficacy of Mebendazole in School Children in Six Countries Where Soil-Transmitted Helminths Are Endemic

PubMed Central

Levecke, Bruno; Montresor, Antonio; Albonico, Marco; Ame, Shaali M.; Behnke, Jerzy M.; Bethony, Jeffrey M.; Noumedem, Calvine D.; Engels, Dirk; Guillard, Bertrand; Kotze, Andrew C.; Krolewiecki, Alejandro J.; McCarthy, James S.; Mekonnen, Zeleke; Periago, Maria V.; Sopheak, Hem; Tchuem-Tchuenté, Louis-Albert; Duong, Tran Thanh; Huong, Nguyen Thu; Zeynudin, Ahmed; Vercruysse, Jozef

2014-01-01

Background Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking. However, they are urgently needed to ensure detection of reduced efficacies that are predicted to occur due to growing drug pressure. Here, using a standardized methodology, we assessed the FECR rate of a single oral dose of mebendazole (MEB; 500 mg) against STHs in six trials in school children in different locations around the world. Our results are compared with those previously obtained for similarly conducted trials of a single oral dose of albendazole (ALB; 400 mg). Methodology The efficacy of MEB, as assessed by FECR, was determined in six trials involving 5,830 school children in Brazil, Cambodia, Cameroon, Ethiopia, United Republic of Tanzania, and Vietnam. The efficacy of MEB was compared to that of ALB as previously assessed in 8,841 school children in India and all the above-mentioned study sites, using identical methodologies. Principal Findings The estimated FECR rate [95% confidence interval] of MEB was highest for A. lumbricoides (97.6% [95.8; 99.5]), followed by hookworm (79.6% [71.0; 88.3]). For T. trichiura, the estimated FECR rate was 63.1% [51.6; 74.6]. Compared to MEB, ALB was significantly more efficacious against hookworm (96.2% [91.1; 100], p<0.001) and only marginally, although significantly, better against A. lumbricoides infections (99.9% [99.0; 100], p = 0.012), but equally efficacious for T. trichiura infections (64.5% [44.4; 84.7], p = 0.906). Conclusions/Significance A minimum FECR rate of 95% for A. lumbricoides, 70% for hookworm, and 50% for T. trichiura is expected in MEB-dependent PC programs. Lower FECR results may indicate the development of potential drug resistance. PMID:25299391

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis.

PubMed

Nicolle, Lindsay; Duckworth, Heather; Sitar, Dan; Bryski, Lisa; Harding, Godfrey; Zhanel, George

2008-03-01

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered. The mean pharmacokinetic parameters for the first dose were: maximum serum concentration (C(max)) 12.5+/-4.7 mg/L (range 5.6-16.0mg/L) (fC(max) 8.8+/-3.3, where f indicates the levofloxacin free or non-protein-bound fraction), area under the serum concentration-time curve (AUC) 85.4+/-14.1 mgh/L (range 66.2-96.8 mgh/L) (fAUC 59.8+/-9.9) and serum half-life (t(1/2)) 6.7+/-0.5h. Mean urine concentrations were 88.0+/-100mg/L at the 0-3 h collection, 307+/-143 mg/L at 3-6 h, 170+/-107 mg/L at 6-12 h and 85+/-8 mg/L at 12-24 h. Mean levofloxacin serum pharmacodynamics for infecting Escherichia coli were: C(max)/minimum inhibitory concentration (MIC) 323+/-185(fC(max)/MIC 226+/-129); and AUC/MIC 2339+/-830(fAUC/MIC 1647+/-579). Mean urine levofloxacin concentration/MIC ratios were: 900+/-1389 for 0-3 h, 12100+/-4950 for 3-6 h, 5922+/-3912 for 6-12 h and 2233+/-1037 for 12-24 h. Levofloxacin eradicated E. coli from the urine by 3-6 h after the first dose. Levofloxacin 750 mg once daily for 5 days has pharmacodynamics that support further evaluation of this regimen for treatment of women with acute uncomplicated pyelonephritis.

Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-Resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands

PubMed Central

Mase, Sundari R.; Jereb, John A.; Gonzalez, Daniel; Martin, Fatma; Daley, Charles L.; Fred, Dorina; Loeffler, Ann; Menon, Lakshmy; Morris, Sapna Bamrah; Brostrom, Richard; Chorba, Terence; Peloquin, Charles A.

2016-01-01

Background In the Federated States of Micronesia (FSM) and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics (PK) were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15–20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis (MDR TB) disease or latent infection after MDR TB exposure, to inform future dosing strategies. Methods Blood samples were collected at 0 (RMI only), 1, 2, and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and levofloxacin Cmax, elimination half-life (t1/2), and area under the curve from 0 to 24 hours (AUC0–24 hours * µg/mL) were correlated to determine optimal dosage and to examine associations. Population PK and target attainment were modeled. With results from FSM, dosages were increased in RMI toward the target maximal drug concentration (Cmax) for Mycobacterium tuberculosis, 8–12 µg/ml. Results Cmax correlated linearly with per-weight dosage. Neither Cmax nor t1/2 was associated with gender, age, body mass index, concurrent medications, or pre-dose meals. At levofloxacin dosage of 15–20 mg/kg, Cmax ≥ 8 µg/ml was observed, and modeling corroborated a high target attainment across the ratio of the area under the free-concentration-versus-time curve to minimum inhibitory concentration (fAUCss,0–24/MIC) values. Conclusions Levofloxacin dosage should be 15–20 mg/kg for Cmax ≥ 8 µg/ml and a high target attainment across fAUCss,0–24/MIC values in children ≥2 years of age. PMID:26658531

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

PubMed Central

Smith, Heidi L.; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C.

2016-01-01

ABSTRACT Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16–21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38–59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans. PMID:27070129

Impact of high-flux haemodialysis on the probability of target attainment for oral amoxicillin/clavulanic acid combination therapy.

PubMed

Hui, Katrina; Patel, Kashyap; Kong, David C M; Kirkpatrick, Carl M J

2017-07-01

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT >MIC ) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT >0.1 mg/L ) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration-time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20-30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model.

PubMed

Smith, Heidi L; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C

2016-08-17

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

PubMed

Udy, Andrew A; Lipman, Jeffrey; Jarrett, Paul; Klein, Kerenaftali; Wallis, Steven C; Patel, Kashyap; Kirkpatrick, Carl M J; Kruger, Peter S; Paterson, David L; Roberts, Michael S; Roberts, Jason A

2015-01-30

The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing. To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures. Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.

SU-C-BRD-04: Comparison of Shallow Fluence to Deep Point Dose Measurements for Spine VMAT SBRT Patient-Specific QA

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

Cheung, J; Held, M; Morin, O

2015-06-15

Purpose: To investigate the sensitivity of traditional gamma-index-based fluence measurements for patient-specific measurements in VMAT delivered spine SBRT. Methods: The ten most recent cases for spine SBRT were selected. All cases were planned with Eclipse RapidArc for a TrueBeam STx. The delivery was verified using a point dose measurement with a Pinpoint 3D micro-ion chamber in a Standard Imaging Stereotactic Dose Verification Phantom. Two points were selected for each case, one within the target in a low dose-gradient region and one in the spinal cord. Measurements were localized using on-board CBCT. Cumulative and separate arc measurements were acquired with themore » ArcCheck and assessed using the SNC patient software with a 3%/3mm and 2%/2mm gamma analysis with global normalization and a 10% dose threshold. Correlations between data were determined using the Pearson Product-Moment Correlation. Results: For our cohort of patients, the measured doses were higher than calculated ranging from 2.2%–9.7% for the target and 1.0%–8.2% for the spinal cord. There was strong correlation between 3%/3mm and 2%/2mm passing rates (r=0.91). Moderate correlation was found between target and cord dose with a weak fit (r=0.67, R-Square=0.45). The cumulative ArcCheck measurements showed poor correlation with the measured point doses for both the target and cord (r=0.20, r=0.35). If the arcs are assessed separately with an acceptance criteria applied to the minimum passing rate between all arcs, a moderate negative correlation was found for the target and cord (r=−0.48, r= −0.71). The case with the highest dose difference (9.7%) received a passing rate of 97.2% for the cumulative arcs and 87.8% for the minimum with separate arcs. Conclusion: Our data suggest that traditional passing criteria using ArcCheck with cumulative measurements do not correlate well with dose errors. Separate arc analysis shows better correlation but may still miss large dose errors. Point dose verifications are recommended.« less

Evaluation of oral therapy on Mansonial Schistosomiasis using single dose of Balanites aegyptiaca fruits and praziquantel.

PubMed

Koko, W S; Abdalla, H S; Galal, M; Khalid, H S

2005-01-01

The efficacy of Balanites aegyptiaca fruit mesocarp was compared with praziquantel in mice infected with Sudanese strain of Schistosoma mansoni. Infected mice were given a single dose of 200 mg/kg body weight of B. aegyptiaca fruit mesocarp and 200 mg/kg b.w. of praziquantel after 6 weeks from the onset of the infection. A significant reduction was observed in EPG (egg count per gram of faeces), eggs burden in tissues and recovery of adult worms (P<0.05) for both the plant and the drug-treated animals.

Spatio-temporal variations and genetic diversity of Anaplasma spp. in cattle from the North of Tunisia.

PubMed

Belkahia, Hanène; Ben Said, Mourad; El Mabrouk, Narjesse; Saidani, Mariem; Cherni, Chayma; Ben Hassen, Mariem; Bouattour, Ali; Messadi, Lilia

2017-09-01

In cattle, anaplasmosis is a tick-borne rickettsial disease caused by Anaplasma marginale, A. centrale, A. phagocytophilum, and A. bovis. To date, no information concerning the seasonal dynamics of single and/or mixed infections by different Anaplasma species in bovines are available in Tunisia. In this work, a total of 1035 blood bovine samples were collected in spring (n=367), summer (n=248), autumn (n=244) and winter (n=176) from five different governorates belonging to three bioclimatic zones from the North of Tunisia. Molecular survey of A. marginale, A. centrale and A. bovis in cattle showed that average prevalence rates were 4.7% (minimum 4.1% in autumn and maximum 5.6% in summer), 7% (minimum 3.9% in winter and maximum 10.7% in autumn) and 4.9% (minimum 2.7% in spring and maximum 7.3% in summer), respectively. A. phagocytophilum was not detected in all investigated cattle. Seasonal variations of Anaplasma spp. infection and co-infection rates in overall and/or according to each bioclimatic area were recorded. Molecular characterization of A. marginale msp4 gene indicated a high sequence homology of revealed strains with A. marginale sequences from African countries. Alignment of 16S rRNA A. centrale sequences showed that Tunisian strains were identical to the vaccine strain from several sub-Saharan African and European countries. The comparison of the 16S rRNA sequences of A. bovis variants showed a perfect homology between Tunisian variants isolated from cattle, goats and sheep. These present data are essential to estimate the risk of bovine anaplasmosis in order to develop integrated control policies against multi-species pathogen communities, infecting humans and different animal species, in the country. Copyright © 2017 Elsevier B.V. All rights reserved.

Infectivity titration of a prototype strain of hepatitis E virus in cynomolgus monkeys.

PubMed

Tsarev, S A; Tsareva, T S; Emerson, S U; Yarbough, P O; Legters, L J; Moskal, T; Purcell, R H

1994-06-01

The infectivity titer of a standard stock of the SAR-55 strain of hepatitis E virus (HEV) was determined in cynomolgus macaques (Macaca fascicularis) and the effect of dose on the course of the infection was examined by weekly monitoring of alanine aminotransferase (ALT) and anti-HEV levels. Antibody to HEV (anti-HEV) was measured with ELISAs based on ORF-2 recombinant antigens consisting of either a 55 kDa region expressed in insect cells or shorter regions expressed as fusion proteins in bacteria. The ELISA based on the 55 kDa antigen was generally more sensitive. The infectivity titer of SAR-55 was 10(6) cynomolgus 50% infectious doses per gram of feces. The infectivity titer corresponded to the HEV genome titer of the inoculum as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Anti-HEV IgM was detected in only a portion of the animals that had an anti-HEV IgG response. Biochemical evidence of hepatitis was most prominent in animals that were inoculated with the higher concentrations of virus and the incubation period to seroconversion was prolonged in animals that received the lower doses.

Optimization of the temporal pattern of radiation: An IMRT based study

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

Altman, Michael B.; Chmura, Steven J.; Deasy, Joseph O.

Purpose: To investigate how the temporal pattern of dose applied during a single-intensity modulated radiation therapy (IMRT) fraction can be arranged to maximize or minimize cell kill. Methods and Materials: Using the linear-quadratic repair-time model and a simplified IMRT delivery pattern model, the surviving fraction of cells for a single fraction was calculated for all permutations of the dose delivery pattern for an array of clinically based IMRT cases. Maximization of cell kill was achieved by concentrating the highest doses in the middle of a fraction, while minimization was achieved by spreading the highest doses between the beginning and end.more » The percent difference between maximum and minimum cell kill (%Diff{sub min/max}) and the difference between maximum and minimum total doses normalized to 2 Gy/fx ({delta}NTD{sub 2Gy}) was calculated for varying fraction durations (T), {alpha}/{beta} ratios, and doses/fx. Results: %Diff{sub min/max} and {delta}NTD{sub 2Gy} both increased with increasing T and with decreasing {alpha}/{beta}. The largest increases occurred with dose/fx. With {alpha}/{beta} = 3 Gy and 30 min/fx, %Diff{sub min/max} ranged from 2.7-5.3% for 2 Gy/fx to 48.6-74.1% for 10 Gy/fx, whereas {delta}NTD{sub 2Gy} ranged from 1.2 Gy-2.4 Gy for 30 fractions of 2 Gy/fx to 2.3-4.8 Gy for 2 fractions of 10.84 Gy/fx. Using {alpha}/{beta} = 1.5 Gy, an analysis of prostate hypofractionation schemes yielded differences in clinical outcome based on the pattern of applied dose ranging from 3.2%-6.1% of the treated population. Conclusions: Rearrangement of the temporal pattern of dose for a single IMRT fraction could be used to optimize cell kill and to directly, though modestly, affect treatment outcome.« less

Quantifying the Combined Effect of Radiation Therapy and Hyperthermia in Terms of Equivalent Dose Distributions

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

Kok, H. Petra, E-mail: H.P.Kok@amc.uva.nl; Crezee, Johannes; Franken, Nicolaas A.P.

2014-03-01

Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia. Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy{sup −1}) and β (Gy{sup −2}) of the linear–quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normalmore » tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear–quadratic model. Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma. Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different treatment modalities.« less

SU-E-J-33: Cardiac Movement in Deep Inspiration Breath-Hold for Left-Breast Cancer Radiotherapy

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

Kim, M; Lee, S; Suh, T

Purpose: The present study was designed to investigate the displacement of heart using Deep Inspiration Breath Hold (DIBH) CT data compared to free-breathing (FB) CT data and radiation exposure to heart. Methods: Treatment planning was performed on the computed tomography (CT) datasets of 20 patients who had received lumpectomy treatments. Heart, lung and both breasts were outlined. The prescribed dose was 50 Gy divided into 28 fractions. The dose distributions in all the plans were required to fulfill the International Commission on Radiation Units and Measurement specifications that include 100% coverage of the CTV with ≥ 95% of the prescribedmore » dose and that the volume inside the CTV receiving > 107% of the prescribed dose should be minimized. Displacement of heart was measured by calculating the distance between center of heart and left breast. For the evaluation of radiation dose to heart, minimum, maximum and mean dose to heart were calculated. Results: The maximum and minimum left-right (LR) displacements of heart were 8.9 mm and 3 mm, respectively. The heart moved > 4 mm in the LR direction in 17 of the 20 patients. The distances between the heart and left breast ranged from 8.02–17.68 mm (mean, 12.23 mm) and 7.85–12.98 mm (mean, 8.97 mm) with DIBH CT and FB CT, respectively. The maximum doses to the heart were 3115 cGy and 4652 cGy for the DIBH and FB CT dataset, respectively. Conclusion: The present study has demonstrated that the DIBH technique could help to reduce the risk of radiation dose-induced cardiac toxicity by using movement of cardiac; away from radiation field. The DIBH technique could be used in an actual treatment room for a few minutes and could effectively reduce the cardiac dose when used with a sub-device or image acquisition standard to maintain consistent respiratory motion.« less

Zika and Chikungunya virus detection in naturally infected Aedes aegypti in Ecuador.

PubMed

Cevallos, Varsovia; Ponce, Patricio; Waggoner, Jesse J; Pinsky, Benjamin A; Coloma, Josefina; Quiroga, Cristina; Morales, Diego; Cárdenas, Maria José

2018-01-01

The wide and rapid spread of Chikungunya (CHIKV) and Zika (ZIKV) viruses represent a global public health problem, especially for tropical and subtropical environments. The early detection of CHIKV and ZIKV in mosquitoes may help to understand the dynamics of the diseases in high-risk areas, and to design data based epidemiological surveillance to activate the preparedness and response of the public health system and vector control programs. This study was done to detect ZIKV and CHIKV viruses in naturally infected fed female Aedes aegypti (L.) mosquitoes from active epidemic urban areas in Ecuador. Pools (n=193; 22 pools) and individuals (n=22) of field collected Ae. aegypti mosquitoes from high-risk arboviruses infection sites in Ecuador were analyzed for the presence of CHIKV and ZIKV using RT-PCR. Phylogenetic analysis demonstrated that both ZIKV and CHIKV viruses circulating in Ecuador correspond to the Asian lineages. Minimum infection rate (MIR) of CHIKV for Esmeraldas city was 2.3% and the maximum likelihood estimation (MLE) was 3.3%. The minimum infection rate (MIR) of ZIKV for Portoviejo city was 5.3% and for Manta city was 2.1%. Maximum likelihood estimation (MLE) for Portoviejo city was 6.9% and 2.6% for Manta city. Detection of arboviruses and infection rates in the arthropod vectors may help to predict an outbreak and serve as a warning tool in surveillance programs. Copyright © 2017 Elsevier B.V. All rights reserved.

Cost-effectiveness of malaria preventive treatment for HIV-infected pregnant women in sub-Saharan Africa.

PubMed

Choi, Sung Eun; Brandeau, Margaret L; Bendavid, Eran

2017-10-06

Malaria is a leading cause of morbidity and mortality among HIV-infected pregnant women in sub-Saharan Africa: at least 1 million pregnancies among HIV-infected women are complicated by co-infection with malaria annually, leading to increased risk of premature delivery, severe anaemia, delivery of low birth weight infants, and maternal death. Current guidelines recommend either daily cotrimoxazole (CTX) or intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for HIV-infected pregnant women to prevent malaria and its complications. The cost-effectiveness of CTX compared to IPTp-SP among HIV-infected pregnant women was assessed. A microsimulation model of malaria and HIV among pregnant women in five malaria-endemic countries in sub-Saharan Africa was constructed. Four strategies were compared: (1) 2-dose IPTp-SP at current IPTp-SP coverage of the country ("2-IPT Low"); (2) 3-dose IPTp-SP at current coverage ("3-IPT Low"); (3) 3-dose IPTp-SP at the same coverage as antiretroviral therapy (ART) in the country ("3-IPT High"); and (4) daily CTX at ART coverage. Outcomes measured include maternal malaria, anaemia, low birth weight (LBW), and disability-adjusted life years (DALYs). Sensitivity analyses assessed the effect of adherence to CTX. Compared with the 2-IPT Low Strategy, women receiving CTX had 22.5% fewer LBW infants (95% CI 22.3-22.7), 13.5% fewer anaemia cases (95% CI 13.4-13.5), and 13.6% fewer maternal malaria cases (95% CI 13.6-13.7). In all simulated countries, CTX was the preferred strategy, with incremental cost-effectiveness ratios ranging from cost-saving to $3.9 per DALY averted from a societal perspective. CTX was less effective than the 3-IPT High Strategy when more than 18% of women stopped taking CTX during the pregnancy. In malarious regions of sub-Saharan Africa, daily CTX for HIV-infected pregnant women regardless of CD4 cell count is cost-effective compared with 3-dose IPTp-SP as long as more than 82% of women adhere to daily dosing.

Infection dynamics of western equine encephalomyelitis virus (Togaviridae: Alphavirus) in four strains of Culex tarsalis (Diptera: Culicidae): an immunocytochemical study.

PubMed

Oviedo, Marco V Neira; Romoser, William S; James, Calvin Bl; Mahmood, Farida; Reisen, William K

2011-04-18

BACKGROUND: Vector competence describes the efficiency with which vector arthropods become infected with and transmit pathogens and depends on interactions between pathogen and arthropod genetics as well as environmental factors. For arbovirus transmission, the female mosquito ingests viremic blood, the virus infects and replicates in midgut cells, escapes from the midgut, and disseminates to other tissues, including the salivary glands. Virus-laden saliva is then injected into a new host. For transmission to occur, the virus must overcome several "barriers", including barriers to midgut infection and/or escape and salivary infection and/or escape. By examining the spatial/temporal infection dynamics of Culex tarsalis strains infected with western equine encephalomyelitis virus (WEEV), we identified tissue tropisms and potential tissue barriers, and evaluated the effects of viral dose and time postingestion. METHODS: Using immunostained paraffin sections, WEEV antigens were tracked in four Cx. tarsalis strains: two recently colonized California field strains - Coachella Valley, Riverside County (COAV) and Kern National Wildlife Refuge (KNWR); and two laboratory strains selected for WEEV susceptibility (high viremia producer, HVP), and WEEV resistance (WR). RESULTS AND CONCLUSIONS: Tissues susceptible to WEEV infection included midgut epithelium, neural ganglia, trachea, chorionated eggs, and salivary glands. Neuroendocrine cells in the retrocerebral complex were occasionally infected, indicating the potential for behavioral effects. The HVP and COAV strains vigorously supported viral growth, whereas the WR and KNWR strains were less competent. Consistent with earlier studies, WEEV resistance appeared to be related to a dose-dependent midgut infection barrier, and a midgut escape barrier. The midgut escape barrier was not dependent upon the ingested viral dose. Consistent with midgut infection modulation, disseminated infections were less common in the WR and KNWR strains than in the HVP and COAV strains. Once the virus disseminated from the midgut, all strains were able to develop salivary gland infections. The possible roles of observed pathology will be discussed in a subsequent paper.

Infection dynamics of western equine encephalomyelitis virus (Togaviridae: Alphavirus) in four strains of Culex tarsalis (Diptera: Culicidae): an immunocytochemical study

PubMed Central

Oviedo, Marco V Neira; Romoser, William S; James, Calvin BL; Mahmood, Farida; Reisen, William K

2012-01-01

Background Vector competence describes the efficiency with which vector arthropods become infected with and transmit pathogens and depends on interactions between pathogen and arthropod genetics as well as environmental factors. For arbovirus transmission, the female mosquito ingests viremic blood, the virus infects and replicates in midgut cells, escapes from the midgut, and disseminates to other tissues, including the salivary glands. Virus-laden saliva is then injected into a new host. For transmission to occur, the virus must overcome several “barriers”, including barriers to midgut infection and/or escape and salivary infection and/or escape. By examining the spatial/temporal infection dynamics of Culex tarsalis strains infected with western equine encephalomyelitis virus (WEEV), we identified tissue tropisms and potential tissue barriers, and evaluated the effects of viral dose and time postingestion. Methods Using immunostained paraffin sections, WEEV antigens were tracked in four Cx. tarsalis strains: two recently colonized California field strains – Coachella Valley, Riverside County (COAV) and Kern National Wildlife Refuge (KNWR); and two laboratory strains selected for WEEV susceptibility (high viremia producer, HVP), and WEEV resistance (WR). Results and conclusions Tissues susceptible to WEEV infection included midgut epithelium, neural ganglia, trachea, chorionated eggs, and salivary glands. Neuroendocrine cells in the retrocerebral complex were occasionally infected, indicating the potential for behavioral effects. The HVP and COAV strains vigorously supported viral growth, whereas the WR and KNWR strains were less competent. Consistent with earlier studies, WEEV resistance appeared to be related to a dose-dependent midgut infection barrier, and a midgut escape barrier. The midgut escape barrier was not dependent upon the ingested viral dose. Consistent with midgut infection modulation, disseminated infections were less common in the WR and KNWR strains than in the HVP and COAV strains. Once the virus disseminated from the midgut, all strains were able to develop salivary gland infections. The possible roles of observed pathology will be discussed in a subsequent paper. PMID:22629118

Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane.

PubMed

Hui, Xiaoying; Chan, Thomas C K; Barbadillo, Sherry; Lee, Christine; Maibach, Howard I; Wester, Ronald C

2003-01-01

This study determines the enhancing effects of 2-n-nonyl-1,3-dioxolane on the penetration of econazole, an antifungal drug, into the deeper layers of the human nail where fungal infection resides. Aliquots (10 microL) of Econail lacquer formulation containing 0.45 mg of [(14)C]-econazole with 18% 2-n-nonyl-1,3-dioxolane (test group) or without 2-n-nonyl-1,3-dioxolane (control group) were applied twice daily for 14 days to human nails that had been washed with ethanol before each morning's application. The hydration of the nail sample was well controlled to simulate normal physiological conditions. After 14 days of dosing, the inner ventral section of the nail plate was assayed for absorbed drug content, using a micrometer-controlled drilling and nail powder removal system. The mass balance values of [(14)C]-econazole in this study were 90.8 and 96.4% for the test and control groups, respectively. The weight-normalized econazole content in the ventral/intermediate nail plate center in the test group was 6-fold greater than that in the control (p = 0.008). The total econazole absorbed into the supporting bed cotton ball in the test group was nearly 200-fold greater than that in the control group (p = 0.008) over the 14-day period. The amount of econazole after dosing in the inner part of the human nail (potential diseased area) was 11.1 +/- 2.6 (SD) microg/mg of nail powder with 2-n-nonyl-1,3-dioxolane in the lacquer and 1.78 +/- 0.32 microg/mg without 2-n-nonyl-1,3-dioxolane (p = 0.008). The surface nail contained more econazole (p = 0.004), that is, nonabsorbed drug, where 2-n-nonyl-1,3-dioxolane was not part of the dosing solution. Econazole in the support bed under the nail (the total absorbed dose) was 47.5 +/- 22.0 mg in the lacquer with 2-n-nonyl-1,3-dioxolane and 0.2 +/- 0.1 mg in the lacquer without 2-n-nonyl-1,3-dioxolane (p = 0.008). Moreover the concentration in the deep nail layer in the test group is 14,000 times higher than minimum inhibitory concentration (MIC) believed necessary to inhibit the growth of infecting fungi (Dermatophytes species). In a subsequent study, [(14)C]-dioxolane did not penetrate the nail well. Therefore, the mechanism of enhancement of econazole penetration is at the formulation/nail interface. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

Comparative susceptibility of Atlantic salmon, lake trout and rainbow trout to Myxobolus cerebralis in controlled laboratory exposures

USGS Publications Warehouse

Blazer, V.S.; Densmore, Christine L.; Schill, W.B.; Cartwright, Deborah D.; Page, S.J.

2004-01-01

The susceptibility of lake trout Salvelinus namaycush, rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar to Myxobolus cerebralis, the causative agent of whirling disease, was compared in controlled laboratory exposures. A total of 450 (225 for each dose) fry for each species were exposed to a low (200 spores per fish) or high (2000 spores per fish) dose of the infective triactinomyxon. At 22 wk post-exposure, 60 fish from each group, as well as controls for each species, were examined for clinical signs (whirling behavior, blacktail, deformed heads and skeletal deformities), microscopic lesions, and presence of spores. Rainbow trout were highly susceptible to infection, with 100% being positive for spores and with microscopic pathological changes in both exposure groups. Rainbow trout were the only species to show whirling behavior and blacktail. Atlantic salmon were less susceptible, with only 44 and 61% being positive for spores, respectively, in the low and high dose groups, while 68 and 75%, respectively, had microscopic pathology associated with cartilage damage. Rainbow trout heads contained mean spore concentrations of 2.2 (low dose) or 4.0 (high dose) ?? 106 spores g tissue-1. The means for positive Atlantic salmon (not including zero values) were 1.7 (low) and 7.4 (high) ?? 104 spores g tissue-1. Lake trout showed no clinical signs of infection, were negative for spores in both groups and showed no histopathological signs of M. cerebralis infection.

Comparative susceptibility of Atlantic salmon, lake trout and rainbow trout to Myxobolus cerebralis in controlled laboratory exposures.

PubMed

Blazer, V S; Densmore, C L; Schill, W B; Cartwright, D D; Page, S J

2004-01-28

The susceptibility of lake trout Salvelinus namaycush, rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar to Myxobolus cerebralis, the causative agent of whirling disease, was compared in controlled laboratory exposures. A total of 450 (225 for each dose) fry for each species were exposed to a low (200 spores per fish) or high (2000 spores per fish) dose of the infective triactinomyxon. At 22 wk post-exposure, 60 fish from each group, as well as controls for each species, were examined for clinical signs (whirling behavior, blacktail, deformed heads and skeletal deformities), microscopic lesions, and presence of spores. Rainbow trout were highly susceptible to infection, with 100% being positive for spores and with microscopic pathological changes in both exposure groups. Rainbow trout were the only species to show whirling behavior and blacktail. Atlantic salmon were less susceptible, with only 44 and 61% being positive for spores, respectively, in the low and high dose groups, while 68 and 75%, respectively, had microscopic pathology associated with cartilage damage. Rainbow trout heads contained mean spore concentrations of 2.2 (low dose) or 4.0 (high dose) x 10(6) spores g tissue(-1). The means for positive Atlantic salmon (not including zero values) were 1.7 (low) and 7.4 (high) x 10(4) spores g tissue(-1). Lake trout showed no clinical signs of infection, were negative for spores in both groups and showed no histopathological signs of M. cerebralis infection.

Does cemented or cementless single-stage exchange arthroplasty of chronic periprosthetic hip infections provide similar infection rates to a two-stage? A systematic review.

PubMed

George, D A; Logoluso, N; Castellini, G; Gianola, S; Scarponi, S; Haddad, F S; Drago, L; Romano, C L

2016-10-10

The best surgical modality for treating chronic periprosthetic hip infections remains controversial, with a lack of randomised controlled studies. The aim of this systematic review is to compare the infection recurrence rate after a single-stage versus a two-stage exchange arthroplasty, and the rate of cemented versus cementless single-stage exchange arthroplasty for chronic periprosthetic hip infections. We searched for eligible studies published up to December 2015. Full text or abstract in English were reviewed. We included studies reporting the infection recurrence rate as the outcome of interest following single- or two-stage exchange arthroplasty, or both, with a minimum follow-up of 12 months. Two reviewers independently abstracted data and appraised quality assessment. After study selection, 90 observational studies were included. The majority of studies were focused on a two-stage hip exchange arthroplasty (65 %), 18 % on a single-stage exchange, and only a 17 % were comparative studies. There was no statistically significant difference between a single-stage versus a two-stage exchange in terms of recurrence of infection in controlled studies (pooled odds ratio of 1.37 [95 % CI = 0.68-2.74, I 2  = 45.5 %]). Similarly, the recurrence infection rate in cementless versus cemented single-stage hip exchanges failed to demonstrate a significant difference, due to the substantial heterogeneity among the studies. Despite the methodological limitations and the heterogeneity between single cohorts studies, if we considered only the available controlled studies no superiority was demonstrated between a single- and two-stage exchange at a minimum of 12 months follow-up. The overalapping of confidence intervals related to single-stage cementless and cemented hip exchanges, showed no superiority of either technique.

The in vivo efficacy of neuraminidase inhibitors cannot be determined from the decay rates of influenza viral titers observed in treated patients

NASA Astrophysics Data System (ADS)

Palmer, John; Dobrovolny, Hana M.; Beauchemin, Catherine A. A.

2017-01-01

Antiviral therapy is a first line of defence against new influenza strains. Current pandemic preparations involve stock- piling oseltamivir, an oral neuraminidase inhibitor (NAI), so rapidly determining the effectiveness of NAIs against new viral strains is vital for deciding how to use the stockpile. Previous studies have shown that it is possible to extract the drug efficacy of antivirals from the viral decay rate of chronic infections. In the present work, we use a nonlinear mathematical model representing the course of an influenza infection to explore the possibility of extracting NAI drug efficacy using only the observed viral titer decay rates seen in patients. We first show that the effect of a time-varying antiviral concentration can be accurately approximated by a constant efficacy. We derive a relationship relating the true treatment dose and time elapsed between doses to the constant drug dose required to approximate the time- varying dose. Unfortunately, even with the simplification of a constant drug efficacy, we show that the viral decay rate depends not just on drug efficacy, but also on several viral infection parameters, such as infection and production rate, so that it is not possible to extract drug efficacy from viral decay rate alone.

Fractional Dosing of Yellow Fever Vaccine to Extend Supply: A Modeling Study

PubMed Central

Peak, Corey M.; Leung, Gabriel M.

2016-01-01

Background The ongoing yellow fever (YF) epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa in July–August 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidating the conditions under which dose fractionation would reduce transmission. Methods We estimate the effective reproductive number for YF in Angola using disease natural history and case report data. With simple mathematical models of YF transmission, we calculate the infection attack rate (IAR, the proportion of population infected over the course of an epidemic) under varying levels of transmissibility and five-fold fractional-dose vaccine efficacy for two vaccination scenarios: (i) random vaccination in a hypothetical population that is completely susceptible; (ii) the Kinshasa vaccination campaign in July–August 2016 with different age cutoff for fractional-dose vaccines. Findings We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (i.e. a proportion VE of vaccinees receives complete and the remainder receive no protection), n-fold fractionation can dramatically reduce IAR as long as efficacy VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (i.e. the susceptibility of each vaccinee is reduced by a factor that is equal to the vaccine efficacy VE). The age cutoff for fractional-dose vaccines chosen by the WHO for the Kinshasa vaccination campaign (namely, 2 years) provides the largest reduction in IAR if the efficacy of five-fold fractional-dose vaccines exceeds 20%. Interpretation Dose fractionation is a very effective strategy for reducing infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected. PMID:27837923

[Effects of complementary food supplements on respiratory infections and diarrhea of infants and young children in poor rural].

PubMed

Yu, Dongmei; Wang, Yuying; Wang, Fuzhen

2007-05-01

To investigate the effect of complementary food supplements with protein and multi-micronutrients on respiratory infections and diarrhea of infants and yound children in poor rural China. In 5 poor county of Gansu Province, 1478 children aged 4 - 12 months were enrolled and divided into two groups. In addition to the usual home-made complementary food, all the children were fed one package of either formula I or formula II per day, usual home-made complementary food, all the children were fed one package of either formula I or formula II per day, protein and micronutrient were supplemented in formula I group. Every 6 months, a massive dose of vitamin A was protein and micronutrient were supplemented in formula I group. Every 6 months, a massive dose of vitamin A was supplemented to all children, weight and height measurements have been done every 3 months until they were 24 months old. During the follow-up of 12 months supplementation, prevalence of respiratory infection and diarrhea reduce significantly compared with baseline survey (P < 0.0001), there is no difference between the two group at the same survey, lasting time of respiratory infection is shortened in formula I group, and medical cost of disease in the two groups Complementary food supplements, with large-dose vitamin A, reduce prevalence of reduced significantly. Complementary food supplements, with large-dose vitamin A, reduce prevalence of respiratory infections, diarrhea and medical cost of those diseases.

Orthopaedic surgery in natural disaster and conflict settings: how can quality care be ensured?

PubMed

Alvarado, Oscar; Trelles, Miguel; Tayler-Smith, Katie; Joseph, Holdine; Gesline, Rodné; Wilna, Thélusma Eli; Mohammad Omar, Mohammad Karim; Faiz Mohammad, Niaz Mohammad; Muhima Mastaki, John; Chingumwa Buhu, Richard; Caluwaerts, An; Dominguez, Lynette

2015-10-01

Médecins sans Frontières (MSF) is one of the main providers of orthopaedic surgery in natural disaster and conflict settings and strictly imposes a minimum set of context-specific standards before any surgery can be performed. Based on MSF's experience of performing orthopaedic surgery in a number of such settings, we describe: (a) whether it was possible to implement the minimum standards for one of the more rigorous orthopaedic procedures--internal fixation--and when possible, the time frame, (b) the volume and type of interventions performed and (c) the intra-operative mortality rates and postoperative infection rates. We conducted a retrospective review of routine programme data collected between 2007 and 2014 from three MSF emergency surgical interventions in Haiti (following the 2010 earthquake) and three ongoing MSF projects in Kunduz (Afghanistan), Masisi (Democratic Republic of the Congo) and Tabarre (Haiti). The minimum standards for internal fixation were achieved in one emergency intervention site in Haiti, and in Kunduz and Tabarre, taking up to 18 months to implement in Kunduz. All sites achieved the minimum standards to perform amputations, reductions and external fixations, with a total of 9,409 orthopaedic procedures performed during the study period. Intraoperative mortality rates ranged from 0.6 to 1.9 % and postoperative infection rates from 2.4 to 3.5 %. In settings affected by natural disaster or conflict, a high volume and wide repertoire of orthopaedic surgical procedures can be performed with good outcomes when minimum standards are in place. More demanding procedures like internal fixation may not always be feasible.

Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells

PubMed Central

Choi, In-Wook; Ismail, Hassan Ahmed Hassan Ahmed; Zhou, Wei; Cha, Guang-Ho; Zhou, Yu; Yuk, Jae-Min; Jo, Eun-Kyeong; Lee, Young-Ha

2015-01-01

Interleukin (IL)-23 and IL-12 are closely related in structure, and these cytokines regulate both innate and adaptive immunity. However, the precise signaling networks that regulate the production of each in Toxoplasma gondii-infected THP-1 monocytic cells, particularly the PI3K/AKT and MAPK signaling pathways, remain unknown. In the present study, T. gondii infection upregulated the expression of IL-23 and IL-12 in THP-1 cells, and both cytokines increased with parasite dose. IL-23 secretion was strongly inhibited by TLR2 monoclonal antibody (mAb) treatment in a dose-dependent manner and by TLR2 siRNA transfection, whereas IL-12 secretion was strongly inhibited by TLR4 mAb treatment dose-dependently and by TLR4 siRNA transfection. IL-23 production was dose-dependently inhibited by the PI3K inhibitors LY294002 and wortmannin, whereas IL-12 production increased dose-dependently. THP-1 cells exposed to live T. gondii tachyzoites underwent rapid p38 MAPK, ERK1/2 and JNK activation. IL-23 production was significantly upregulated by the p38 MAPK inhibitor SB203580 dose-dependently, whereas pretreatment with 10 μM SB203580 significantly downregulated IL-12 production. ERK1/2 inhibition by PD98059 was significantly downregulated IL-23 production but upregulated IL-12 production. JNK inhibition by SP600125 upregulated IL-23 production, but IL-12 production was significantly downregulated dose-dependently. T. gondii infection resulted in AKT activation, and AKT phosphorylation was inhibited dose-dependently after pretreatment with PI3K inhibitors. In T. gondii-infected THP-1 cells, ERK1/2 activation was regulated by PI3K; however, the phosphorylation of p38 MAPK and JNK was negatively modulated by the PI3K signaling pathway. Collectively, these results indicate that IL-23 production in T. gondii-infected THP-1 cells was regulated mainly by TLR2 and then by PI3K and ERK1/2; however, IL-12 production was mainly regulated by TLR4 and then by p38 MAPK and JNK. Our findings provide new insight concerning the intracellular networks of the PI3K/AKT and MAPK signaling cascades for regulating T. gondii-induced IL-23 and IL-12 secretion in human monocytic cells. PMID:26528819

Humoral, Mucosal, and Cell-Mediated Immunity Against Vaccine and Nonvaccine Genotypes After Administration of Quadrivalent Human Papillomavirus Vaccine to HIV-Infected Children

PubMed Central

Weinberg, Adriana; Song, Lin-Ye; Saah, Alfred; Brown, Martha; Moscicki, Anna B.; Meyer, William A.; Bryan, Janine; Levin, Myron J.

2012-01-01

Objectives. To characterize the immunogenicity of a quadrivalent human papillomavirus vaccine (QHPV) in human immunodeficiency virus (HIV)–infected children, we studied their immune responses to 3 or 4 doses. Methods. HIV-infected children aged 7–12 years with a CD4 cell percentage of ≥15% of lymphocytes, received 3 doses of QHPV with or without a fourth dose after 72 weeks. Type-specific and cross-reactive antibodies and cell-mediated immunity were measured. Results. Type-specific antibodies to HPV6, 11, and 16 were detected in 100% and ≥94% of children at 4 and 72 weeks, respectively, after the third QHPV dose. Corresponding numbers for HPV18 were 97% and 76%, respectively. A fourth QHPV dose increased seropositivity to ≥96% for all vaccine genotypes. Four weeks after the third QHPV dose, 67% of vaccinees seroconverted to HPV31, an HPV16-related genotype not in the vaccine; 69% and 39% of vaccinees developed mucosal HPV16 and 18 immunoglobulin G antibodies, respectively; and 60% and 52% of vaccinees developed cytotoxic T lymphocytes (CTLs) for HPV16 and 31, respectively. Conclusions. Three QHPV doses generated robust and persistent antibodies to HPV6, 11, and 16 but comparatively weaker responses to HPV18. A fourth dose increased antibodies against all vaccine genotypes in an anamnestic fashion. CTLs and mucosal antibodies against vaccine genotypes, as well as cross-reactive antibodies and CTL against nonvaccine genotypes, were detected. PMID:22859825

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

PubMed Central

Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

2011-01-01

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID:21537018

Sphinganine to sphingosine ratio and predictive biochemical markers of fumonisin B1 exposure in ducks.

PubMed

Tran, S T; Bailly, J D; Tardieu, D; Durand, S; Benard, G; Guerre, P

2003-07-25

The kinetics of free sphinganine (Sa), sphinganine to sphingosine ratio (Sa/So), proteins, cholesterol, alanine aminotransferase (ALAT) and lactate dehydrogenase (LDH) were investigated in the course of fumonisin B1 (FB1) exposure in ducks (20 growing males divided into four groups of 5 receiving, respectively, a daily dose of 0, 5, 15 or 45 mg/kg FB1 via oral administration over 12 days). Descriptive statistics of these parameters were also studied in a large number of ducks not exposed to mycotoxins and free of known pathology. Although the toxin at the end of the treatment affected all the parameters investigated, only 2 days of treatment appeared necessary to increase free Sa concentrations in serum, whereas 6 days were necessary to detect a significant effect on Sa/So ratio. Significant differences between control and treated ducks were observed after 4 days of treatment for ALAT and LDH and after 6 and 8 days for cholesterol and proteins concentrations. The minimum doses of FB1 required to determine an effect were assessed using three different methods. This approach reveals that FB1 has greater effects when it is ingested at a low dose for a long time than when ingested at a high dose for a short time. Although the minimum toxic dose of FB1 in ducks remains to be determined, this result must be considered in the context of chronic exposure to the toxin, not only in avian populations.

Determinants of Hepatitis A Vaccine Immunity in a Cohort of Human Immunodeficiency Virus-Infected Children Living in Switzerland

PubMed Central

Crisinel, Pierre Alex; Posfay-Barbe, Klara Maria; Aebi, Christoph; Cheseaux, Jean-Jacques; Kahlert, Christian; Rudin, Christoph; Nadal, David

2012-01-01

Vaccination in HIV-infected children is often less effective than in healthy children. The goal of this study was to assess vaccine responses to hepatitis A virus (HAV) in HIV-infected children. Children of the Swiss Mother and Child HIV Cohort Study (MoCHiV) were enrolled prospectively. Recommendations for initial, catch-up, and additional HAV immunizations were based upon baseline antibody concentrations and vaccine history. HAV IgG was assessed by enzyme-linked immunosorbent assay (ELISA) with a protective cutoff value defined as ≥10 mIU/ml. Eighty-seven patients were included (median age, 11 years; range, 3.4 to 21.2 years). Forty-two patients were seropositive (48.3%) for HAV. Among 45 (51.7%) seronegative patients, 36 had not received any HAV vaccine dose and were considered naïve. Vaccine responses were assessed after the first dose in 29/35 naïve patients and after the second dose in 33/39 children (25 initially naïve patients, 4 seronegative patients, and 4 seropositive patients that had already received 1 dose of vaccine). Seroconversion was 86% after 1 dose and 97% after 2 doses, with a geometric mean concentration of 962 mIU/ml after the second dose. A baseline CD4+ T cell count below 750 cells/μl significantly reduced the post-2nd-dose response (P = 0.005). Despite a high rate of seroconversion, patients with CD4+ T cell counts of <750/μl had lower anti-HAV antibody concentrations. This may translate into a shorter protection time. Hence, monitoring humoral immunity may be necessary to provide supplementary doses as needed. PMID:22933400

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

PubMed

El-Khoueiry, Anthony B; Sangro, Bruno; Yau, Thomas; Crocenzi, Todd S; Kudo, Masatoshi; Hsu, Chiun; Kim, Tae-You; Choo, Su-Pin; Trojan, Jörg; Welling, Theodore H; Meyer, Tim; Kang, Yoon-Koo; Yeo, Winnie; Chopra, Akhil; Anderson, Jeffrey; Dela Cruz, Christine; Lang, Lixin; Neely, Jaclyn; Tang, Hao; Dastani, Homa B; Melero, Ignacio

2017-06-24

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd. All rights reserved.