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Rationale: Firefighters are at risk for cardiovascular disease due to occupational-related inflammation, oxidative stress, and lifestyle practices. Astaxanthin (AX) possesses anti-inflammatory/antioxidant and purported ergogenic properties. This study examined the impact of supplementing the diet with 12 mg/d AX for four weeks on markers of inflammation, oxidative stress, cardiometabolic health, exercise capacity, and occupation-related performance in career firefighters., Methods: In a randomized, double-blinded, placebo-controlled, crossover fashion, 15 male career firefighters (34.5 ± 7.4 years; 177.7 ± 7.0 cm; 95.6 ± 12.0 kg; 30.1 ± 2.9 kg/m 2 ; 11.03 ± 6.85 years of service) ingested 12 mg/d of AX (AstaReal®, AstaReal AB, Nacka, SWE) or placebo (PLA) for four weeks while following a standardized resistance training program. After each treatment, testing sessions were completed to assess inflammatory markers, oxidative stress markers, cardiopulmonary exercise capacity, and performance to a fire ground test (FGT) consisting of nine fire suppressive activities. Data were analyzed using general linear model (GLM) analysis with repeated measures. Clinical significance was assessed via mean changes from baseline with 95% confidence intervals., Results: Analysis of mean percent changes from baseline revealed that AX supplementation lessened the inflammatory response to to performing an incremental maximal exercise test and attenuated increases in interleukin-1β, cortisol, and uric acid in response to performing fire suppressive activities compared to when they ingested PLA. However, most of these effects were within groups rather than between groups. Additionally, there was evidence that AX ingestion increased the ventilatory anaerobic threshold. Four weeks of AX supplementation did not significantly affect fasting markers of oxidative stress, blood lipids, performance during the FGT, general clinical chemistry panels, or self-reported side effects., Conclusions: Results provide some evidence that AX supplementation may help mediate occupation-related inflammation in response to high-intensity, short-duration exercise in firefighters. More research is warranted to determine if long-term supplementation can improve cardiometabolic risk in this population., Clinical Trial Registration: ISRCTN10901752.

Phaeodactylum tricornutum ( PT ) is a microalgae extract that contains fucoxanthin and has been shown to enhance cognitive function in younger populations. The present study assessed if PT supplementation affects cognition in healthy, young-old, physically active adults with self-perceptions of cognitive and memory decline., Methods: Forty-three males and females (64.3 ± 6.0 years, 79.8 ± 16.0 kg, 27.0 ± 4.0 kg/m 2 ) with perceptions of cognitive and memory decline completed the double-blind, randomized, parallel-arm, placebo-controlled intervention clinical trial. Participants were counterbalanced by sex and BMI and randomly allocated to their respective 12-week supplementation interventions, which were either the placebo (PL) or 1100 mg/day of PT containing 8.8 mg of fucoxanthin (FX). Fasting blood samples were collected, and cognitive assessments were performed during the testing session at 0, 4, and 12 weeks of intervention. The data were analyzed by multivariate and univariate general linear model (GLM) analyses with repeated measures, pairwise comparisons, and mean changes from baseline analysis with 95% confidence intervals (CIs) to assess the clinical significance of the findings., Results: FX supplementation significantly affected ( p < 0.05) or exhibited tendencies toward significance ( p > 0.05 to p < 0.10 with effect sizes ranging from medium to large) for word recall, picture recognition reaction time, Stroop color-word test, choice reaction time, and digit vigilance test variables. Additionally, FX supplementation promoted a more consistent clinical improvement from baseline values when examining mean changes with 95% CIs, although most differences were seen over time rather than between groups., Conclusions: The results demonstrate some evidence that FX supplementation can improve working and secondary memory, vigilance, attention, accuracy, and executive function. There was also evidence that FX promoted more positive effects on insulin sensitivity and perceptions about sleep quality with no negative effects on clinical blood panels or perceived side effects. Additional research should investigate how FX may affect cognition in individuals perceiving memory and cognitive decline. Registered clinical trial #NCT05759910.

Background: Ashwagandha has been reported to reduce stress and attenuate cognitive decline associated with inflammation and neurodegeneration in clinical populations. However, the effects as a potential nootropic nutrient in younger populations are unclear. This study examined the effects of liposomal ashwagandha supplementation on cognitive function, mood, and markers of health and safety in healthy young men and women., Methods: 59 men and women (22.7 ± 7 yrs., 74.9 ± 16 kg, 26.2 ± 5 BMI) fasted for 12 h, donated a fasting blood sample, and were administered the COMPASS cognitive function test battery (Word Recall, Word recognition, Choice Reaction Time Task, Picture Recognition, Digit Vigilance Task, Corsi Block test, Stroop test) and profile of mood states (POMS). In a randomized and double-blind manner, participants were administered 225 mg of a placebo (Gum Arabic) or ashwagandha ( Withania somnifera ) root and leaf extract coated with a liposomal covering. After 60-min, participants repeated cognitive assessments. Participants continued supplementation (225 mg/d) for 30 days and then returned to the lab to repeat the experiment. Data were analyzed using a general linear model (GLM) univariate analysis with repeated measures and pairwise comparisons of mean changes from baseline with 95% confidence intervals (CI)., Results: Ashwagandha supplementation improved acute and/or 30-day measures of Word Recall (correct and recalled attempts), Choice Reaction Time (targets identified), Picture Recognition ("yes" correct responses, correct and overall reaction time), Digit Vigilance (correct reaction time), Stroop Color-Word (congruent words identified, reaction time), and POMS (tension and fatigue) from baseline more consistently with several differences observed between groups., Conclusion: Results support contentions that ashwagandha supplementation (225 mg) may improve some measures of memory, attention, vigilance, attention, and executive function while decreasing perceptions of tension and fatigue in younger healthy individuals. Retrospectively registered clinical trial ISRCTN58680760.

Background: This study evaluates a novel multidisciplinary program providing expanded access to hepatitis C virus (HCV) treatment for rural Appalachian patients in South Carolina. This program identified patients via an opt-out emergency department screening program, and it aimed to achieve HCV cure by using community paramedics (CPs) to link and monitor patients from treatment initiation through 12-week sustained virologic response (SVR)., Methods: Patients aged ≥18 years who were HCV RNA positive were eligible for enrollment if they failed to appear for a scheduled HCV appointment or reported barriers to accessing office-based treatment. CPs provided home visits (initial and 4, 12, and 24 weeks) using a mobile Wi-Fi hotspot to support telemedicine appointments (compliant with the Health Insurance Portability and Accountability Act) and perform focused physical assessments, venipuncture, and coordinated home delivery of medications. Statistics described participant characteristics, prevalence of SVR, and patient satisfaction results at 12 weeks posttreatment., Results: Thirty-four patients were eligible for SVR laboratory tests by 31 August 2023; the majority were male (61.7%) and White (64.7%) with an average age of 56 years (SD, 11.7). Twenty-eight (82.4%) completed treatment and achieved 12-week SVR. Six (17.6%) were lost to follow-up. Two-thirds strongly agreed that they were satisfied with the overall care that they received, and half strongly agreed that their overall health had improved., Conclusions: This CP-augmented treatment program demonstrated success curing HCV for rural patients who lacked access to office-based treatment. Other health care systems may consider this novel delivery model to treat hard-to-reach individuals who are HCV positive., Competing Interests: Potential conflicts of interest. A. H. L. has served on advisory board for Merck Pharmaceuticals, AbbVie and Gilead Sciences. A. H. L. has received research grants from Merck Pharmaceuticals and Gilead Sciences. P. M. has received research grants from Gilead Sciences. No other authors declared any conflict of interest related to this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Transfusion of blood products is life-saving and time-sensitive in the setting of acute blood-loss anemia, and is increasingly common in the emergency medical services (EMS) setting. Prehospital blood products are generally "cold-stored" at 4°C, then warmed with a portable fluid-warming system for the purpose of preventing the "lethal triad" of hypothermia, acidosis, and coagulopathy. This study aims to evaluate body temperature changes of EMS patients receiving packed red blood cells (PRBC) and/or fresh frozen plasma (FFP) when using the LifeWarmer Quantum Blood & Fluid Warming System (LifeWarmer, https://www.lifewarmer.com/)., Methods: From 1 January 2020 to 31 August 2021, patients who qualified for and received PRBC and/or FFP were retrospectively reviewed. Body-temperature homeostasis pre- and post-transfusion were evaluated with attention given to those who arrived to the emergency department (ED) hypothermic (<36°C)., Results: For all 69 patients analyzed, the mean initial prehospital temperature (°C) was 36.5 ± 1.0, and the mean initial ED temperature was 36.7 ± 0.6, demonstrating no statically significant change in value pre- or post-transfusion (0.2 ± 0.8, p = .09). Shock index showed a statistically significant decrease following transfusion: 1.5 ± 0.5 to 0.9 ± 0.4 (p < .001)., Conclusion: Use of the Quantum prevents the previously identified risk of hypothermia with respect to unwarmed prehospital transfusions. The data is favorable in that body temperature did not decrease in critically ill patients receiving cold-stored blood warmed during administration with the Quantum., (2023.)

Despite technological advancement, nosocomial infections are prevalent due to the rise of antibiotic resistance. A combinatorial approach with multimechanistic antibacterial activity is desired for an effective antibacterial medical device surface strategy. In this study, an antimicrobial peptide, nisin, is immobilized onto biomimetic nitric oxide (NO)-releasing medical-grade silicone rubber (SR) via mussel-inspired polydopamine (PDA) as a bonding agent to reduce the risk of infection. Immobilization of nisin on NO-releasing SR (SR-SNAP-Nisin) and the surface characteristics were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy with energy-dispersive X-ray spectroscopy and contact angle measurements. The NO release profile (7 days) and diffusion of SNAP from SR-SNAP-Nisin were quantified using chemiluminescence-based nitric oxide analyzers and UV-vis spectroscopy, respectively. Nisin quantification showed a greater affinity of nisin immobilization toward SNAP-doped SR. Matrix-assisted laser desorption/ionization mass spectrometry analysis on surface nisin leaching for 120 h under physiological conditions demonstrated the stability of nisin immobilization on PDA coatings. SR-SNAP-Nisin shows versatile in vitro anti-infection efficacy against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus in the planktonic and adhered states. Furthermore, the combination of NO and nisin has a superior ability to impair biofilm formation on polymer surfaces. SR-SNAP-Nisin leachates did not elicit cytotoxicity toward mouse fibroblast cells and human umbilical vein endothelial cells, indicating the biocompatibility of the material in vitro . The preventative and therapeutic potential of SR-SNAP-Nisin dictated by two bioactive agents may offer a promising antibacterial surface strategy.

Biomedical surface-associated infections and thrombus formation are two major clinical issues that challenge patient safety and patient the fate of a medical device in the body . Single platform multifunctional surfaces are critical to address both these indwelling medical device-related problems. In this work, bio-inspired approaches are employed to fabricate a polymer composite with a versatile surface that can reduce bacterial infections and platelet adhesion in vitro. In the first bio-inspired approach, the functionality of nitric oxide (NO) produced by endothelial cell lining of blood vessels is mimicked through incorporation of S-nitroso-N-acetylpenicillamine (SNAP) within a CarboSil-2080A™ (CarboSil) polymer composite matrix. The second approach involves utilizing mussel adhesive chemistry, via polydopamine (PDA) to immobilize polytetrafluoroethylene (PTFE) particles on the polymer composite surface. The PTFE coating facilitates a decrease in wettability by making the polymer composite surface highly hydrophobic (contact angle ca. 120°). The surface of the fabricated polymer composite , CarboSil SNAP-PTFE, had a cobblestone-like structured appearance as characterized through scanning electron microscopy (SEM). Water contact angle (WCA) and surface tension measurements indicated no significant coating losses after 24 h under physiological conditions. NO surface flux was measured and analyzed for 5 days using a chemiluminescence-based nitric oxide analyzer and was found to be within the physiological range. CarboSil SNAP-PTFE reduced adhered bacteria (99.3 ± 0.5% for Gram-positive S. aureus and 99.1 ± 0.4% for Gram-negative E. coli) in a 24 h in vitro study. SEM analysis showed the absence of biofilm formation on CarboSil SNAP-PTFE polymer composites, while present on CarboSil in 24 h exposure to S. aureus. Platelet adhesion was reduced by 83.3 ± 4.5%. Overall, the results of this study suggest that a combination of NO-releasing CarboSil with PTFE coating can drastically reduce infection and platelet adhesion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Dr. Hitesh Handa is the founder of inNOveta Biomedical LLC. inNOveta Biomedical LLC is exploring possibilities of using nitric oxide releasing materials for medical applications.’., (Copyright © 2020 Elsevier Inc. All rights reserved.)

By collecting data at spatial and temporal scales that are inaccessible to satellite and field observation, unmanned aerial vehicles (UAVs) are revolutionizing a number of scientific and management disciplines. UAVs may be particularly valuable for precision agricultural applications, offering strong potential to improve the efficiency of water, nutrient, and disease management. However, some authors have suggested that the UAV industry has overhyped the potential value of this technology for agriculture, given that it is difficult for non-specialists to operate UAVs as well as to process and interpret the resulting data. Here, we analyze the barriers to applying UAVs for precision agriculture, which range from regulatory issues to technical requirements. We then evaluate how new developments in the nano- and micro-UAV (NAV and MAV, respectively) markets may help to overcome these barriers. Among the possible breakthroughs that we identify is the ability of NAV/MAV platforms to directly quantify plant traits using methods (e.g., object-oriented classification) that require less image calibration and interpretation than spectral index-based approaches. We suggest that this potential, when combined with steady improvements in sensor miniaturization, flight precision, and autonomy as well as cloud-based image processing, will make UAVs a tool with much broader adoption by agricultural managers in the near future. If this wider uptake is realized, then UAVs have real potential to improve agriculture's resource-use efficiency. © 2020 by John Wiley & Sons, Inc., (© 2020 John Wiley & Sons, Inc.)

To understand ecological phenomena, it is necessary to observe their behaviour across multiple spatial and temporal scales. Since this need was first highlighted in the 1980s, technology has opened previously inaccessible scales to observation. To help to determine whether there have been corresponding changes in the scales observed by modern ecologists, we analysed the resolution, extent, interval and duration of observations (excluding experiments) in 348 studies that have been published between 2004 and 2014. We found that observational scales were generally narrow, because ecologists still primarily use conventional field techniques. In the spatial domain, most observations had resolutions ≤1 m 2 and extents ≤10,000 ha. In the temporal domain, most observations were either unreplicated or infrequently repeated (>1 month interval) and ≤1 year in duration. Compared with studies conducted before 2004, observational durations and resolutions appear largely unchanged, but intervals have become finer and extents larger. We also found a large gulf between the scales at which phenomena are actually observed and the scales those observations ostensibly represent, raising concerns about observational comprehensiveness. Furthermore, most studies did not clearly report scale, suggesting that it remains a minor concern. Ecologists can better understand the scales represented by observations by incorporating autocorrelation measures, while journals can promote attentiveness to scale by implementing scale-reporting standards.

Land cover maps increasingly underlie research into socioeconomic and environmental patterns and processes, including global change. It is known that map errors impact our understanding of these phenomena, but quantifying these impacts is difficult because many areas lack adequate reference data. We used a highly accurate, high-resolution map of South African cropland to assess (1) the magnitude of error in several current generation land cover maps, and (2) how these errors propagate in downstream studies. We first quantified pixel-wise errors in the cropland classes of four widely used land cover maps at resolutions ranging from 1 to 100 km, and then calculated errors in several representative "downstream" (map-based) analyses, including assessments of vegetative carbon stocks, evapotranspiration, crop production, and household food security. We also evaluated maps' spatial accuracy based on how precisely they could be used to locate specific landscape features. We found that cropland maps can have substantial biases and poor accuracy at all resolutions (e.g., at 1 km resolution, up to ∼45% underestimates of cropland (bias) and nearly 50% mean absolute error (MAE, describing accuracy); at 100 km, up to 15% underestimates and nearly 20% MAE). National-scale maps derived from higher-resolution imagery were most accurate, followed by multi-map fusion products. Constraining mapped values to match survey statistics may be effective at minimizing bias (provided the statistics are accurate). Errors in downstream analyses could be substantially amplified or muted, depending on the values ascribed to cropland-adjacent covers (e.g., with forest as adjacent cover, carbon map error was 200%-500% greater than in input cropland maps, but ∼40% less for sparse cover types). The average locational error was 6 km (600%). These findings provide deeper insight into the causes and potential consequences of land cover map error, and suggest several recommendations for land cover map users., (© 2017 John Wiley & Sons Ltd.)

Agriculture is the leading driver of biodiversity loss. However, its future impact on biodiversity remains unclear, especially because agricultural intensification is often neglected, and high path-dependency is assumed when forecasting agricultural development-although the past suggests that shock events leading to considerable agricultural change occur frequently. Here, we investigate the possible impacts on biodiversity of pathways of expansion and intensification. Our pathways are not built to reach equivalent production targets, and therefore they should not be directly compared; they instead highlight areas at risk of high biodiversity loss across the entire option space of possible agricultural change. Based on an extensive database of biodiversity responses to agriculture, we find 30% of species richness and 31% of species abundances potentially lost because of agricultural expansion across the Amazon and Afrotropics. Only 21% of high-risk expansion areas in the Afrotropics overlap with protected areas (compared with 43% of the Neotropics). Areas at risk of biodiversity loss from intensification are found in India, Eastern Europe and the Afromontane region (7% species richness, 13% abundance loss). Many high-risk regions are not adequately covered by conservation prioritization schemes, and have low national conservation spending and high agricultural growth. Considering rising agricultural demand, we highlight areas where timely land-use planning may proactively mitigate biodiversity loss.

Rapidly rising populations and likely increases in incomes in sub-Saharan Africa make tens of millions of hectares of cropland expansion nearly inevitable, even with large increases in crop yields. Much of that expansion is likely to occur in higher rainfall savannas, with substantial costs to biodiversity and carbon storage. Zambia presents an acute example of this challenge, with an expected tripling of population by 2050, good potential to expand maize and soya bean production, and large areas of relatively undisturbed miombo woodland and associated habitat types of high biodiversity value. Here, we present a new model designed to explore the potential for targeting agricultural expansion in ways that achieve quantitatively optimal trade-offs between competing economic and environmental objectives: total converted land area (the reciprocal of potential yield); carbon loss, biodiversity loss and transportation costs. To allow different interests to find potential compromises, users can apply varying weights to examine the effects of their subjective preferences on the spatial allocation of new cropland and its costs. We find that small compromises from the objective to convert the highest yielding areas permit large savings in transportation costs, and the carbon and biodiversity impacts resulting from savannah conversion. For example, transferring just 30% of weight from a yield-maximizing objective equally between carbon and biodiversity protection objectives would increase total cropland area by just 2.7%, but result in avoided costs of 27-47% for carbon, biodiversity and transportation. Compromise solutions tend to focus agricultural expansion along existing transportation corridors and in already disturbed areas. Used appropriately, this type of model could help countries find agricultural expansion alternatives and related infrastructure and land use policies that help achieve production targets while helping to conserve Africa's rapidly transforming savannahs.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'., (© 2016 The Author(s).)

Piperacillin-tazobactam (PTZ) is known to cause false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA), due to contamination with galactomannan (GM). We tested 32 lots of PTZ and 27 serum specimens from patients receiving PTZ. GM was not detected in the lots of PTZ; one serum specimen (3.7%) was positive. PTZ formulations commonly used in the United States today appear to be a rare cause for false-positive GM results., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

A method is described for modeling the effects of spatial apertures on optical sensor systems. The method consists of defining a set of basis functions that is obtained by partitioning the aperture image plane into a series of rectangular regions and replacing the field in each rectangular subregion with an orthogonal function series approximation. Each orthogonal function has a finite extent that is matched to the aperture image. The individual functions are propagated by application of the Fresnel approximation of the Rayleigh-Sommerfeld diffraction formula to other ranges, and the resultant functions are shown to be valid basis functions for defining a field at any other range. The technique is applied to a scattering problem using complex Fourier series.

The linear mechanism for optical-to-acoustic energy conversion is explored for optoacoustic communication from an in-air platform or surface vessel to a submerged vessel such as a submarine or unmanned undersea vehicle. The communication range that can be achieved is addressed. A number of conventional signals used in underwater acoustic telemetry applications are shown to be capable of being generated experimentally through the linear optoacoustic regime conversion process. These results are in agreement with simulation based on current theoretical models. A number of practical issues concerning linear optoacoustic communication are addressed that lead to a formulation of a linear-regime optoacoustic communication scheme. The use of oblique laser beam incidence at the air-water interface to obtain considerable in-air range from the laser source to the in-water receiver is addressed. Also, the effect of oblique incidence on in-water range is examined. Next, the optimum and suboptimum linear optoacoustic sound-generation techniques for selecting the optical wavelength and signaling frequency for optimizing in-water range are addressed and discussed. Optoacoustic communication techniques employing M-ary frequency shift keying and multifrequency shift keying are then compared with regard to communication parameters such as bandwidth, data rate, range coverage, and number of lasers employed.

Purpose: Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study., Methods: Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs., Results: Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD., Conclusions: These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.

Many analogues of the antitumor agent irofulven have been readily prepared by replacing the allylic hydroxyl with a variety of nucleophiles. Analogues of acylfulvene (the precursor to irofulven) were also prepared by Michael reaction with acrolein. The toxicity of the analogues was determined, as well as preclinical antitumor activity. Several analogues exhibited good activity in mouse xenografts. Structural requirements for activity are discussed.

Objective: To reduce prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery by using a targeted allergy consultation and penicillin allergy skin testing., Patients and Methods: The participants in this practice improvement study were patients with a history of penicillin or cephalosporin allergy who were scheduled for elective orthopedic surgery and referred by orthopedic surgeons for allergy consultation and penicillin allergy skin testing between September 22, 1998, and April 15, 1999. The primary outcome measure was the percentage of participants who received prophylactic cefazolin during the study period compared with historical controls., Results: Of the 60 study patients, 59 received a penicillin allergy skin test, 58 underwent orthopedic surgery, and 55 received antibiotic prophylaxis. Fifty-five patients had a history of allergy to penicillin, a cephalosporin, or both, and 5 had a history of nonspecific antibiotic allergy. Of the 59 patients, 55 (93%) had negative penicillin allergy skin test results. Fifty-four (90%) of the 60 patients were given clearance by the allergist to receive cefazolin. Of the 55 study patients who received antibiotic prophylaxis, 6 (11%) received vancomycin compared with 38 (30%) of 127 historical controls (P < or = .05). None of the study patients had an immediate reaction to cefazolin or to vancomycin., Conclusion: Prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery can be reduced by a targeted allergy consultation and penicillin allergy skin testing.

This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agents. MGI 114 is a novel semisynthetic anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human MDR1/gp170+ solid tumor xenografts. Recent evidence suggests overexpression of the MRP protein may also be clinically relevant to development of drug resistance in solid tumors. We evaluated the efficacy of MGI 114 against a human MRP+ lung carcinoma xenograft. Parent MV522 lung carcinoma cells were transfected with a MRP cDNA expression vector and resistant cells selected by exposure to vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP mRNA and MRP protein. Administration of MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x/week for 3 weeks) to MRP tumor-bearing mice demonstrated this novel agent was active against MRP+ tumors and significantly extended their lifespan (p<0.001). In contrast, other cytotoxic agents had minimal activity against this MRP+ xenograft. These results indicate MGI 114 should retain activity in vivo against MRP+ tumor types. The development of this MRP+ xenograft model, in conjunction with the parent MV522 and MDR1/gp170+ xenograft models, will be useful for screening new classes of agents for activity against multidrug-resistant tumors.

Background: Antiretroviral therapy for HIV-1 infection has become increasingly complex. The availability of new and potent drugs and progress in understanding the pathogenesis of HIV-1 infection have led to the establishment of new treatment paradigms. The varying dosing regimens, associated toxicities, and the potential for drug-drug and food-drug interactions further complicate treatment. This complexity contributes to patient nonadherence. Because clinicians have no tools to monitor adherence or drug-drug interactions and because response requires that therapy exceed the known inhibiting concentration, serum monitoring of antiretroviral therapy may play a role in improving treatment of HIV-1 infection. We report methods to quantify serum concentrations of antiretroviral drugs used to treat HIV-1 infection, precision and interference studies of these methods, and results observed in a pilot evaluation of blood serum concentrations from 12 human subjects., Methods: HPLC offers adequate sensitivity to measure peak or trough serum concentrations of delavirdine, lamivudine, nevirapine, indinavir, nelfinavir, ritonavir, and saquinavir and peak serum concentrations of stavudine, zidovudine, and didanosine with reasonable precision., Results: Peak indinavir serum concentrations in most patients were in the range of 1-10 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak stavudine concentrations were in the range of 0.3-1.3 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak zidovudine concentrations were in the range of 0.1-1.1 mg/L., Conclusions: Because this was a blood serum concentration-seeking pilot study to evaluate analytic performance, we do not report on the correlation of drug response to blood concentration. However, the concentrations observed in patients are generally consistent with blood concentrations reported from studies of monotherapy.

Objective: To describe the development, test-retest reliability, internal consistency, and convergent validity of the McKnight Risk Factor Survey-III (MRFS-III). The MRFS-III was designed to assess a number of potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls., Method: Several versions of the MRFS were pilot tested before the MRFS-III was administered to a sample of 651 4th through 12th- grade girls to establish its psychometric properties., Results: Most of the test-retest reliability coefficients of individual items on the MRFS-III were r > .40. Alpha coefficients for each risk and protective factor domain on the MRFS-III were also computed. The majority of these coefficients were r > .60. High convergent validity coefficients were obtained for specific items on the MRFS-III and measures of self-esteem (Rosenberg Self-Esteem Scale) and weight concerns (Weight Concerns Scale)., Conclusions: The test-retest reliability, internal consistency, and convergent validity of the MRFS-III suggest that it is a useful new instrument to assess potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls.

Purpose: The acylfulvenes are a class of antitumor agents derived from the fungal toxin illudin S. One acylfulvene derivative, MGI 114 (HMAF), demonstrates marked efficacy in xenograft carcinoma models when compared to the parent acylfulvene or related illudin compounds. The maximum tolerated dose (MTD) of the two analogs in animals, however, is similar. To help elucidate the basis of the increased therapeutic efficacy of MGI 114, we determined the in vitro cytotoxicity, cellular accumulation and DNA incorporation of this drug and compared the results with those from the parent acylfulvene analog., Methods: The cytotoxicity of acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabeled MGI 114 was used for cellular accumulation and DNA incorporation studies., Results: MGI 114 retained relative histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines previously noted with the parent acylfulvene compound. Markedly fewer intracellular molecules of MGI 114 were required to kill human tumor cells in vitro as compared to the parent acylfulvene, indicating that MGI 114 was markedly more toxic on a cellular level. At equitoxic concentrations, however, the incorporation of MGI 114 into genomic tumor cell DNA was equivalent to that of acylfulvene. Analysis of cellular accumulation of MGI 114 into tumor cells revealed a lower Vmax for tumor cells, and a markedly lower Vd for diffusion accumulation as compared to acylfulvene., Conclusions: The addition of a single methylhydroxyl group to acylfulvene to produce MGI 114 results in a marked increase in cytotoxicity in vitro towards tumor cells as demonstrated by the reduction in IC50 values. There was a corresponding decrease in the number of intracellular molecules of MGI 114 required to kill tumor cells, but no quantitative alteration in covalent binding of the drugs to DNA at equitoxic concentrations. This indicates that cellular metabolism plays a role in the in vitro cytotoxicity of MGI 114. The equivalent incorporation into genomic DNA at equitoxic doses suggests that DNA damage produced by acylfulvene and MGI 114 is equivalent in regard to cellular toxicity and ability to repair DNA. This increased cellular toxicity, together with the decrease in diffusion rate, may explain the increased therapeutic efficacy of MGI 114 as compared to the parent acylfulvene analog.

Pharmacokinetics is a science that has long been used in ascertaining the appropriate antimicrobial dose. It refers to the disposition of drugs in the body and includes absorption, bioavailability, distribution, protein binding, metabolism, and elimination. Pharmacodynamics is a newer science that relates to the interaction between the drug concentration at the site of action over time and the desired antimicrobial effect. This article reviews the principles of pharmacokinetics and pharmacodynamics as well as the clinical application of these two sciences to design antimicrobial dosing regimens for optimal results in individual patients.

Objective: This study examined the association of weight concerns with potential risk factors for the development of eating disorders., Method: A self-report survey was given to 103 elementary (Grades 4 and 5) and 420 middle (Grades 6-8) school students in Arizona and California. Of these, 78 elementary and 333 middle school students provided complete data and were used in the analyses., Results: In a multivariate stepwise regression analysis, the importance that peers put on weight and eating was most strongly related to weight concerns in the elementary school girls, accounting for 34% of the variance after adjusting for site differences. Trying to look like girls/women on TV and in magazines as well as body mass index (BMI) entered the final model that accounted for 57% of the variance in weight concerns. In middle school, the importance that peers place on weight and eating was also the strongest predictor accounting for 33% of the variance followed by confidence, BMI, trying to look like girls/women on TV and in magazines, and being teased about weight. Together these variables accounted for 55% of the variance., Discussion: Prevention programs aimed at reducing weight concerns need to address these factors.

Objective: The purpose of this study was to assess the association between attachment style and weight concerns, a major risk factor for eating disorders, in preadolescent and adolescent girls., Method: Three hundred and five female elementary and middle school students completed measures of attachment style and weight concerns., Results: Insecurely attached subjects reported higher weight concerns than did securely attached subjects. A greater proportion of insecurely attached subjects obtained "at risk" weight concerns scores than securely attached subjects., Discussion: The findings suggest that attachment style may play an important role in the development of weight concerns, which, in turn, have been shown to be associated with the onset of eating disorders.

Purpose: Acylfulvene derivatives demonstrate marked efficacy in xenograft carcinoma models as compared with the parent illudin compounds. To elucidate the increased therapeutic efficacy of acylfulvene analogs, we compared them with the illudin compounds in terms of their in vitro cytotoxicity, cellular accumulation and DNA incorporation., Methods: The cytotoxicity of various acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabelled acylfulvene analog was prepared and used for cellular accumulation and DNA incorporation studies., Results: The prototype acylfulvene analog retained selective histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines. In vitro killing of tumor cells by acylfulvene required up to a 30-fold increase in molecules per cell, as compared with illudin S, indicating that acylfulvene was less toxic on a cellular level. At equitoxic concentrations, acylfulvene incorporation into genomic tumor cell DNA was equivalent to illudin S suggesting that cellular metabolism has a role in acylfulvene cytotoxicity. Analysis of cellular accumulation of acylfulvene into tumor cells revealed a markedly higher Vmax for tumor cells, and a lower Vd for diffusion accumulation into other cells., Conclusions: The combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.