In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens.

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-ß-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 µg/ml for B. anthracis, ≤0.0005 - 0.03 µg/ml for Y. pestis, 0.25 - 1 µg/ml for B. mallei, and 1 - 4 µg/ml for B. pseudomallei In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats.

The AV7909 vaccine, consists of the Anthrax Vaccine Adsorbed (AVA) bulk drug substance and the immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide adjuvant CPG 7909. The purpose of this research was to evaluate the potential maternal, reproductive, and developmental toxicity of AV7909 in rats to support licensure for use in women of childbearing potential. Groups of first generation (F0 ) female Sprague Dawley rats were dosed by intramuscular injection with water for injection, adjuvant or AV7909 at a volume of 0.5 ml/dose. Each rat received three vaccinations: 14 days prior to start of the mating period, on the first day of the mating period and on gestation day (GD) 7. There was no maternal mortality. Body weights, weight gain, and food consumption were comparable between groups. Findings in F0 females were limited to transient injection site edema and nodules consistent with immunostimulatory effects of the vaccine and adjuvant. Administration of AV7909 did not affect mating, fertility, pregnancy, embryo-fetal viability, growth, or morphologic development, parturition, maternal care of offspring or postnatal survival, growth, or development. There was no evidence of systemic inflammation in pregnant rats, based on evaluation of serum concentrations of the acute phase proteins alpha-2-macroglobulin and alpha-1-acid glycoprotein on GD 21. Anthrax lethal toxin-neutralizing antibodies were detected in AV7909-vaccinated F0 females. The antibodies were also detected in the sera of fetuses and F1 pups. Exposure of the fetuses and pups to maternally derived anthrax lethal toxin-neutralizing antibodies was not associated with developmental toxicity.

Comparative immunogenicity and efficacy of thermostable (lyophilized) and liquid formulation of anthrax vaccine candidate AV7909.

The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the anthrax vaccine adsorbed (AVA) (Emergent BioSolutions Inc., Lansing, MI) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. Emergent has produced a thermostable (lyophilized) formulation of AV7909 vaccine utilizing drying technology. The purpose of the study described here was to assess the immunogenicity and efficacy of the lyophilized formulation of the AV7909 vaccine candidate as compared with the liquid formulation in the guinea pig general-use prophylaxis (GUP) model. The study also provides initial information on the relationship between the immune response induced by the thermostable formulation of the vaccine, as measured by the toxin neutralization assay (TNA), and animal survival following lethal anthrax aerosol challenge. Results demonstrated that there were no significant differences in the immunogenicity or efficacy of lyophilized AV7909 against lethal anthrax spore aerosol challenge in the guinea pig model as compared to liquid AV7909. For both vaccine formulations, logistic regression modeling showed that the probability of survival increased as the pre-challenge antibody levels increased.

Tests of a full-scale ITER toroidal interferometer and polarimeter (TIP) prototype on the DIII-D tokamak (invited).

A full-scale ITER toroidal interferometer and polarimeter (TIP) prototype, including an active feedback alignment system, has been installed and tested on the DIII-D tokamak. In the TIP prototype, a two-color interferometry measurement of line-integrated density is carried out at 10.59 µm and 5.22 µm using a CO2 and quantum cascade laser, respectively, while a separate polarimetry measurement of the plasma-induced Faraday effect is made at 10.59 µm. The TIP prototype is equipped with a piezo tip/tilt stage active feedback alignment system that minimizes noise in the measurement and keeps the diagnostic aligned throughout DIII-D discharges. The measured phase resolution for the polarimeter and interferometer is 0.05° (100 Hz bandwidth) and 1.9° (1 kHz bandwidth), respectively. The corresponding line-integrated density resolution for the vibration-compensated interferometer is δnL = 1.5 × 1018 m-2, and the magnetic field-weighted line-integrated density from the polarimeter is δnBL = 1.5 × 1019 Tm-2. Both interferometer and polarimeter measurements during DIII-D discharges compare well with the expectations based on calculations using Thomson scattering measured density profiles and magnetic equilibrium reconstructions. Additionally, larger bandwidth interferometer measurements show that the diagnostic is a sensitive monitor of core density fluctuations with demonstrated measurements of Alfvén eigenmodes and tearing modes.

Influence of environmental conditions on the attenuation of ricin toxin on surfaces.

Ricin is a highly-toxic compound derived from castor plant beans. Several incidents involving contamination of residences and buildings due to ricin production or dissemination have occurred in recent years. The goal of this study was to determine whether ricin bioactivity could be attenuated in reasonable time via simple modifications of the indoor environment. Attenuation was assessed on six different materials as a function of temperature, relative humidity (RH), and contact time, using both a pure and crude preparation of the toxin. Ricin bioactivity was quantified via a cytotoxicity assay, and attenuation determined as the difference in ricin recovered from test and positive controls. The results showed that pure ricin could be attenuated successfully, while the crude ricin was generally more persistent and results more variable. We found no significant attenuation in crude ricin after two weeks at typical indoor environmental conditions, except on steel. Attenuation mostly improved with increasing temperature, but the effect of RH varied. For pure ricin, heat treatments at 40°C for 5 days or 50°C for 2-3 days achieved greater than 96% attenuation on steel. In contrast, appreciable recovery of the crude ricin preparation still occurred at 40°C after two weeks.

Upper wide-angle viewing system for ITER.

The Upper Wide Angle Viewing System (UWAVS) will be installed on five upper ports of ITER. This paper shows major requirements, gives an overview of the preliminary design with reasons for some design choices, examines self-emitted IR light from UWAVS optics and its effect on accuracy, and shows calculations of signal-to-noise ratios for the two-color temperature output as a function of integration time and divertor temperature. Accurate temperature output requires correction for vacuum window absorption vs. wavelength and for self-emitted IR, which requires good measurement of the temperature of the optical components. The anticipated signal-to-noise ratio using presently available IR cameras is adequate for the required 500 Hz frame rate.

A prospective evaluation of angiography-guided coronary stent implantation with high versus very high balloon inflation pressure.

BACKGROUND: High inflation pressure (HP) after coronary stent deployment has become a standard approach because it has been associated with a decreased subacute stent thrombosis (SAT) rate. However, the impact of HP on long-term outcomes is still unclear. We compared the long-term results of a strategy of increasing HP (>/=12 atm) until the achievement of angiographic success (<20% residual stenosis) with a prespecified very high inflation pressure (VHP) strategy of 20 atm without intermediate inflations. METHODS AND RESULTS: We conducted a parallel-group, nonrandomized study to evaluate the short- and long-term results in 136 consecutive eligible patients who underwent successful single Palmaz-Schatz stent implantation in vessels >/=3 mm. Major adverse cardiac events (MACE), that is, death, myocardial infarction, and target lesion revascularization (TLR), were monitored for a minimum of 6 months. No significant differences were observed between the two strategies in terms of final minimal lumen diameter (HP, 3.0 +/- 0.5 vs VHP, 3. 1 +/- 0.5 mm) and acute gain (HP, 2.1 +/- 0.7 vs VHP, 2.2 +/- 0.6). The overall rate of subacute stent thrombosis was 0.7%. During a 405 +/- 148-day follow-up, 21 (28.8%) patients in the VHP group and 6 (9. 5%) in the HP group (P =.005) had MACE, with a TLR rate of 27.4% versus 7.9% (P =.009), respectively. By multivariate analysis, the use of VHP increased the odds of long-term MACE by a factor of 3.48 (P =.009). Among patients undergoing TLR, those treated with VHP had a greater lumen loss (HP, 1.83 +/- 0.57 vs VHP, 2.15 +/- 0.36 mm, P =.02) and a more frequent pattern of diffuse restenosis (71% vs 16%, P =.06). CONCLUSIONS: In our study, the two strategies had similar acute and short-term results, but VHP was associated with a poorer long-term outcome. These data provide a rationale for a less aggressive strategy for stent deployment by optimizing rather than attempting to maximize inflation pressure and stent expansion.

Comparison of Florida Hispanic and non-Hispanic Caucasian women in their health beliefs related to breast cancer and health locus of control.

PURPOSE/OBJECTIVES: To compare Florida Hispanic and non-Hispanic Caucasian women in their health beliefs about breast cancer and health locus of control (LOC). DESIGN: Exploratory, comparative. SETTING: A variety of healthcare settings in an urban area in Florida. SAMPLE: Hispanic (n = 113) and non-Hispanic (n = 197) Caucasian women who could read and understand either English or Spanish. METHODS: The Health Screening Questionnaire, which assesses health beliefs and health LOC, was administered in either Spanish or English, and the results were analyzed. MAIN RESEARCH VARIABLES: Attitudes about health in general, perceptions about susceptibility to cancer, beliefs about benefits of early diagnosis, and perceptions about the seriousness of cancer; LOC. FINDINGS: Florida Hispanic women are better educated than the Mexican American Hispanic women described in the literature. Hispanic and non-Hispanic women were significantly different in their health beliefs and LOC. With age and education controlled statistically, these differences remained. Hispanic women who preferred to speak/read English were more like the non-Hispanic women in their responses than were the women who preferred Spanish. CONCLUSIONS: Cultural differences exist between Hispanic and non-Hispanic women; however, differences also exist between groups of Hispanic women in Florida versus Hispanics in the southwestern United States. IMPLICATIONS FOR NURSING PRACTICE: Outreach programs for cancer screening should be culturally relevant and may need to be different for subgroups of Hispanics in the United States.

Certification. Hospital versus national standards.

"Certification" and "credential" are frequently used terms in nursing. How these terms are used and what they mean to nursing practice is the focus of this article. Definitions, history, and application of these concepts are explored. Recommendations are made that a hospital not assume responsibility for the granting of certification or credentials to nursing staff members. Nurses and nursing administrators are urged to support nationally recognized certification programs.

Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy.

A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.

Leukemia during pregnancy.

PURPOSE/OBJECTIVE: To review the literature on pregnancy and leukemia and present a case report that describes the effects of cancer treatment on a developing fetus. DATA SOURCES: Published articles, book chapters, personal observation. DATA SYNTHESIS: A diagnosis of acute myelogenous leukemia requires urgent initiation of intensive treatment. During pregnancy, chemotherapy treatment is determined by gestational development and the woman's general health status. CONCLUSIONS: Babies born to leukemic mothers treated after the first trimester rarely are affected by the disease. Meticulous medical and nursing management is critical to ensure that treatment and side effects do not adversely affect the baby or the patient. IMPLICATIONS FOR NURSING PRACTICE: Goals of care are to prevent bleeding, infection, injury, and premature delivery; to assist the patient and family in coping with a new diagnosis, alteration in role performance, and body image changes; and to maintain adequate nutritional status.

A balance of tastes. Chefs & dietitians roundtable discussion.

The demands from foodservice customers for healthier foods that also taste good have compelled chefs & dietitians to break off their traditional separation of powers & begin forming working partnerships. These new partnerships are producing menus that strike a balance just as new--a balance between the preferences & priorities of both professions. It means a combining of two different but not incompatible perspectives that magnifies both the pleasure & the benefit of the good food they serve. In recognition of these new partnerships, FM convened the first roundtable with chefs & dietitians, all of whom are on the leading edge of this emerging trend. Excerpts of their discussion reflect striking similarities in opinion--as well as differences still to be reconciled.

Organic osmolytes in the kidney of domesticated red deer, Cervus elaphus.

The cortex, inner and outer medulla, and papilla of kidneys of domestic red deer were analysed. In hydrated animals the urine concentration was found to be 672 +/- 45 mOsm.l-1. The medullary and papillary regions of the kidney were rich in the osmolytes betaine, glycerophosphorylcholine (GPC), inositol and sorbitol, all of which showed a steep rise in concentration from cortex to papilla. The kidney was rich in free amino acids, in particular taurine, glutamate (+glutamine), glycine and alanine, which were present at concentrations sufficient to suggest a possible role as osmolytes.

Nucleolar size polymorphisms in commercial layer chickens; determination of incidence, inheritance, and nucleolar sizes.

In the chicken, one chromosome pair encodes the ribosomal (r)RNA genes and two nucleoli are formed in interphase cells. The nucleolus is the site of rRNA synthesis and ribosome biogenesis. Nucleolar size polymorphisms have been detected in research strains of chickens and found to represent heterozygosity for rRNA gene copy number. The objectives of the present study were to determine whether nucleolar size polymorphisms exist in commercial chicken flocks and whether such polymorphisms are under genetic control. The occurrence of nucleolar size polymorphisms was studied in three lines of commercial layer chickens (designated A, B, and C). Nucleolar size polymorphisms were found in all three lines. However, the lines differed in the proportion of individuals exhibiting the polymorphic phenotype of two unequal-sized nucleoli (2P). The 2P phenotype, determined in successive years, was found in 10 to 14% of Line A birds, 18 to 23% of Line B birds, and 41 to 63% of Line C birds. The inheritance pattern of the nucleolar size polymorphism and nucleoli sizes were studied in Line C birds. The 2P phenotype was found to be inherited in Mendelian fashion. The large nucleolus was 1.7x and 1.6x that of the smaller nucleolus in 2P males and females, respectively, and was larger than the nucleoli of 2E birds (2E = nonpolymorphic phenotype of two equal-sized nucleoli). Total nucleolar size was greater in cells of 2P birds than in cells of 2E birds. These data suggest that the genetic basis for the large nucleolus in Line C 2P cells is a "larger than normal" rDNA cluster.

Phase I trial of valaciclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease.

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of < 150 cells per microliters) who received oral valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stable without any changes in underlying HIV-related medications for > or = 6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in < or = 31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not clinically significant. There were no renal or neurologic adverse events. Valaciclovir was rapidly absorbed and converted to acyclovir, with plasma valaciclovir levels generally undetectable or levels of < or = 0.4 microgram/ml. After 3 h postdosing, valaciclovir was not detectable in plasma. Acyclovir was measurable in plasma as early as 15 min following valaciclovir dosing, and plasma concentrations of acyclovir greatly exceeded those of valaciclovir. The mean values for the maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve from 0 h to infinity, and apparent half-life of acyclovir obtained after single- and multiple-dose valaciclovir administration in HIV-infected patients were similar to those reported in normal healthy volunteers. The time to maximum concentration in serum and half-life of acyclovir after valaciclovir administration were approximately 2 and 3 h, respectively, which were similar to those reported after oral administration of acyclovir itself. The mean trough and peak acyclovir concentrations and the daily area under the concentration-time curve acyclovir values at steady state were 2.5 and 8.4 micrograms/ml and 120 h micrograms/ml, respectively, after a dosage of 2,000 mg of valaciclovir four times daily. These values were approximately fivefold greater than those achieved with high dosages of oral acyclovir (800 mg, five times daily) and were not affected by continued use of medications necessary for management of advanced HIV disease. Thus, 2,000 mg of valaciclovir given orally four times daily should be evaluated for its potential efficacy in suppressing cytomegalovirus and other herpes group virus infections not optimally managed with current oral acyclovir therapy.

Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers.

The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (approximately threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

Pertussis is rare in human immunodeficiency virus disease.

Many adults are susceptible to pertussis, and Bordetella pertussis has been isolated from five patients with HIV disease. The prevalence of B. pertussis in 60 HIV-infected adults with nasopharyngeal (NP) swab cultures were studied and questionnaires were used that assessed HIV-related risk behaviors and disease status, immunization history, and symptoms of respiratory disease. Although 72% had cough and 33% had cough for > 14 days, no nasopharyngeal (NP) swab cultures were positive for Bordetella species. Of the 44 (73%) patients who had follow-up NP swab cultures at 6 months, all were still negative. On the basis of these data from our HIV-infected population, the estimated population prevalence of pertussis is zero, with an upper 95% confidence limit of 0.00065, or fewer than 6.5 cases of pertussis per 10,000 HIV-infected adults. Given this low prevalence, HIV-infected patients with respiratory symptoms do not appear to be a reservoir for B. pertussis in the community.