Search

The purpose of this study wa~ to deteraine the pharaacokinetics of calcium leucoYorin in nor•al subjects and in patients undergoing High-Dose methotrexa~e therapy for the treat•ent of neoplastic diseaseBy characterizing the disposition of leucovorin it was hoped that the the efficacy of the aethotrexate therapy might be i•proved, while at the sa•e time, the incidence of toxicity could be di•inished. An assay for the separation and quantification of leucovorin in serua was developed. The reduced folate vas extracted from seru• using re•erse-phase chromatographic •inicoluans and a paired-ion reagent. Leucovorin was eluted from this systea in methanol and e•aporated to dryness under nitrogen. The extracted samples were stable for 3 days vhen stored at -4oc. Bigh pressure liquid chroaatoqraphy vas used to separate leuco•orin from the extracted Rerua coaponents using a reverse-phase, paired-ion mode. Aamonium phosphate, dibasic, vas found to be a suitable pairing agent. The recently developed radially coapressed reverse-phase coluans vere found to provide superior resolution of serua components than vas possible with conventional stainless steel columns. The effects of flov rate, pH, column teaperature, and buffer concentration on the separation of leucoYorin vere investigated. Electrochemical detection vas used to quantify the reduced folate in the extracted serum samples. An applied potential of 0.8 volts vas used to produce a sensitive and selective aeans of detecting leucovorin. The apparent lover limit of sensitivity under the conditions employed vas 12 ng leuco•orin. The effects of pH, buffer concentration, methanol concentration, and mobile phase flow rate on detector response vere investigated. The protein binding of leucovorin and its major aetabolite 5-aethyltetrahydrofolate to hu•an serum albumin was determined. Over the concentration range of 5.0x10-78 to 1x10-•K neither folate saturated the available binding sites. Leucovorin binding was a constant 701, vhile aethyltetrahydrofolate decreased slightly over this range. When both folates vere present in the albumin solution, there was a significant decrease in the degree of binding of each. ftethotrexate did not affect the binding of leucovorin or its metabolite. The pharaacokinetics of leucovorin vas determined in 6 noraal subjects and in 5 cancer patient s. There were no siqnif icant differences in the kinetic parameters calculated fro• either group. The disposition of leucovorin is best characterized by a two coapartment open aodel. ln initial half-life of 8.79 ± 4.44 minutes and a second, slower elimination phase of 231.46 ± 31.76 minutes vas determined. The volume of the central compartment vas calculated as 5.49 ± 3.53 Liters. Leucovorin serum concentrations in 3 cancer patients receiving HighDose methotrexate vere deterained to be 3 to 11 times greater than vas predicted using methotrexate pharmacokinetic paraaeters. This study clearly deaonstrates that there are significant differences in the pharmacokinetics of leucovorin and methotrexate. The data presented in this study suggests that it aight be possible to reduce the aaount of leucovorin administered to patients being treated vith met.hotrexate. This may be expected to improve the efficacy of the antimetabolite therapy without additional risk of toxicity. ( ABSTRACT ACKNOilLEDGEftENT TABLE OF CONTENTS LIST OP TABLES LIST OP FIGURES

Additional file 1: Table S1. Core taxa within each lung disease category. Given is prevalence, the number of samples a given core taxon was detected in, and average relative abundance across those samples. Operational taxonomic unit (OTU) identifications have been used for bacterial taxon names. OTU numbers have been used to differentiate between taxa within the same genus. Given the length of the ribosomal sequences analysed, species identities should be considered putative.

Additional file 5: Table S4. PERMANOVA summary statistics from testing for significant differences in microbiota composition between lung function categories. Given in each instance are mean Bray-Curtis similarity within and between categories (± standard deviation of the mean), F-statistic, and significance (P). Asterisks denote significant differences in composition following one-way PERMANOVA tests with Bonferroni correction.

Additional file 2: Table S2. Kruskal-Wallis summary statistics for testing for significant differences in diversity between lung function categories. Given for each test is the mean Fisher's alpha diversity index, standard deviation of the mean, H-statistic, and significance (P), and mean of ranks values. Asterisks denote significant differences in diversity following Kruskal-Wallis with post-hoc Dunn test.

Excessive alcohol consumption can be associated with cognitive impairment not only in drinkers but also in their offspring. Studies of children of alcoholics (COA’s), and particularly of sons of male alcoholics (SOMA’s), have identified a characteristic cognitive profile. COA’s frequently have deficits in verbal skills, classification of verbal and visual stimuli, abstract thinking, and goal-directed planning. SOMA’s show additional deficits in visuospatial abilities, perceptual motor skills, and learning and memory. A model is described that explains how the observed cognitive deficits may contribute to the behavioral problems frequently observed in COA’s and to their risk of becoming alcoholic themselves. However, only some, but not all, COA’s exhibit a cognitive profile predictive of behavioral problems.

International audience

The lack of adequate quantity and quality of water is a world-wide problem, which fosters concerns about the impacts of climate change. Obtaining forecasts of future water changes are important to allow early impact mitigation and adaption efforts.This study forecasts precipitation changes, not through climate models, but by analysis of observations to derive trends of three metrics: event Intensity, event Duration, and lull Pause. From 50 long-term stations in California we obtained median trends of Intensity -0.45% per decade, Duration 0.50% per decade, and Pause 0.13% per decade.One problem in the analysis of observations was proper techniques to handle gaps from missing data. Multiple Imputation (MI) was applied through fitting of Weibull probability distributions to the three metrics. This was tested by artificially injecting gaps into the mostly complete Sacramento record. MI partially restored deviations caused by that injection.viiiPermutation resampling techniques were applied with MI to derive significance p-values for each trend. Significance at 95% for Intensity was from 11 of the 50 stations, Duration from 16, and Pause from 19, of which 12 were 99% significant. Trends were combined by weighting them with the reciprocal of their p-values. Significance weighted California trends are Intensity -4.61% per decade, Duration 3.49% per decade, and Pause 3.58% per decade.Two California basins with hydrologic models were studied: Feather River in the northern Sierra Nevada mountains and central coast Soquel-Aptos. Most hydrologic components between the two basins were shown to behave differently primarily because of climate differences.Three metric trends were computed for each basin by combining trends from nearby observations. Each metric was changed without change to other metrics or the total precipitation and input into the models. Most hydrologic impacts were modest with magnitudes less than half the corresponding precipitation changes.Feather River Basin's critical supply to Lake Oroville and the State Water Project were benefited from a streamflow increase by 0.5%. Soquel-Aptos Basin's value for water supply was harmed by groundwater recharge decrease by -2.5% and streamflow decrease by -1.1%. Neither of these impacts seem amenable to mitigation, thus adaptation is indicated.

Previous research has shown that many people experience a temporary worsening of mood following acute tryptophan depletion (ATD) and that concurrent use of serotonergic medications may influence such mood responses. We investigated mood and other consequences of ATD in women with bulimia nervosa who were or were not using concurrent serotonergic medications compared with women without bulimia.Women self-referred for treatment of bulimia who were either not currently using psychoactive medications (n = 26) or who were using serotonin reuptake inhibitor medications exclusively (n = 13), as well as medication-free normal-eater control women (n = 25) completed interviews and questionnaires assessing eating and comorbid psychopathology and then participated in an ATD procedure involving balanced and tryptophan-depleted conditions.In the tryptophan-depleted condition, the groups displayed similar and significant decrements in plasma tryptophan levels and mood. Women with bulimia who were using serotonin reuptake inhibitors, but not the other groups, also reported an increased urge to binge eat in the tryptophan-depleted condition.Application of medication in participants with bulimia was not random.Acute reductions in serotonin availability produced similar mood-reducing effects in bulimic and nonbulimic women. To the extent that ATD affected subjective experiences pertinent to eating (i.e., urge to binge eat), such effects appeared to depend upon ATD-induced competition with the therapeutic effects of serotonergic medications.

The IEEE Computer Society announced the approval of the world’s first Storage System Standards were approved on June 21st, 2000 [1], for the IEEE Media Management System (MMS) describing its architecture, data model, core media management protocol, and drive management and library management protocols. Four standards were approved, 1244.1 [2], 1244.3 [3], 1244.4 [4], and 1244.5 [5]. Notable by its absence in this announcement was the standard IEEE 1244.2, the “Session Security, Authentication, Initialization Protocol” (SSAIP) [6]. The IEEE Storage Systems Standards Working Group (SSSWG) [7] has spent considerable discussion time arriving at an understanding of the requirements for security in the 1244 family of standards. This paper discusses some of the issues surrounding the evolution of the requirements as they are currently used in defining the standard 1244.2.

Using data from the Public Use Sample files of the 1981 and 1986 Canadian censuses, this thesis sets out to characterize and explain primary (migration from the province of birth), return (migration back to the province of birth following an initial migration) and onward (migration to a province other than the province of birth following an initial migration) interprovincial migration within Canada for the 1976-81 and 1981-86 periods. Three major themes are developed and expanded over the course of the thesis. The first theme is one of characterization. In order to study the propensities of in- and outmigration, appropriate in- and outmigration rates are computed (Long, 1988; Rogers and Belanger, 1990). The major finding is that the Canadian migration patterns are similar to those observed in the United States. The second theme is the explanation of return and onward migration amongst non-natives (those whose province of residence was different from their province of birth) aged 22-44 within Canada by applying a three-level nested logit model to the 1976-81 micro data. Research has tended to take either a macro-adjustment or micro-behavioral stance in modeling migration flows, but the complementary frameworks suggest the need for an integrative approach incorporating structural-institutional forces and personal factors. Important factors include mother tongue, level of education, age and family type. Influential provincial attributes include economic variables, distance and cultural similarity. The main finding is that return migrants also responded to interprovincial variations in economic opportunities in a rational way. The final theme is the temporal analysis of primary, return and onward migration through the economic boom of 1976-81 and economic bust of 1981-86. Relative to return migration, primary and onward migration became less important during the period of economic bust, although migration became less important during the period of economic bust, although migration selectively with respect to personal factors remained basically the same. In making migration decisions, non-natives continued to respond to the spatial variation in economic opportunities so that the spatial patterns of migration changed in response to the changing spatial economy. Doctor of Philosophy (PhD)

Since World V^ar II , the Navy has relied upon volunteer enlistments to maintain its force structure. However, it is recognized that many men were motivated to enlist by the prospect of being drafted into the Army. Now that the All-Volunteer Force policy is in effect for all services , there is speculation that the quality of new Naval recruits will diminish. This paper makes a quality comparison of enlistees under the Draft Lottery system and enlistees under the All-Volunteer Force policy from data obtained in the Monterey Peninsula, California area of the Eighth Naval Recruiting District. The results indicate that no significant change in quality has occurred during the first four months of the All-Volunteer policy. The implications are that 1) no reduction in the quality of new enlistees is a good indication that the Navy is maintaining a quality status quo, and 2) no increasing trend in quality might reflect the effectiveness of the Navy's program to enlist the highest caliber of recruit needed to form a future smaller, but more professional, naval force. http://archive.org/details/qualitycompariso1094516767 Lieutenant, United States Navy Approved for public release; distribution is unlimited.

Background: Chronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF. Results: We tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa. Conclusions: Our findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF. BBFJdPr3cu-jH3LTAhe361Video Abstract

BACKGROUND: Chronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF. RESULTS: We tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa. CONCLUSIONS: Our findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF. Video Abstract.

Background: Chronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF. Results: We tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa. Conclusions: Our findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF. Video Abstract

Additional file 4: Figure S1. Measures of Hedges’ d effect size based on comparisons of (A) diversity and (B) dominance in the microbiota, core taxa, and satellite taxa, when stratified into lung disease categories. Columns represent the effect size and error bars represent the standard error of effect size. Standard error bars that cross zero indicate no significant effect on diversity or dominance between lung disease categories. In each instance, within (A) positive effect sizes represent higher diversity in the second of the two lung disease categories being compared. Within (B) negative effect sizes represent lower dominance in the 2nd of the two lung disease categories being compared. Measures of diversity and dominance when stratified by lung disease category are presented in Fig. 3a and b, respectively.

Additional file 3: Table S3. Kruskal-Wallis summary statistics for testing for significant differences in diversity between lung function categories. Given for each test is the mean Berger-Parker index of dominance, standard deviation of the mean, H-statistic, and significance (P), and mean of ranks values. Asterisks denote significant differences in diversity following Kruskal-Wallis with post-hoc Dunn test.

Additional file 3: Table S3. Kruskal-Wallis summary statistics for testing for significant differences in diversity between lung function categories. Given for each test is the mean Berger-Parker index of dominance, standard deviation of the mean, H-statistic, and significance (P), and mean of ranks values. Asterisks denote significant differences in diversity following Kruskal-Wallis with post-hoc Dunn test.

International audience; BACKGROUND: How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. METHODS: We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. RESULTS: Here we show a temperature of ~38°C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38°C vs 30°C revealed increased virulence traits and characteristic cell wall changes. CONCLUSION: Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.