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Four different methods for interpreting the results of checkerboard synergy testing were compared by applying each to a set of synergy study data. Statistically significant differences in synergy were detected among methods (% synergy ranged from 10 to 83%). As interpretations were found to vary widely based upon method, one should be aware of this in interpreting the relevant literature.
Aztreonam has been commonly used in various combinations to enhance antimicrobial spectrum of co-drugs and produce potential synergistic activity. Although well studied in vitro over 10 years ago, aztreonam combination testing has been poorly documented with newer or commonly used agents against contemporary isolates. All MIC tests (alone or in combination) used in this experiment were reference broth microdilution methods in checkerboard tray designs. Aztreonam was combined with ciprofloxacin, gatifloxacin, levofloxacin, cefepime, ceftazidime and imipenem at clinically relevant concentrations. Interaction categories were defined by established criteria. Forty strains each of Pseudomonas aeruginosa and Enterobacteriaceae (12 species; aztreonam MIC, 1-16 microg/ml) were tested for each antimicrobial combination (480 total determinations). No antagonism or indeterminate interactions were identified. The overall rates of synergy or partial synergy for aztreonam with fluoroquinolone combinations was 63.4% versus P. aeruginosa, greatest for aztreonam with gatifloxacin (67.5%). Interaction categories varied greatly among aztreonam with beta-lactam combinations. Aztreonam with ceftazidime or cefepime versus P. aeruginosa had 75.0 - 85.0% partial or complete synergy rates, but aztreonam with imipenem showed dominant indifference (65.0%). In contrast, aztreonam with imipenem was more likely to exhibit synergy (32.5%) when tested against Enterobacteriaceae. Aztreonam, often used as an aminoglycoside substitute in antimicrobial combinations, continues to demonstrate enhanced, but variable drug activity interactions for contemporary antimicrobial combinations when tested against recent (2002) clinical isolates.
In this study, we investigated the hypothesis that the problem of motor redundancy could be solved using synergies representing rules for relative joint involvement to ensure a desired endpoint trajectory which may be context-dependent and may change with practice. Subjects practised a planar movement 'as fast as possible' from an initial to a final position, avoiding three round obstacles. The improvement in motor performance included a decrease in movement time and in the error scores. It was accompanied by the emergence of two distinct synergies. The first one involved elbow and shoulder movements and was used to move from the initial position to the first obstacle, and from obstacle to obstacle, whereas the second, involving the wrist, was used while going around the obstacles. The first synergy was seen before practice and showed an increase in joint coupling with practice. The second synergy was not seen prior to practice; it could not be explained by the pseudo-inverse transformation. We concluded that the central nervous system (CNS) has options for solving the redundancy problem, and that the solutions may be chosen based on such considerations as accuracy requirements, inertial properties of segments, and efficacy of particular joints to move the endpoint along a desired trajectory.
A central issue in motor control is how the central nervous system generates the muscle activity patterns necessary to achieve a variety of behavioral goals. The many degrees of freedom of the musculoskeletal apparatus provide great flexibility but make the control problem extremely complex. Muscle synergies--coherent activations, in space or time, of a group of muscles--have been proposed as building blocks that could simplify the construction of motor behaviors. To evaluate this hypothesis, we developed a new method to extract invariant spatiotemporal components from the simultaneous recordings of the activity of many muscles. We used this technique to analyze the muscle patterns of intact and unrestrained frogs during kicking, a natural defensive behavior. Here we show that combinations of three time-varying muscle synergies underlie the variety of muscle patterns required to kick in different directions, that the recruitment of these synergies is related to movement kinematics, and that there are similarities among the synergies extracted from different behaviors.
AIMS: To demonstrate the effect that non-linear dose responses have on the appearance of synergy in mixtures of antimicrobials. METHODS AND RESULTS: A mathematical model, which allows the prediction of the efficacy of mixtures of antimicrobials with non-linear dose responses, was produced. The efficacy of antimicrobial mixtures that would be classified as synergistic by time-kill methodology was shown to be a natural consequence of combining antimicrobials with non-linear dose responses. CONCLUSIONS: The effectiveness of admixtures of biocides and other antimicrobials with non-linear dose responses can be predicted. If the dose response (or dilution coefficient) of any biocidal component, in a mixture, is other than one, then the time-kill methodology used to ascertain the existence of synergy in antimicrobial combinations is flawed. SIGNIFICANCE AND IMPACT OF THE STUDY: The kinetic model developed allows the prediction of the efficacy of antimicrobial combinations. Combinations of known antimicrobials, which reduce the time taken to achieve a specified level of microbial inactivation, can be easily assessed once the kinetic profile of each component has been obtained. Most patented cases of antimicrobial synergy have not taken into account the possible effect of non-linear dose responses of the component materials. That much of the earlier literature can now be predicted, suggests that future cases will require more thorough proof of the alleged synergy.
BAL9141 has been reported to have inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA), many enterococci, and streptococci with various resistant patterns. BAL9141 potency was assessed by time-kill curves alone or with subinhibitory concentrations of gentamicin (MIC/4). BAL9141 exhibited bactericidal activity alone against all the streptococci and staphylococci. Among ampicillin-susceptible enterococci, BAL9141 was bactericidal against some strains, but no BAL9141 inhibition was observed of ampicillin-resistant Enterococcus faecium. The activity of BAL9141 with gentamicin was slightly enhanced (not synergy) or indifferent against staphylococci. BAL9141 demonstrated bactericidal action alone against Enterococcus faecalis and some E. faecium strains (-4.8 to -6.0 log10 CFU/mL), but static effects were also noted. Drug interactions with gentamicin showed early synergy (4-8 h) for all enterococci, and indifference or synergy at 24 h (no antagonism). BAL9141 (< or = 8 mg/L) showed promising bactericidal activity alone and synergy with gentamicin against some of the vancomycin-resistant enterococci tested.
Selecting the appropriate muscle pattern to achieve a given goal is an extremely complex task because of the dimensionality of the search space and because of the nonlinear and dynamical nature of the transformation between muscle activity and movement. To investigate whether the central nervous system uses a modular architecture to achieve motor coordination we characterized the motor output over a large set of movements. We recorded electromyographic activity from 13 muscles of the hind limb of intact and freely moving frogs during jumping, swimming, and walking in naturalistic conditions. We used multidimensional factorization techniques to extract invariant amplitude and timing relationships among the muscle activations. A decomposition of the instantaneous muscle activations as combinations of nonnegative vectors, synchronous muscle synergies, revealed a spatial organization in the muscle patterns. A decomposition of the same activations as a combination of temporal sequences of nonnegative vectors, time-varying muscle synergies, further uncovered specific characteristics in the muscle activation waveforms. A mixture of synergies shared across behaviors and synergies for specific behaviors captured the invariances across the entire dataset. These results support the hypothesis that the motor controller has a modular organization.
We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) beta deficiency. Egr-1 activates the LHbeta gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function. To test if this synergy is essential for gonadotropin-releasing hormone (GnRH) stimulation of LHbeta, we examined the activity of the LHbeta promoter in the gonadotrope cell line LbetaT2. GnRH markedly stimulated the LHbeta promoter (15-fold). Mutation of either Egr-1 or SF-1 elements within the LHbeta promoter attenuated this stimulation, whereas mutation of both promoter elements abrogated GnRH induction of the LHbeta promoter. Furthermore, GnRH stimulated Egr-1 but not SF-1 expression in LbetaT2 cells. Importantly, overexpression of Egr-1 alone was sufficient to enhance LHbeta expression. Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust. We also found that the nuclear receptor DAX-1, a repressor of SF-1 activity, reduced Egr-1-SF-1 synergy and diminished GnRH stimulation of the LHbeta promoter. We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LHbeta gene and plays a central role in the dynamic regulation of LHbeta expression.
Expression of the mouse immunoglobulin kappa locus is regulated by the intron and 3' enhancers. Previously, we have reported that these enhancers can synergize at mature B cell stages. Here we present our recent studies on the identification and characterization of the 3' enhancer sequences that play important roles in this synergy. By performing mutational analyses with novel reporter constructs, we find that the 5' region of the cAMP response element (CRE), the PU. 1/PIP, and the E2A motifs of the 3' enhancer are critical for the synergy. These motifs are known to contribute to the enhancer activity. However, we also show that mutating other functionally important sequences has no significant effect on the synergy. Those sequences include the 3' region of the CRE motif, the BSAP motif, and the region 3' of the E2A motif. We have further demonstrated that either the 5'-CRE, the PU.1/PIP, or the E2A motif alone is sufficient to synergize with the intron enhancer. Moreover, the PU.1 motif appears to act as a negative element at pre-B cell stages but as a positive element at mature B cell stages. We have also identified a novel negative regulatory sequence within the 3' enhancer that contributes to the regulation of synergy, as well as developmental stage and tissue specificity of expression. While the levels of many of the 3' enhancer binding factors change very little in cell lines representing different B cell stages, the intron enhancer binding factors significantly increase at more mature B cell stages.
Combination therapies treating human immunodeficiency virus type 1 (HIV-1) infection delay the emergence of drug-resistant virus and exhibit synergistic inhibition. This synergy is observed within the two classes of inhibitors that target the essential viral reverse transcriptase (RT): the chain-terminating nucleoside analogs (NRTIs) and the allosteric nonnucleosides (NNRTIs) that bind in a pocket distinct from the active site. A general mechanism to define the molecular basis for synergy between these two classes remains to be elucidated. Previous mechanistic studies from our laboratory (Spence, R. A., Kati, W. M., Anderson, K. S., and Johnson, K. A. (1995) Science 267, 988-993) have shown that the natural deoxynucleoside triphosphate and the NNRTI can simultaneously bind to their respective sites. This work also suggests communication between the two sites, since the inhibition of RT by NNRTIs is manifested through a remote effect on the chemical step. This interplay between the two sites offers a plausible hypothesis for understanding synergy in which binding of NNRTIs modulates the chain termination by NRTIs. The present study supports this hypothesis by illustrating that the clinically approved NNRTIs, nevirapine and efavirenz, inhibit the ATP-mediated removal of AZTMP, d4TMP, ddCMP, (-)3TCMP, (-)FTCMP, and (+)3TCMP, thereby prolonging the effectiveness of chain termination. This inhibition is mediated through an effect on both the rate of the chemical step and binding of ATP, resulting in an overall decrease in efficiency of removal. This work substantiates communication between the two binding pockets, the sustained use of combination therapy to treat HIV infection, and a molecular basis for understanding synergy.
Tight regulation of luteinizing hormone-beta subunit (LHbeta) expression is critical for differentiation and maturation of mammalian sexual organs and reproductive function. Two transcription factors, steroidogenic factor-1 (SF-1) and early growth response-1 (Egr-1), play a central role in activating LHbeta promoter, and the synergy between these two factors is essential in mediating gonadotropin-releasing hormone stimulation of LHbeta promoter. Here we demonstrate that the transcriptional co-activator p300 regulates this synergy. Overexpression of p300 results in strong stimulation of LHbeta promoter but only in the presence of both SF-1 and Egr-1, and not in the presence of other Egr proteins. Mutation of the binding sites for either SF-1 or Egr-1 completely abolishes the synergy between these two factors, as well as the influence of p300. Importantly, LHbeta promoter is precipitated using p300 antibodies in a chromatin immunoprecipitation assay with LbetaT2 gonadotropes, and this effect is enhanced by gonadotropin-releasing hormone. The influence of p300 on LHbeta promoter is potentiated by steroid receptor co-activator, as well as by E1A proteins, and attenuated by Smad nuclear interacting protein 1. Taken together, these results suggest that p300 is recruited to LHbeta promoter where it coordinates the functional synergy between SF-1 and Egr-1.
Cell adhesion and migration on fibronectin (FN) extracellular matrix are mediated by integrin receptors. Integrins alpha5beta1 and alphavbeta3 require the RGD cell-binding sequence in FN, but alpha5beta1 also requires the nearby synergy site for maximal binding. In this study, we investigated how differences in the numbers of RGD or synergy sites within a three-dimensional (3D) FN-rich matrix influence cell adhesion and migration. CHO cell adhesion, spreading, and migration were reduced on 3D chimeric matrix containing FN lacking RGD (FN(RGD-)). Incorporation of FN with mutation of the synergy site (FN(syn-)), however, resulted in selective usage of integrins. CHO cells expressing alpha5beta1 showed decreased interactions with FN(syn-) chimeric matrix. In contrast, the presence of FN(syn-) had no effect on CHOalphavbeta3 cell migration. Interestingly, CHOalpha5/alphavbeta3 cells expressing both integrins selectively used alpha5beta1 for migration on wild type FN matrix but preferred alphavbeta3 for migration on FN(syn-) chimeric matrix. Thus sequestration or exposure of the FN synergy site within a 3D matrix may represent a novel mechanism for regulating cell functions through differential usage of integrin receptors. [Supplementary materials are available for this article. Go to the publisher's online edition of Cell Communication and Adhesion for the following free supplemental resource: a video recording shows migration of HT1080 cells on 3D matrix. HT1080 cells were allowed to attach to the matrix in serum-free DMEM for 2 h. FBS was then added to the medium to a final concentration of 10% and video recording was started. Images were taken every 5 min for 2 h. The video plays at 6 frames/s.].
Initiation of fibronectin (FN) matrix assembly is dependent on specific interactions between FN and cell surface integrin receptors. Here, we show that de novo FN matrix assembly exhibits a slow phase during initiation of fibrillogenesis followed by a more rapid growth phase. Mn2+, which acts by enhancing integrin function, increased the rate of FN fibril growth, but only after the initial lag phase. The RGD cell-binding sequence in type III repeat 10 is an absolute requirement for initiation by alpha5beta1 integrin. To investigate the role of the cell-binding synergy site in the adjacent repeat III9, a full-length recombinant FN containing a synergy mutation, FN(syn-), was tested for its ability to form fibrils. Mutation of this site drastically reduced FN assembly by CHOalpha5 cells. Only sparse short fibrils were formed even after prolonged incubation, indicating that FN(syn-) is defective in progression of the assembly process. These results show that the synergy site is essential for alpha5beta1-mediated accumulation of a FN matrix. However, the incorporation of FN(syn-) into fibrils and the deoxycholate-insoluble matrix could be stimulated by Mn2+. Therefore, exogenous activation of integrin receptors can overcome the requirement for FN's synergy site as well as modulate the rate of FN matrix formation.
Children with spastic hemiplegia have impaired dexterity in the affected extremity. The purpose of the present study was to investigate whether the force co-ordination pattern during precision grip in 13 children between 4 and 10 years of age with predominant unilateral brain lesions is related to manual dexterity and to the location and size of the brain lesion. The force co-ordination pattern was investigated by means of a specially designed object that monitored the isometric fingertip forces applied to the contact surfaces during precision grip. Hand function was measured by means of neurological examination, functional hand-grips and dexterity. Brain lesions were identified by series of ultrasound and MRI scans. Normally, the fingertip forces are applied to the object in the initial phase of the lift in an invariant force co-ordination pattern (i.e. grip-lift synergy), in which the grip and load forces are initiated simultaneously and increase in parallel with unimodal force rate trajectories. A majority of children with unilateral brain lesions had not developed the force co-ordination pattern typical for their age, but produced an immature or a pathological pattern. The developmental level of the grip-lift synergy was determined and quantified according to criteria derived from earlier studies on normally developed children. There was a clear relationship between the developmental level of the grip-lift synergy and impaired dexterity, indicating that proper development of the force co-ordination pattern is important for skilled hand function. The grip-lift synergy correlated with the total extent of lesions in the contralateral cortex and white matter and with lesions in the thalamus/basal ganglia, while no correlation was found for isolated cortical lesions. The results suggest that the neural circuits involved in the control of the precision grip are organized in a parallel and distributed system in the hemispheres, and that the basal ganglia are important during the formation of these circuits. Perinatal lesions in specific cortical motor areas may be compensated for by circuits elsewhere in the grip-lift motor system, while large lesions exclude this possibility.
The in vitro effect of nine antibiotic combinations was investigated in Staphylococcus epidermidis biofilms using ATP-bioluminescence for viable bacterial cell quantification. Four slime-producing (SP) strains were used to form biofilms 6, 24 and 48 h old. These biofilms were exposed for 24 h to antibiotics at 4 x, 2 x, 1 x and 0.5 x MIC. Combinations involving tetracycline together with another antibiotic were the most efficient at the biofilm age and concentration range under study. The combination vancomycin-rifampicin produced the highest bactericidal effect on 6 h biofilms at 4 x MIC, but this effect decreased dramatically in older biofilms. To detect possible antibiotic synergy in combinations that had a significant killing effect, antibiotics were studied not only in combination but also individually. Synergic effects were observed in all the combinations tested. Differences between the effect in combination and the sum of individual antibiotic effects (degree of synergy) were significant (mostly P< 0.001) and exceeded 1 log10 cfu/mL in the majority of cases. In 48 h biofilms, antibiotics caused a significant bactericidal effect when applied in combination, but never when used individually. These results indicate that the biofilm test applied allows the detection of synergy between antibiotics and suggests that this assay could be useful in clinical and extensive synergy studies on S. epidermidis biofilms.
We used a novel screening method to look for synergy between daptomycin and 18 other antibiotics against 19 strains of high-level vancomycin-resistant enterococci (VRE) (vancomycin MIC > or = 256 mg/L). In this approach, daptomycin was incorporated into Ca(2+)-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Etest MICs on agar with and without daptomycin. A striking reduction in the rifampicin MIC was seen in 11/15 (73.3%) VRE that were resistant to rifampicin, from > or =12 mg/L to a mean +/- s.d. of 0.22 +/- 0.21 mg/L at daptomycin 0.25 x MIC and 0.85 +/- 0.90 mg/L at daptomycin 0.125 x MIC. Synergy was also observed for 13/19 (68%) isolates with ampicillin (MIC > or = 128 mg/L). There was no significant synergy between daptomycin and any other antibiotic by this screening method. If confirmed by further studies, daptomycin with either rifampicin or ampicillin may be useful in the management of infections caused by VRE.
STUDY DESIGN: This prospective study evaluated the abdominal muscle activity during the Isometric bent knee curl and double straight leg lowering exercise. OBJECTIVES: To compare the magnitude of the electromyographic activity across the curl and double straight leg lowering exercise and determine if the muscle synergies were specific to a given exercise. SUMMARY OF BACKGROUND DATA: Abdominal muscle strengthening exercises are frequently recommended in the prevention and rehabilitation of individuals with low back pain. Previous studies comparing the curl exercise with the double straight leg lowering exercise did not support the notion that the double straight leg lowering exercise is more demanding on the abdominal muscles. No previous study examined these two exercises while maintaining a constant pelvic position. METHODS: Fifteen male subjects had the electromyographic activity of the rectus abdominis, the external oblique, and the internal oblique abdominal muscles evaluated during the curl and double straight leg lowering exercise. The same position of the posterior pelvic tilt was maintained between each exercise using feedback from an electrogoniometer attached to the pelvis. RESULTS: The double straight leg lowering exercise resulted in significantly greater activation of the abdominal muscles compared with the curl. Two abdominal muscle synergies emerged during the double straight leg lowering exercise: synergy I exhibited high rectus abdominis, high external oblique, and low internal oblique muscle activity, whereas synergy II exhibited low rectus abdominis, high external oblique, and high internal oblique. CONCLUSIONS: The results support the use of the double straight leg lowering with the posterior pelvic tilt for achieving greater abdominal muscle coactivation in an exercise program.
The effect of in-vitro granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of neutrophils, monocytes or monocyte-derived macrophages (MDM) on candidacidal activity was tested. Synergy of effector cells with fluconazole (FCZ) for enhanced killing was also investigated. Incubation of neutrophils with GM-CSF 0.67 microg/L plus Candida albicans Sh27 for 24 h significantly increased candidacidal activity (36% versus 74%). Synergy with FCZ for killing was also significantly increased from 93% to 97% when neutrophils were incubated with GM-CSF. Monocytes cultured with GM-CSF and C. albicans for 24 h had significantly increased fungistatic activity compared to controls and synergy with FCZ for killing was significantly enhanced from 40% to 59%. Monocytes cultured for 3 days with GM-CSF had increased fungistatic activity compared to control MDM and showed synergy with FCZ for significantly enhanced killing (46%) compared to control MDM (12%).