Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects.

The ex vivo bactericidal activity and pharmacodynamics of fosfomycin in urine were evaluated in 18 healthy subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses or vice versa. Serial urine samples were collected before and up to 24 h after dosing on days 1 and 5. Eight bacterial strains with various genotypic and phenotypic susceptibilities to fosfomycin were used for all experiments (5 Escherichia coli, 2 Klebsiella pneumoniae, and 1 Proteus mirabilis). MICs were performed via agar dilution. Urinary bactericidal titers (UBTs) were performed via modified Schlichter test using participant's drug-free urine as the diluent. Urinary time-kill analyses were performed on pooled 24-h urine aliquots from days 1 and 5. All experiments were performed in triplicate with and without the addition of 25 mg/liter of glucose-6-phosphate (G6P). Mean 24-h urine concentrations of fosfomycin ranged from 324.7 to 434.6 mg/liter regardless of study day or dosing regimen. The urinary antibacterial activity of fosfomycin was also similar across study days and dosing regimens. UBT values did not correlate with MICs determined in the presence of G6P. Fosfomycin was reliably bactericidal in urine only against the 5 E. coli strains, regardless of genotype or MIC value. Together, these data do not support the use of oral fosfomycin tromethamine for pathogens other than E. coli or at a dosing frequency higher than QOD. Fosfomycin MICs determined in the presence of G6P may not accurately reflect the in vivo activity given the lack of G6P in human urine. (This study has been registered at ClinicalTrials.gov under identifier NCT02570074.).

The influence of the biological pump on ocean chemistry: implications for long-term trends in marine redox chemistry, the global carbon cycle, and marine animal ecosystems.

The net export of organic matter from the surface ocean and its respiration at depth create vertical gradients in nutrient and oxygen availability that play a primary role in structuring marine ecosystems. Changes in the properties of this 'biological pump' have been hypothesized to account for important shifts in marine ecosystem structure, including the Cambrian explosion. However, the influence of variation in the behavior of the biological pump on ocean biogeochemistry remains poorly quantified, preventing any detailed exploration of how changes in the biological pump over geological time may have shaped long-term shifts in ocean chemistry, biogeochemical cycling, and ecosystem structure. Here, we use a 3-dimensional Earth system model of intermediate complexity to quantitatively explore the effects of the biological pump on marine chemistry. We find that when respiration of sinking organic matter is efficient, due to slower sinking or higher respiration rates, anoxia tends to be more prevalent and to occur in shallower waters. Consequently, the Phanerozoic trend toward less bottom-water anoxia in continental shelf settings can potentially be explained by a change in the spatial dynamics of nutrient cycling rather than by any change in the ocean phosphate inventory. The model results further suggest that the Phanerozoic decline in the prevalence ocean anoxia is, in part, a consequence of the evolution of larger phytoplankton, many of which produce mineralized tests. We hypothesize that the Phanerozoic trend toward greater animal abundance and metabolic demand was driven more by increased oxygen concentrations in shelf environments than by greater food (nutrient) availability. In fact, a lower-than-modern ocean phosphate inventory in our closed system model is unable to account for the Paleozoic prevalence of bottom-water anoxia. Overall, these model simulations suggest that the changing spatial distribution of photosynthesis and respiration in the oceans has exerted a first-order control on Earth system evolution across Phanerozoic time.

Efficacy of sporicidal wipes for inactivation of a Bacillus anthracis surrogate.

AIMS: To evaluate five commercially available sporicidal wipes and two disinfecting wipes for their ability to inactivate Bacillus atrophaeus spores deposited onto various material surfaces. METHODS AND RESULTS: Decontamination efficacy of the wipes was initially tested on glass Petri dishes (150 mm diameter). Following exposure for a specified time of contact, survival of the spores was assessed by quantification of the remaining viable spores, both on the coupon surface and on the towelette itself, with efficacy quantified in terms of mean log reduction. Based on these data, five wipes were down-selected for evaluation on a larger scale, using 36 × 36 cm coupons of five different material types. CONCLUSIONS: Results suggest that sodium hypochlorite-based sporicidal wipes were most effective, having completely inactivated the Bacillus spores on the glass Petri dish and several materials. Additionally, results demonstrate that the manufacturer-prescribed contact times for Clostridium difficile achieved a 6 log10 reduction of B. atrophaeus spores. Moreover, commercially available disinfecting wipes were not able to kill Bacillus spores as evaluated. SIGNIFICANCE AND IMPACT OF THE STUDY: These data show the potential of sporicidal wipes for decontamination of small, contained areas of biological contamination and may help on-scene coordinators develop remediation plans following a biological terrorism event.

Robustness and management adaptability in tropical rangelands: a viability-based assessment under the non-equilibrium paradigm.

Rangelands provide the main forage resource for livestock in many parts of the world, but maintaining long-term productivity and providing sufficient income for the rancher remains a challenge. One key issue is to maintain the rangeland in conditions where the rancher has the greatest possibility to adapt his/her management choices to a highly fluctuating and uncertain environment. In this study, we address management robustness and adaptability, which increase the resilience of a rangeland. After reviewing how the concept of resilience evolved in parallel to modelling views on rangelands, we present a dynamic model of rangelands to which we applied the mathematical framework of viability theory to quantify the management adaptability of the system in a stochastic environment. This quantification is based on an index that combines the robustness of the system to rainfall variability and the ability of the rancher to adjust his/her management through time. We evaluated the adaptability for four possible scenarios combining two rainfall regimes (high or low) with two herding strategies (grazers only or mixed herd). Results show that pure grazing is viable only for high-rainfall regimes, and that the use of mixed-feeder herds increases the adaptability of the management. The management is the most adaptive with mixed herds and in rangelands composed of an intermediate density of trees and grasses. In such situations, grass provides high quantities of biomass and woody plants ensure robustness to droughts. Beyond the implications for management, our results illustrate the relevance of viability theory for addressing the issue of robustness and adaptability in non-equilibrium environments.

Fumigation of a laboratory-scale HVAC system with hydrogen peroxide for decontamination following a biological contamination incident.

AIMS: To evaluate hydrogen peroxide vapour (H2 O2 ) for its ability to inactivate Bacillus spores within a laboratory-scale heating, ventilation and air-conditioning (HVAC) duct system. METHODS AND RESULTS: Experiments were conducted in a closed-loop duct system, constructed of either internally lined or unlined galvanized metal. Bacterial spores were aerosol-deposited onto 18-mm-diameter test material coupons and strategically placed at several locations within the duct environment. Various concentrations of H2 O2 and exposure times were evaluated to determine the sporicidal efficacy and minimum exposure needed for decontamination. For the unlined duct, high variability was observed in the recovery of spores between sample locations, likely due to complex, unpredictable flow patterns within the ducts. In comparison, the lined duct exhibited a significant desorption of the H2 O2 following the fumigant dwell period and thus resulted in complete decontamination at all sampling locations. CONCLUSIONS: These findings suggest that decontamination of Bacillus spore-contaminated unlined HVAC ducts by hydrogen peroxide fumigation may require more stringent conditions (higher concentrations, longer dwell duration) than internally insulated ductwork. SIGNIFICANCE AND IMPACT OF THE STUDY: These data may help emergency responders when developing remediation plans during building decontamination.

Carotenoid biomarkers as an imperfect reflection of the anoxygenic phototrophic community in meromictic Fayetteville Green Lake.

Organic biomarkers in marine sedimentary rocks hold important clues about the early history of Earth's surface environment. The chemical relicts of carotenoids from anoxygenic sulfur bacteria are of particular interest to geoscientists because of their potential to signal episodes of marine photic-zone euxinia such as those proposed for extended periods in the Proterozoic as well as brief intervals during the Phanerozoic. It is therefore critical to constrain the environmental and physiological factors that influence carotenoid production and preservation in modern environments. Here, we present the results of coupled pigment and nucleic acid clone library analyses from planktonic and benthic samples collected from a microbially dominated meromictic lake, Fayetteville Green Lake (New York). Purple sulfur bacteria (PSB) are abundant and diverse both in the water column at the chemocline and in benthic mats below oxygenated shallow waters, with different PSB species inhabiting the two environments. Okenone (from PSB) is an abundant carotenoid in both the chemocline waters and in benthic mats. Green sulfur bacteria and their primary pigment Bchl e are also represented in and below the chemocline. However, the water column and sediments are devoid of the green sulfur bacteria carotenoid isorenieratene. The unexpected absence of isorenieratene and apparent benthic production of okenone provide strong rationale for continued exploration of the microbial ecology of biomarker production in modern euxinic environments.

Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants.

OBJECTIVE: To determine association of anemia and red blood cell (RBC) transfusions with necrotizing enterocolitis (NEC) in preterm infants. STUDY DESIGN: A total of 111 preterm infants with NEC ≥ stage 2a were compared with 222 matched controls. In all, 28 clinical variables, including hematocrit (Hct) and RBC transfusions were recorded. Propensity scores and multivariate logistic regression models were created to examine effects on the risk of NEC. RESULT: Controlling for other factors, lower Hct was associated with increased odds of NEC (odds ratio (OR)=1.10, P=0.01). RBC transfusion has a temporal relationship with NEC onset. Transfusion within 24 h (OR=7.60, P=0.001) and 48 h (OR=5.55, P=0.001) has a higher odds of developing NEC but this association is not significant by 96 h (OR=2.13, P=0.07), post-transfusion. CONCLUSION: Anemia may increase the risk of developing NEC in preterm infants. RBC transfusions are temporally related to NEC. Prospective studies are needed to better evaluate the potential influence of transfusions on the development of NEC.

Empirical and theoretical challenges in aboveground-belowground ecology.

A growing body of evidence shows that aboveground and belowground communities and processes are intrinsically linked, and that feedbacks between these subsystems have important implications for community structure and ecosystem functioning. Almost all studies on this topic have been carried out from an empirical perspective and in specific ecological settings or contexts. Belowground interactions operate at different spatial and temporal scales. Due to the relatively low mobility and high survival of organisms in the soil, plants have longer lasting legacy effects belowground than aboveground. Our current challenge is to understand how aboveground-belowground biotic interactions operate across spatial and temporal scales, and how they depend on, as well as influence, the abiotic environment. Because empirical capacities are too limited to explore all possible combinations of interactions and environmental settings, we explore where and how they can be supported by theoretical approaches to develop testable predictions and to generalise empirical results. We review four key areas where a combined aboveground-belowground approach offers perspectives for enhancing ecological understanding, namely succession, agro-ecosystems, biological invasions and global change impacts on ecosystems. In plant succession, differences in scales between aboveground and belowground biota, as well as between species interactions and ecosystem processes, have important implications for the rate and direction of community change. Aboveground as well as belowground interactions either enhance or reduce rates of plant species replacement. Moreover, the outcomes of the interactions depend on abiotic conditions and plant life history characteristics, which may vary with successional position. We exemplify where translation of the current conceptual succession models into more predictive models can help targeting empirical studies and generalising their results. Then, we discuss how understanding succession may help to enhance managing arable crops, grasslands and invasive plants, as well as provide insights into the effects of global change on community re-organisation and ecosystem processes.

Detectability of residual Epiphany and gutta-percha after root canal retreatment using a dental operating microscope and radiographs--an ex vivo study.

AIM: To compare the detectability of residual Epiphany and gutta-percha after root canal retreatment using a dental operating microscope and radiographic examination with the residual area measured after rendering the roots transparent. METHODOLOGY: Sixty extracted single-rooted maxillary central incisor teeth were enlarged to apical size 40. Thirty canals were filled using vertically compacted Epiphany, the remainder were filled with vertically compacted gutta-percha and AH Plus sealer. After re-instrumentation to apical size 50, radiographs of the roots were taken in buccolingual and mesiodistal direction. Residual filling material was categorized by three observers using the radiographs and a dental operating microscope. The area of remaining material that was made visible by radiographs was measured with the aid of a computer image analysis programme. After clearing the roots, areas of residual filling material on the root canal wall were measured using a microscope. RESULTS: Computer image analysis of the radiographs showed significantly smaller areas of remaining gutta-percha and Epiphany compared with the analysis of the transparent teeth that revealed only one absolutely clean root (Epiphany). Especially in the gutta-percha group, the scores determined by the observers using radiographic examination gave an over-optimistic impression of cleanliness compared with the scores determined by the visualization through the microscope. CONCLUSION: Especially for remaining gutta-percha, the operating microscopes provided better detection of residual root filling material in retreated maxillary incisor teeth.

Effectiveness of hand and rotary instrumentation for removing a new synthetic polymer-based root canal obturation material (Epiphany) during retreatment.

AIM: To evaluate the effectiveness of hand and rotary instrumentation for removal of vertically compacted Epiphany and gutta-percha during retreatment. METHODOLOGY: Sixty extracted single-rooted maxillary central incisors were enlarged to size 40 using FlexMaster instruments. The teeth were randomly divided into four groups of 15 specimens each. The canals of two groups were obturated using vertically compacted Epiphany. The others were filled with vertically compacted gutta-percha and AH Plus sealer. One Epiphany group and one gutta-percha group was reinstrumented with Gates Glidden burs and Hedström files. In the other two groups, obturation material was removed using Gates Glidden burs and RaCe rotary instruments. After clearing the roots, the area of remaining obturation material on the root canal wall was measured using a computer image analysis program. Statistical analysis was performed using Repeated Measures Analysis of Variance and anova. RESULTS: Retreatment of specimens obturated with gutta-percha showed significantly more remaining obturation material than specimens filled with Epiphany (P < 0.05). No difference was found between the removal with Hedström files and with RaCe instruments (P > 0.05). Regarding the mean time of retreatment and time required for reaching the working length, Hedström files were significantly faster than RaCe instruments (P < 0.05). The times did not depend on the kind of obturation material (P > 0.05). CONCLUSIONS: Vertically compacted Epiphany in combination with Epiphany Root Canal Sealant was removed more effectively than gutta-percha and AH Plus sealer. Hedström files were more rapid than RaCe rotary instruments.

Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light.

The tumor suppressor protein, p53, plays a critical role as a transcriptional activator of downstream target genes involved in the cellular response to DNA damaging agents. We examined the cell cycle checkpoint response of human mammary epithelial cells (HMEC) and their isogenic fibroblast counterparts to ionizing (IR) and ultraviolet (UV) radiation, two genotoxic agents whose DNA damage response pathways involve p53. Using flow cytometric analysis, we found that both mortal and immortalized HMEC, which contain wild-type p53 sequence, do not exhibit a G1 arrest in response to IR, but show an intact G2 checkpoint. Supportive evidence from Western analyses revealed that there was neither an increase in p53 nor one of its downstream targets, p21WAF1, in HMEC exposed to IR. In contrast, isogenic mammary fibroblasts arrest at the G1 checkpoint and induce the p53 and p21WAF1 proteins following IR. By comparison, HMEC exposed to UV displayed an S phase arrest and induced the expression of p53 and p21WAF1. Our results show that the cellular response to DNA damage depends on both the type of damage introduced into the DNA and the specific cell type.

Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.

OBJECTIVE: The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level. STUDY DESIGN: Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT). RESULTS: In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L. CONCLUSION: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.

A retrospective study of the efficacy of transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunts (TIPS) are being used increasingly for complications of portal hypertension, including active and recurrent variceal hemorrhage and intractable ascites, as well as for portal decompression in patients awaiting orthotopic liver transplantation. We reviewed the initial 2-year experience with TIPS at Louisiana State University Medical Center-Shreveport and Willis-Knighton Medical Center, Shreveport, Louisiana, which involved 31 patients. Clinical findings (with some patients having more than one finding) revealed that 16 per cent (five) of the patients had active hemorrhage; 61 per cent (19), multiple episodes of (recurrent) variceal hemorrhage; and 48 per cent (15), ascites. The mean follow-up period was 6.2 months, with a patient mortality of 13 per cent. Results showed that in 87 per cent (27 of 31) of patients the TIPS procedure was successfully placed. There was 100 per cent control of active variceal hemorrhage (five patients) and ascites (12 patients; excludes three patients who died). Rebleeding occurred in 18 per cent (four of 22) of patients, all related to stenosis or occlusion of the TIPS. The overall incidence of occlusion and stenosis was 11 per cent and 22 per cent, respectively. Seventy-seven per cent (seven of nine) of the patients experiencing the latter complications underwent successful angioplasty or revision of their TIPS. The results of our experience indicate that TIPS placement can be performed successfully with low procedural morbidity. The procedure is effective in controlling active variceal hemorrhage refractory to endoscopic sclerotherapy. The use of TIPS may be particularly beneficial for patients who are either awaiting liver transplantation or poor candidates for surgical shunt procedures. TIPS may not be a long-term solution for patients with portal hypertension, given the current rates of occlusion and stenosis.

Lack of evidence for aromatase in human prostatic tissues: effects of 4-hydroxyandrostenedione and other inhibitors on androgen metabolism.

The effects of 4-hydroxyandrostenedione (4-OHA) and other aromatase inhibitors, 10-propargylestr-4-ene-3,17-dione and imidazo[1,5-alpha]-3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile), as well as 5 alpha-reductase inhibitors N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxyamide and 4-methyl-3-oxo-4-aza-androsta-5-ene-17-ol were investigated in prostatic tissue from six patients with benign prostatic hypertrophy and seven patients with prostatic cancer, and from normal men at autopsy. We attempted to measure aromatase activity in the tissue incubations by quantitating 3H2O released from androstenedione or testosterone labeled at the C-1 position. High performance liquid chromatography and thin layer chromatography were used to isolate steroid products. Although the amount of 3H2O released was at least twice that of the heat-inactivated tissue samples, no estrone or estradiol was detected on high performance liquid chromatography. The 3H2O release was significantly inhibited by 4-OHA and N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxyamide, but not by the other aromatase inhibitors. 4-OHA also inhibited 5 alpha-reductase in both benign prostatic hypertrophy and cancer tissue, although to a lesser extent than N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxyamide. The other aromatase inhibitors were without effect on 5 alpha-reductase. Our results indicate that 3H2O released from [1 beta-3H]androstenedione and [1,2,6,7-3H]androstenedione does not correlate with estrogen formation and may be the result of other metabolic reactions. Although it appears that the prostate lacks aromatase, 4-OHA may be of benefit in patients with benign prostatic hypertrophy or prostatic cancer by inhibiting this enzyme in peripheral tissue.

Electromyographic evaluation of adult Labrador retrievers with type-II muscle fiber deficiency.

Labrador Retrievers with type-II muscle fiber deficiency were examined electrodiagnostically. Electromyographic changes consisted of positive sharp waves, fibrillation potentials, bizarre high-frequency discharges, and, rarely, myotonic-like discharges. Fasciculation potentials were recorded infrequently. Fibrillation potentials and bizarre high-frequency discharges were the most commonly observed electromyographic changes. Bizarre high-frequency discharges were prominent in muscles of the head and neck, proximal muscles of the thoracic limbs, and the thoracolumbar paraspinal musculature. Marked abnormalities were not observed in the motor nerve conduction velocity. Decremental responses of the evoked compound muscle action potential to repetitive nerve stimulation were not observed.

[Obstructive anuria due to renal candidiasis in a newborn male (author's transl)]. / Mechanische Anurie eines Säuglings bei Candidapyelonephritis.

Mechanical anuria developed in a neonate during a period of intensive care following birth trauma. The obstruction of the urinary tract was due to yeast clumps from a candida pyelonephritis. Urine flow was reestablished after a unilateral nephrostomy and antimycotic therapy. There were no anatomical abnormalities of the urinary tract.