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PubMed2004

Phenotypic plasticity of body pigmentation in Drosophila melanogaster: genetic repeatability of quantitative parameters in two successive generations.

In Drosophila melanogaster, body pigmentation is a quantitative trait that depends on developmental temperature. When investigated over the whole thermal range of the species, pigmentation exhibits nonlinear reaction norms that differ among segments. The isofemale line method was used to analyse the genetic variability in two natural populations that affected the shape of reaction norms. Each line was considered as an experimental repeat, and polynomial reaction norms fitted to calculate the characteristic values (eg the coordinates of a maximum). In total, 20 lines from two geographically distant populations (France and India) were investigated at seven developmental temperatures (12-31 degrees C) in two successive generations (G2 and G3). We analysed the genetic repeatability (ie the correlation between generations) of three kinds of parameters: intraclass correlation coefficients (isofemale heritability), family means at different temperatures and the characteristic values of the reaction norms. For intraclass correlation, a low genetic repeatability was found. For family mean values grown at various temperatures, an overall positive and highly significant repeatability was found (r=0.55+/-0.024). Finally, a positive significant G2-G3 correlation was also the rule for the characteristic values of the reaction norms. Significant differences could be found between values describing either the trait or its plasticity, but with no general trend. A slightly higher repeatability was observed in the Indian population. These results show that, with a family selection design, the shape of the reaction norms might be modified in various ways.

Abdomen↗

PubMedDate not supplied

The effects of age, sex, and shoulder dominance on range of motion of the shoulder.

To determine the effects of age, sex, and arm dominance on shoulder range of motion, we measured active and passive forward elevation, abduction, internal and external rotation at 90 degrees of abduction, external rotation with the arm adducted, and extension bilaterally in 280 subjects ranging in age from 4 to 70 years. Linear regression analyses were performed for all motions except forward elevation. This motion, which showed a nonlinear pattern of decline with age, was evaluated with 3-way analysis of variance. Shoulder range of motion decreased with age for all measured motions with the exception of internal rotation, which increased with age. Female subjects had a significantly greater range of motion than male subjects for all motions measured. Dominant arms displayed significantly greater external rotation than nondominant, regardless of whether the arm was abducted or adducted at the time of measurement. However, nondominant shoulders demonstrated significantly greater internal rotation and extension than dominant. No significant differences were found between dominant and nondominant sides for forward elevation or abduction.

Adolescent↗

PubMed2005

Estimates of individual factors of the tryptophan requirement based on protein and tryptophan accretion responses to increasing tryptophan supply in broiler chickens 8-21 days of age.

Ten diets (196 g CP and 13.0 MJ ME(N)/kg) with graded levels of tryptophan (Trp) between 0.9 and 2.7 g/kg were offered ad libitum to Ross broilers from day 8-21 post-hatch. Each diet was allocated to three pens of ten birds each. In addition to growth and feed conversion, the accretions of protein, Trp, fat, and energy were determined by comparative whole body analyses. A sigmoidal function was fitted to the data. Responses to Trp supply were nonlinear and attained plateau values (y(max)) within the studied range of Trp supply. The Y(max) values estimated for BW gain, whole body protein gain, and Trp gain during the 14 days under study were 615, 104, and 0.87 g/bird, respectively. Based on the response in whole body protein gain, the estimated requirement was 1.9 g Trp/kg of diet or 0.15 g Trp/MJ of MEN. Estimates made from the other response criteria were similar to this value. While the protein concentration in gained BW was unaffected by Trp intake (169 g of protein per kg of gained BW), fat and energy concentrations of gained BW increased with increasing Trp supply, approaching plateau values of 146 g fat and 9.8 MJ energy per kg of gained BW. This is supposed to result from feed intake increasing with Trp supplementation. The Trp concentration in gained whole body protein (0.84 g Trp/ 16 g of gained N) was not significantly affected by Trp intake. As long as Trp intake was the limiting factor, 59% of supplemented Trp was transferred to gained whole body protein. During the 14 days of the study, broilers inevitably lost 87 mg Trp. This is equivalent to a daily loss of 30 mg/kg BW or a maintenance requirement of 52 mg/kg BW per day. Data determined for the individual factors may be used for future modelling of broilers' Trp requirement.

Animal Feed↗

PubMed1992

The population dynamics of nematode infections of ruminants: the effect of seasonality in the free-living stages.

A previously published differential equation model for the dynamics of nematode infections of ruminants is modified to allow for time-dependent development and loss rates in the free-living stages. This converts the nonlinear autonomous system to one with periodic coefficients. Fourier transform methods are used to analyse the response of the modified system to these forced oscillations. For biologically reasonable parameter values, the annual pattern of parasitism is determined for the nonautonomous system, and compared with that for the autonomous system with periodic perturbations, and a system incorporating both effects. It is found that, whereas periodic perturbations due to management intervention determine the qualitative annual patterns of larval abundance and host infection, the seasonal dynamics of the larval stages change the magnitude of the adult worm burden.

Animals↗

PubMed2007

Lysosomes and trivalent arsenic treatment in acute promyelocytic leukemia.

BACKGROUND: Cells from patients with t(15;17) acute promyelocytic leukemia (APL) express the fusion protein between the promyelocytic leukemia protein and retinoic acid receptor alpha (PML/RAR alpha). Patients with APL respond to differentiation therapy with all-trans-retinoic acid, which induces PML/RAR alpha degradation. When resistance to all-trans-retinoic acid develops, an effective treatment is arsenic trioxide (arsenite), which also induces this degradation. We investigated the mechanism of arsenite-induced PML/RAR alpha degradation. METHODS: NB4-S1 APL cells were treated with clinically relevant concentrations of arsenite. Lysosomes were visualized with a lysosome-specific dye. Lysosomal protein esterase was measured by immunoblot analysis. Lysosomal cathepsin L was detected by immunogold labeling and transmission electron microscopy, and its activity was measured in cytosolic cellular fractions. In vitro degradation assays of PML/RAR alpha in cell lysates were performed with and without protease inhibitors and assessed by immunoblot analysis. Only nonparametric two-sided statistical analyses were used. The nonparametric Wilcoxon test was used for group comparison, and the nonlinear regression technique was used for analysis of dose-response relationship as a function of arsenite concentration. RESULTS: Arsenite treatment destabilized lysosomes in APL cells. Lysosomal proteases, including cathepsin L, were released from lysosomes 5 minutes to 6 hours after arsenite treatment. PML/RAR alpha was degraded by lysate from arsenite-treated APL cells, and the degradation was inhibited by protease inhibitors. At both 6 and 24 hours, substantially fewer arsenite-treated APL cells, than untreated cells, contained cathepsin L clusters, a reflection of cathepsin L delocalization. Cells with cathepsin L clusters decreased as a function of arsenite concentration at rates of -2.03% (95% confidence interval [CI] = -4.01 to -.045; P = .045) and -2.39% (95% CI = -4.54 to -.024; P = .029) in 6- and 24-hour treatment groups, respectively, per 1.0 microM increase in arsenite concentration. Statistically significantly higher cytosolic cathepsin L activity was detected in lysates of arsenite-treated APL cells than in control lysates. For example, the mean increase in cathepsin activity at 6 hours and 1.0 microM arsenite was 26.3% (95% CI = 3.3% to 33%; P < .001), compared with untreated cells. CONCLUSIONS: In APL cells, arsenite may cause rapid destabilization of lysosomes.

Antineoplastic Agents↗

PubMed2007

Melanoma incidence in central Italy will go on increasing also in the near future: a registry-based, age-period-cohort analysis.

The aim of the study was to evaluate malignant melanoma incident trends in central Italy by means of an age-period-cohort approach. A total of 1977 malignant melanoma (15-84 years) incidents in the area of the Tuscany Cancer Registry between 1987 and 2001 were analysed. Poisson regression has been used to estimate age, cohort and period effect. A nonlinear regression model was used to estimate the expected number of new cases in the period 2002-2006. Incidence rates increased in all age, period and cohort groups. The model that best fitted the data included age and 'drift'. The linear effect ('drift') showed, in each age group, an increase of the risk of malignant melanoma diagnosis of about 36.6% every 5 years of period or cohort. For the period 2002-2006, 1112 new cases were predicted with a standardized rate (age 15-84 years) of 19.2x100.000. In the Tuscany Cancer Registry area, no clues for malignant melanoma incidence rates levelling off were documented. Growing rates and number of malignant melanoma are expected in the near future.

Adolescent↗

PubMed2006

Apparent half-lives of hepta- to decabrominated diphenyl ethers in human serum as determined in occupationally exposed workers.

The aim of the present study was to model apparent serum half-lives of polybrominated diphenyl ethers (PBDEs) with 7-10 bromine substituents. Workers with occupational exposure to PBDEs have elevated serum levels of PBDEs, but these substances are also found in the general population and are ubiquitous environmental contaminants. The calculations were based on exposure assessments of rubber workers (manufactured flame-retarded rubber compound) and electronics dismantlers who donated blood during a period with no work-related exposures to PBDEs, and referents without any known occupational exposure (clerks, cleaners, and abattoir workers). The workers had previously been found to have elevated levels of high- and medium-brominated diphenyl ethers compared with the referent populations. We performed nonlinear mixed-effects modeling of kinetics, using data from previous and present chemical analyses. The calculated apparent half-life for decabromodiphenyl ether (BDE-209) was 15 days (95% confidence interval, 11-18 days). The three nona-BDEs and four octa-BDE congeners were found to have half-lives of 18-39 and 37-91 days, respectively. BDE-209 has a short half-life in human blood. Because BDE-209 is commonly present in humans in general, the results of this study imply that humans must be more or less continuously exposed to BDE-209 to sustain the serum concentrations observed. BDE-209 is more readily transformed and/or eliminated than are lower brominated diphenyl ether congeners, and human health risk must be assessed accordingly.

Adult↗

PubMed1998

Establishing the dose response curve for metabolic control with troglitazone, an insulin action enhancer, in type 2 diabetes patients.

Troglitazone is a novel once-daily oral antidiabetic agent for the treatment of type 2 diabetes patients. Here, we report the overall dose response characteristics of troglitazone, with respect to effects on metabolic control, using a pharmacodynamic model. Data from week 12 from two previously reported double-blind, randomized, parallel-group, placebo-controlled, dose-ranging multicentre studies examining once-daily doses of 10, 30, 100, 200, 400, 600 and 800 mg of troglitazone were combined for the analyses. The pharmacodynamic relationships for relevant parameters of metabolic control were modelled using a nonlinear regression modelling programme. The troglitazone dose-concentration relationship was linear over 10-800 mg. Using an inhibitory sigmoid Emax model, ED50 values of approximately 100 mg and 200 mg were found for fasting serum glucose and triglycerides, respectively. The 200 mg dose for HbA1c showed an inconsistent reduction compared with placebo between the two studies; this illustrates the difficulties associated with comparing results from different assay techniques. Insulin and nonesterified fatty acid reductions compared with placebo were not consistent between studies, and no pharmacodynamic modelling was possible. No changes in body weight were observed at any dose. Troglitazone was as well tolerated as placebo across the dose range investigated. This pharmacodynamic analysis has established that 200-600 mg once daily can be considered the therapeutic dose range of troglitazone that significantly improves metabolic control in type 2 diabetes patients.

Adult↗

PubMed1987

Computer modeling and analysis of cross-sectional bone density studies with respect to age and the menopause.

Controversy exists about rates of bone mineral loss from the lumbar spine at the menopause. Cross-sectional studies of lumbar bone mineral against age have been interpreted as evidence for or against a menopause-related change in lumbar bone loss, depending on their goodness of fit to either linear or nonlinear equations. To investigate the ability of cross-sectional studies to detect accelerated lumbar bone loss at the menopause, we constructed models of different patterns of loss and evaluated the findings in cross-sectional analyses of computer-simulated populations of normal women. A sample size of greater than 300 was needed to distinguish between linear and nonlinear patterns of bone loss with a power of 90% when the data was analyzed throughout life. Examining for differences between the slopes of the regressions of pre- and postmenopausal women was more useful for detecting nonlinear bone loss under some circumstances. A difference between slopes was apparent in studies containing 100 subjects if lumbar bone density (BMD) was assumed to be unchanged prior to the menopause, but a larger study size was needed (greater than 1000) if BMD was assumed to fall before the menopause. We also measured lumbar BMD by dual photon absorptiometry in 141 normal females. When the data was analyzed against age throughout life, a nonlinear pattern of bone loss was found, and comparison of pre- and postmenopausal subjects showed a significant difference in the slopes of the linear regressions. Our patient data support the concept of a relatively stable lumbar BMD prior to the menopause with a rapid but transient decline postmenopausally.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1996

One-Handed Juggling: A Dynamical Approach to a Rhythmic Movement Task.

The skill of rhythmically juggling a ball on a racket was investigated from the viewpoint of nonlinear dynamics. The difference equations that model the dynamical system were analyzed by means of local and nonlocal stability analyses. These analyses showed that the task dynamics offer an economical juggling pattern that is stable even for open-loop actuator motion. For this pattern, two types of predictions were extracted: (a) Stable periodic bouncing is sufficiently characterized by a negative acceleration of the racket at the moment of impact with the ball, and (b) a nonlinear scaling relation maps different juggling trajectories onto one topologically equivalent dynamical system. The relevance of these results for the human control of action was evaluated in an experiment in which subjects (N = 6) performed a comparable task of juggling a ball on a paddle. Task manipulations involved different juggling heights and gravity conditions of the ball. The following predictions were confirmed: (a) For stable rhythmic performance, the paddle's acceleration at impact is negative and fluctuations of the impact acceleration follow predictions from global stability analysis; and (b) for each subject, the realizations of juggling for the different experimental conditions are related by the scaling relation. These results permit one to conclude that humans reliably exploit the stable solutions inherent to the dynamics of the given task and do not overrule these dynamics by other control mechanisms. The dynamical scaling serves as an efficient principle for generating different movement realizations from only a few parameter changes and is discussed as a dynamical formalization of the principle of motor equivalence.

Journal Article↗

PubMed2004

Relationship between noradrenaline and nonlinear indexes of blood pressure dynamics in normotensive and spontaneously hypertensive rats.

Recent studies in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats show that some nonlinear indexes derived from the recurrence plot method may be better markers of sympathetic activity than the spectral powers of blood pressure (BP). We herein investigated the relationships between nonlinear indexes and plasma noradrenaline concentration in conscious WKY rats and SHRs. Blood pressure was recorded for 30 min after intravenous injection of saline (0.9% NaCl, 100 microL/kg), hexamethonium (20 mg/kg), atropine (0.5 mg/kg), atenolol (1 mg/kg) or prazosin (1 mg/kg). Spectral power in the low-frequency (LF) band and the nonlinear index (L(max)), calculated on diastolic (DBP) and systolic blood pressures (SBP), were used to analyse the BP signal. Noradrenaline concentration was determined by radioenzymatic technique. A robust stepwise regression analysis - using noradrenaline concentration as dependent variable, and LF, L(max) and treatment, as independent variables -shows that treatment is the main variable explaining the variance of noradrenaline level in WKY rats, excluding the use of the pooled data to explore the relationship between noradrenaline concentration and LF or L(max). In contrast, in SHRs, treatment has no effect on the variance of noradrenaline concentration and the pooled data were then used. In this group, no correlation was observed between noradrenaline concentration and LF. In contrast, very high positive correlation was observed between noradrenaline level and L(max)-DBP (r = 0.59; P = 0.0005) or L(max)-SBP (r = 0.53; P < 0.002). The results strengthen our previous suggestion that nonlinear indexes may be better tools than spectral powers to investigate the sympathetic nervous system.

Animals↗

PubMed1994

Nonlinear kinetics of nortriptyline in relation to nortriptyline clearance as observed during therapeutic drug monitoring.

From routine therapeutic drug monitoring data, samples from 105 patients with two analyses of nortriptyline at different daily doses were collected. The ratio between concentration and daily dose, which is the reciprocal of the apparent clearance, was compared intra-individually to study the occurrence of dose-dependent kinetics. Subjects with a low or intermediate ratio at the low dose had a higher mean ratio at the high dose, indicating a nonlinear relationship between dose and concentration. The magnitude of the difference was inversely correlated to the ratio at the low dose. No major difference was seen in the ca. 10% of the patients that exhibited the highest ratio at the low dose. This fraction corresponds to the frequency of poor metabolizers of debrisoquine in the population. The metabolism of nortriptyline has been shown to be partly dependent on the debrisoquine hydroxylase CYP2D6. We conclude that dose-dependent kinetics of nortriptyline occurs in subjects with a high or intermediate capacity to eliminate the drug, in accord with debrisoquine hydroxylase being a high-affinity, low-capacity pathway in the elimination of nortriptyline.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Flexible modeling of exposure-response relationship between long-term average levels of particulate air pollution and mortality in the American Cancer Society study.

Accurate estimation of the exposure-response relationship between environmental particulate air pollution and mortality is important from both an etiologic and regulatory perspective. However, little is known about the actual shapes of these exposure-response curves. The objective of this study was to estimate the exposure-response relationships between mortality and long-term average city-specific levels of sulfates and fine particulate matter (PM(2.5)). We reanalyzed the data derived from the American Cancer Society (ACS) Cancer Prevention Study II, a large prospective study conducted in the United States between 1982 and 1989. Exposure to particulate air pollution was assessed prior to entry into the cohort. Mean sulfate concentrations for 1980 were available in 151 cities, and median PM(2.5) levels between 1979 and 1983 were available in 50 cities. Two sampling strategies were employed to reduce the computational burden. The modified case-cohort approach combined a random subcohort of 1200 individuals with an additional 1300 cases (i.e., deaths). The second strategy involved pooling the results of separate analyses of 10 disjoint random subsets, each with about 2200 participants. To assess the independent effect of the particulate levels on all-causes mortality, we relied on flexible, nonparametric survival analytical methods. To eliminate potentially restrictive assumptions underlying the conventional models, we employed a flexible regression spline generalization of the Cox proportional-hazards (PH) model. The regression spline method allowed us to model simultaneously the time-dependent changes in the effect of particulate matter on the hazard and a possibly nonlinear exposure-response relationship. The PH and linearity hypotheses were tested using likelihood ratio tests. In all analyses, we stratified by age and 5-yr age groups and adjusted for the subject's age, lifetime smoking exposure, obesity, and education. For both fine particles (PM(2.5)) and sulfates, there was a statistically significant (at.05 level) departure from the conventional linearity assumption. The adjusted effect of fine particles on mortality indicated a stronger relationship in the lower (up to about 16 microg/m(3)) than in the higher range of their values. Increasing levels of sulfates in the lower range (up to about 12 microg/m(3)) had little impact on mortality, suggesting a possible "no-effect threshold." For body mass index (BMI), the risks were lowest in the middle range and increased for both very obese and very lean individuals. It was concluded that flexible modeling yields new insights about the effect of long-term air pollution on mortality.

Air Pollutants↗

PubMed2006

Nonlinear analysis of discharge patterns in monkey basal ganglia.

Spontaneous discharge of basal ganglia neurons is often analyzed with time- or frequency-domain methods. However, it has been shown that sequences of inter-spike interval series are not fully described by such linear procedures. We therefore carried out a characterization of the nonlinear features of spontaneous discharge of neurons in the primate basal ganglia. We studied the spontaneous activity of neurons in the subthalamic nucleus (22 cells), as well as neurons in the external and internal pallidal segments (53 and 39 cells, respectively), recorded with standard extracellular recording methods in two awake Rhesus monkeys. As a measure of the statistical irregularity of neuronal discharge, we compared the approximate entropy of inter-spike interval sequences with that of shuffled representations of the same data. In all three basal ganglia structures, approximately 95% of the original data showed lower approximate entropy values than the shuffled data, suggesting a temporal organization in the original sequence. Fano factor analysis confirmed the presence of a temporal organization of inter-spike interval sequences, and indicated the presence of self-similarity in the great majority of them. In addition, Hurst exponent analysis showed that the inter-spike interval series are persistent. Hurst exponents often differ between short and long scaling ranges. Subsequent principal component analyses allowed us to identify three distinct patterns of the temporal evolution of inter-spike interval sequences in the phase space. These types were found in varying distributions in all three nuclei. Our analyses demonstrate that the discharge of most neurons in the basal ganglia of awake monkeys has nonlinear features that may be important for information coding in the basal ganglia.

Action Potentials↗

PubMed1980

A mathematical model of lung parenchyma.

The geometry of the proposed model of the parenchyma of a mammalian lung reproduces a cluster of alveoli arranged around a lowest-level air duct. The alveolar walls are assumed to be nonlinear elastic membranes, whose properties are described in terms of a strain energy function which reflects the hardening character of the stress-strain curve. The effect of the surfactant is included in terms of a variable (area-dependent) surface tension. Analyses of various mechanical processes in the parenchyma are performed with the aid of the finite element method, with the geometric and physical nonlinearities of the problem taken into account.

Biomechanical Phenomena↗

PubMedDate not supplied

Sexual dimorphism in foot length proportionate to stature.

BACKGROUND: The preponderance of existing results suggests that, relative to stature, women have smaller feet than men. However, several investigations indicate that the relationship between foot length and stature may be curvilinear, a pattern that, due to the dimorphic nature of stature, would mask the true direction of pedal sexual dimorphism in published results. AIM: The study aimed to determine whether proportionate foot length is sexually dimorphic and, if so, the nature of that dimorphism. MATERIALS AND METHODS: Surveying genetically disparate populations (USA, Turkey, and Native North and Central American), we examined data from three previous anthropometric studies (Davis 1990, Parham et al. 1992, Ozaslan et al. 2003) and foot tracings from the Steggerda Collection at the US National Museum of Health and Medicine. Analyses explored sex differences in the ratio between foot length and stature, and tested for nonlinearity. RESULTS: Although varying in degree across populations, proportionate to stature, female foot length is consistently smaller than male foot length. CONCLUSION: Given the biomechanical challenges posed by pregnancy, smaller female proportionate foot length is somewhat surprising, as foot length affects dorsoventral stability. It is possible that the observed pattern reflects intersexual selection for small female foot size, a cue of youth and nulliparity.

Body Height↗

PubMed2006

Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.

AIMS: To characterize determinants of the elimination of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in patients receiving high-dose MTX therapy (HDMTX). METHODS: 24 and 48-h blood samples from 76 patients receiving HDMTX (dose range 300 mg m-2 to 12 g m-2) were analysed, and concentration-time data were subjected to population pharmacokinetic and covariate analysis using nonlinear mixed-effect modelling (NONMEM). RESULTS: Treatment-related mortality was 1.3% (one patient with renal failure). Values for MTX clearance (CLMTX) and 7-OH-MTX clearance (CL7-OH-MTX) were estimated at 8.85 and 2 L-1, respectively. Baseline creatinine clearance correlated with CLMTX and CL7-OH-MTX. Concurrent administration of benzimidazoles led to a 27% decrease in CLMTX and a 39% decrease in CL7-OH-MTX. Prior administration of nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in a 16% decrease in CLMTX and a 38% decrease in CL7-OH-MTX. Plasma MTX concentrations were significantly higher in patients also receiving benzimidazoles at 24 h (2.01 micromol L-1vs. 0.66 micromol L-1, P<10(-4)) and at 48 h (0.25 micromol L-1vs. 0.12 micromol L-1, P<10(-4)). 7-OH-MTX plasma concentrations were also significantly higher in patients with concurrent benzimidazoles as compared with patients without benzimidazoles at 24 h (4.47 micromol L-1vs. 2.52 micromol L-1, P=0.0009) and at 48 h (1.11 micromol L-1vs. 0.72 micromol L-1, P=0.031). CONCLUSIONS: In patients receiving HDMTX, concurrent administration of benzimidazoles was associated with a significant decrease of CLMTX and CL7-OH-MTX, resulting in significantly higher plasma concentrations of MTX and 7-OH-MTX. The data suggest that benzimidazole treatment should be seen as a relative contraindication for HDMTX.

Antimetabolites, Antineoplastic↗

PubMed2002

Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model.

An in vitro pharmacodynamic investigation was conducted to explore whether the area under the concentration time curve from 0 to 24 h (AUC(0-24))/MIC ratio could predict fluoroquinolone performance against Bacteroides fragilis. An in vitro model was used to generate kill curves for trovafloxacin (TVA) and levofloxacin (LVX) at AUC(0-24)/MIC ratios of 1 to 406 against three strains of B. fragilis (ATCC 25285, ATCC 23745, and clinical isolate M97-117). TVA and LVX were bolused prior to the start of experiments to achieve the corresponding AUC(0-24)/MIC ratio. Experiments were performed in duplicate over 24 h and in an anaerobic environment. Analyses of antimicrobial performance were conducted by comparing the rates of bacterial kill (K) using nonlinear regression analysis with 95% confidence intervals. Statistical significance was defined as a lack of overlap in the 95% confidence limits generated from the slope of each kill curve. For both TVA and LVX, K was maximized once an AUC(0-24)/MIC ratio of > or =40 was achieved and was not further increased despite a 10-fold increase in AUC(0-24)/MIC from approximately 40 to 400 against all three strains of B. fragilis. No significant differences were found in K between AUC(0-24)/MIC ratios of approximately 40 to 200. In experiments where AUC(0-24)/MIC ratios that were > or = 5 and < or = 44 were conducted, 64% demonstrated regrowth at 24 h. Resistant strains were selected in 50% of those experiments, demonstrating regrowth, which resulted in increased MICs of two- to 16-fold for both TVA and LVX. Regrowth did not occur, nor were resistant strains selected in any studies with an AUC/MIC that was > 44. Our findings suggest that fluoroquinolones provide antibacterial effects against B. fragilis in a concentration-independent manner associated with an AUC(0-24)/MIC ratio of > or =40. Also, the potential for the selection of resistant strains of B. fragilis may increase with an AUC(0-24)/MIC ratio of < or =44.

Anti-Infective Agents↗