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Modulation of simple reaction time on the background of an oscillatory action: implications for synergy organization.

The hypothesis put forward here is that simple reaction time (SRT) modulation on the background of an oscillatory motor action is due to central neural coupling between signals to the effectors involved in the focal and the oscillatory action. The strength of the coupling may be defined by various factors ranging from anatomy to personal lifetime practice or to a particular task context. In one experiment, subjects performed an SRT task (ipsi or contralateral elbow flexion or ipsilateral ankle plantar flexion) in response to a visual imperative signal presented during a continuous oscillatory movement of the right wrist. Discrete elbow movements lead to nearly simultaneous large bursts of activity in both biceps and the wrist flexor of the arm. Strong modulation of premotor time (peak to peak changes of about 80 ms) with the phase of oscillatory action (f(OSC)) was seen in both biceps and wrist flexor when the two movements were performed by joints of the same limb but not when they were performed by joints of different limbs. The order of recruitment of proximal and distal muscles was also dependent on the phase of oscillatory action: the typical proximal-to-distal order was seen at relatively long premotor times (PMTs) while simultaneous muscle activation was seen at the shortest PMTs. In the second experiment, the subjects held a cylindrical plastic cup in the left hand and applied sine-like isometric force to the bottom of the cup with the other hand. The SRT in the task requiring a quick increase in the grip force in response to a visual imperative stimulus was modulated with the phase of the oscillatory action. This modulation disappeared when the right hand applied similarly modulated force to another surface. The conclusion is that an interaction between control signals for the focal and oscillatory actions at a supraspinal level led to the observed modulation of the SRT during the phase of oscillatory action. The possible role of cortical and subcortical mechanisms is discussed.

Adult↗

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

OBJECTIVE: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. METHODS: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. RESULTS: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); P < 0.01] and IDAOL [2896.60 (736.38) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l x h(-1) x m(-2) vs 139.65 (69.45) l x h(-1) x m(-2); NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) microg x h x l(-1) vs 2896.60 (736.38) microg x h x l(-1); P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. CONCLUSION: The results show that CyA alone at a dose of 10 mg x kg(-1) daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Cyclosporine↗

Tube current reduction in pediatric non-ECG-gated heart CT by combined tube current modulation.

BACKGROUND: Dose reduction by combined tube current modulation has not been evaluated in pediatric low-dose CT. OBJECTIVE: This study was performed to evaluate tube current reduction in non-ECG-gated heart CT angiography in children by combined tube current modulation, and to assess the effects of body weight, age, sex, and scan direction on tube current reduction. MATERIALS AND METHODS: From September 2004 to January 2005, non-ECG-gated heart CT examinations were performed with combined tube current modulation in 50 children (median age 1 year, range 1 month to 16 years; M/F 29/21) with congenital heart disease. Sixteen-slice spiral CT studies were obtained using a weight-based low-dose protocol (80 kVp, 50-160 effective mA). CT scans were obtained in the craniocaudal direction when leg veins (n=36) were used for IV injection of contrast agent and in the caudocranial direction when arm veins (n=13) were used. In one child who underwent a Fontan operation, both arm and leg veins were used. We calculated tube current reduction by combined tube current modulation and evaluated the effects of body weight, age, sex, and scan technique on tube current reduction. The quality of CT angiography images was visually evaluated by an experienced pediatric radiologist. RESULTS: Overall tube current reduction by combined tube current modulation was 15.8+/-11.1%. The reduction was variable among five body weight groups (9.3+/-7.9% for <4.9 kg, 14.3+/-9.3% for 5.0-9.9 kg, 16.4+/-12.5% for 10.0-19.9 kg, 25.8+/-9.8% for 20.0-39.9 kg, 15.9+/-12.7% for 40.0-59.9 kg) and was significantly different among the five groups (P=0.017). When eight children in the 40.0-59.9-kg group were excluded, age showed a significant positive correlation with tube current reduction (gamma=0.4, P=0.003). There was no significant difference in tube current reduction between boys and girls. Tube current reduction was significantly greater for the caudocranial scan (21.2+/-9.2%) than for the craniocaudal scan (14.2+/-11.3%) (P=0.049). All CT angiography images were of diagnostic quality. CONCLUSIONS: Combined tube current modulation reduced tube current in pediatric non-ECG-gated heart CT by 15.8% without degradation of image quality. With our CT protocol, for body weights up to 39.9 kg, age showed a significant positive correlation with tube current reduction, but there was a lower dose-saving effect in children heavier than 40 kg. Tube current reduction was not affected by sex, but was affected by scan direction.

Adolescent↗

Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer.

INTRODUCTION: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. PATIENTS AND METHODS: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m2/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. RESULTS: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. CONCLUSION: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.

Adult↗

Dose reduction in subsecond multislice spiral CT examination of children by online tube current modulation.

The potential of online tube current modulation in subsecond multislice spiral CT (MSCT) examinations of children to reduce the dose without a loss in image quality is investigated in a controlled patient study. The dose can be reduced for oval patient sectional view without an increase in noise if the tube current is reduced where the patient diameter and, consequently, attenuation are small. We investigated a product version of an online control for tube current in a SOMATOM Sensation 4 (Siemens, Forchheim). We evaluated image quality, noise and dose reduction for examinations with online tube current modulation in 30 MSCT of thorax/abdomen and abdomen and compared mA s for tube current modulation to the mA s in standard weight-adapted children protocols. Image quality was rated as "very good," "good," "diagnostic" and "poor" in a consensus by three radiologists. Noise was assessed in comparison to 24 MSCT examinations without tube current modulation measured as SD in ROIs. The dose was reduced from 26 to 43% (mean 36%), depending on the patient's geometry and weight. In general, no loss of image quality was observed. Measured noise showed a decrease up to 26% and an increase up to 36%, although there was no decrease of image quality. Online tube current modulation is now used as a standard in MSCT at our institution. Dose in MSCT examinations of children can be reduced substantially in routine examinations by online tube current modulation without a loss of image quality.

Child↗

Validation of the German prostate-specific module.

Theoretically, all patients newly diagnosed with prostate cancer are faced with a choice of treatment options: radical prostatectomy or radio therapy. Although these different treatments may have no differences in terms of survival, they may have very different consequences on the subsequent quality of life (QoL). Prerequisite to analyze QoL is a reliable and valid instrument to assess these differences not only in terms of general QoL (EORTC QLQ-C30) but prostate specific symptoms with a prostate specific module as well. Therefore, the aim of this study was a psychometric evaluation (validation) of the prostate-specific module (PSM). Five historical cohort studies were put together for an empirical meta-analysis. The main objective was to analyze the module's psychometric properties. The total sample consisted of 1,185 patients, of whom 950 completed the QoL questionnaires (EORTC QLQ-C30 and a prostate specific module developed by Kuechler et al.). First step of analysis was a principal component analysis that revealed the following scales: urinary problems, incontinence, erectile dysfunction, sexual problems, problems with partner, pain, heat, nutrition, and psychic strain. The module showed good reliability and concurrent validity and very good construct validity, since the module is able to discriminate between different treatment regimes, tumor stages and age. The German PSM is a reliable, valid and applicable tool for QoL in patients with prostate cancer.

Adaptation, Psychological↗

Coding of amplitude modulation in the auditory midbrain of the bullfrog (Rana catesbeiana) across metamorphosis.

The functional development of the auditory system across metamorphosis was examined by recording neural activity from the torus semicircularis of larval and postmetamorphic bullfrog froglets in response to amplitude-modulated sound. Multiunit activity in the torus semicircularis during early larval stages showed significant phase-locking to the envelopes of amplitude-modulated noise bursts, up to modulation rates as high as 250 Hz. Beginning at metamorphic climax and continuing into the froglet period, phase locking was restricted to the more limited frequency range characteristic of adult frogs. The onset of operation of the tympanic pathway does not reinstate the highly synchronous neural activity characteristic of the operation of the fenestral pathway. Modulation transfer functions based on spike count did not show tuning for modulation rate in early stage tadpoles, but a greater variety of shapes of these functions emerged as development proceeded. Most of the different kinds of modulation transfer functions seen in adult frogs were also observed in froglets, but band-pass functions were not as sharply peaked. These data suggest that different neural codes for processing of the periodicity of complex signals operate in early stage tadpoles than in postmetamorphic froglets.

Acoustic Stimulation↗

Kinetics and Gbetagamma modulation of Ca(v)2.2 channels with different auxiliary beta subunits.

Modulation of calcium channels by both auxiliary subunits and G proteins was studied in cell-attached patches from COS-7 cells transfected with Ca(v)2.2 channel subunits (N-type, alpha(1)B and either beta(1b) or beta(2a)). These were co-expressed with either Gbeta(1)gamma(2) or the Gbetagamma-binding domain of beta-adrenergic-receptor kinase-1 to sequester endogenous Gbetagamma. Since G protein modulation of Ca(v) channels may affect both inactivation and activation, we examined Gbetagamma modulation of Ca(v)2.2 channels in the presence of two different beta-subunits that affect inactivation differently and compared in detail the single-channel characteristics of N-type channels expressed with either of these beta-subunit isoforms. The single-channel mean amplitude and mean open time were not influenced by the transfection combination. However, the mean closed time at +40 mV was increased for both beta(1b) and beta(2a)-subunits by co-transfection with Gbeta(1)gamma(2). This effect was absent at lower voltages as examined for channels with the beta(1b)-subunit. The distribution of latency-to-first-opening of Ca(v)2.2 channels was similar for both beta-subunit isoforms. However, the inclusion of the beta(2a) subunit resulted in channels with an additional, prominent, slow activation phase. Co-transfection of Gbeta(1)gamma(2) with Ca(v)2.2 channels markedly reduced the ensemble current amplitude and slowed the first latency. The inhibition imposed by Gbeta(1)gamma(2) was largely independent of the beta-subunit species. Facilitation of Gbetagamma-modulated currents (the channel response following a large and brief depolarising prepulse) was observed for channels with both beta-subunits and involved mainly enhancement of the activation, as assessed by the faster first latency. The inactivation process was strongly dependent on the beta-subunit species, with beta(1b) supporting inactivation and beta(2a) reducing this process. This difference was assessed by estimation of both steady-state inactivation (prepulse influence on test pulse responses) and the inactivation time course during depolarisation. At +40 mV, channels with the beta(1b)-subunit had a fast component of inactivation (time constant ~180 ms, 50%) and a slow phase with time constant of approximately 1 s, while the beta(2a)-subunit supported only a very slow inactivation process with time constant of approximately 5 s. Co-transfection of Gbeta(1)gamma(2) with the Ca(v)2.2 channel had no effect on the inactivation properties with either beta-subunit. In summary, we show that the inactivation properties of expressed Ca(v)2.2 channels depend largely on the beta-subunit species and to a minor extent only on the presence or absence of the Gbetagamma modulator. Furthermore, the activation, amplitude, mean open and closed times and G protein modulation of N-type channels were similar for both beta(1b)- and beta(2a)-subunits.

Algorithms↗

Hyperforin modulates gating of P-type Ca2+ current in cerebellar Purkinje neurons.

Whole-cell, patch-clamp recordings from acutely isolated cerebellar Purkinje neurons demonstrate a two-stage modulation of P-type high-voltage-activated (HVA) Ca2+ current by a constituent of St. John's wort, hyperforin (0.04-0.8 microM). The first stage of modulation was voltage dependent and reversible. It comprised slow-down of the activation kinetics and a shift in the voltage dependence of P-current to more negative voltages. Hyperforin (0.8 microM) shifted the maximum of the current/voltage (I/V) relationship by -8+/-2 mV. The second, voltage-independent stage of modulation was manifested as a slowly developing inhibition of P-current that could not be reversed within the period of study. Neither form of modulation was abolished by intracellular guanosine 5'-O-(2-thiodiphosphate) (GDPPS) or guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) or by strong depolarising pre-pulses, indicating that modulation via guanine nucleotide-binding proteins (G proteins) is not involved in the observed phenomenon. Calmidazolium (0.5 microM), an antagonist of the intracellular Ca2+-binding protein calmodulin significantly inhibited the hyperforin-induced shift of the IIV curve maximum and the slow-down of the activation kinetics. It did not, however, affect the delayed inhibition of P-current, indicating that the two stages of modulation are mediated by separate mechanisms.

Animals↗

Characterization and partial purification of the VDAC-channel-modulating protein from calf liver mitochondria.

The mitochondrial channel, VDAC, mediates metabolic flux across the mitochondrial outer membrane. When reconstituted into planar phospholipid membranes, VDAC is voltage-dependent, existing in multiple conformational states with different selectivities and permeabilities. At low membrane potentials, these channels are in the open state and are anion-selective. VDAC channels switch to lower-conductive closed states at high membrane potentials. The VDAC modulator, a soluble mitochondrial protein, has been demonstrated to dramatically increase the voltage dependence of VDAC channels and induce the channels to enter closed states even at low membrane potentials. We have isolated and partially purified this modulating protein and the activity is associated with a 54 kDa protein on SDS-PAGE. Under native reduced conditions the activity eluted around 100 kDa from a gel filtration column. As little as 200 ng/ml of the partially purified protein was sufficient to modulate reconstituted VDAC channels. This protein had a pI of 5.1. A second activity with a pI of 4.8 was far more potent, making VDAC-channel-containing membranes virtually non-conductive in some experiments. The effects of both modulator activities could be completely reversed by the addition of pronase. Simple perfusion of the chamber did not reverse the effect of the modulator on VDAC. By controlling the gating of VDAC channels, the VDAC modulator could play an important role in regulating cellular metabolism.

Animals↗

Modulation of cortical and pyramidal tract induced motor responses by electrical stimulation of the basal ganglia.

Two general mechanisms based on anatomical studies are possible for modulation of motor activity by the caudate nucleus and globus pallidus. These mechanisms are: (1) modulation of the output of cortical neurons that exert motor influences; and (2) modulation of subcortical neurons that exert motor influences. Differentiation between these two mechanisms was accomplished in the present study by two experimental approaches, both of which employed the conditioning-test paradigm. The first approach was an investigation of caudate nucleus or globus pallidus modulation (conditioning stimulus) of flexor responses of the anterior tibialis muscle elicited by electrical stimulation of the sensorimotor cortex (test stimulus) or pyramidal tract (test stimulus). These investigations were carried out in the intact and in decorticate cats. The second approach was an analysis of modulation or cortically induced pyramidal tract responses (direct and indirect, D-I potentials) by conditioning shock trains delivered to various loci within the caudate nucleus or globus pallidus. Both approaches were designed to determine whixh inhibitory and facilitatory motor influences of the basal ganglia occurred at a cortical or subcortical level. Simultaneous stimulation of a locus within the caudate nucleus and the sensorimotor cortex evoked either an enhancement, reduction or no alteration of the cortically induced increase in flexor responses (measured by Ia afferent activity, EMG, myogram). In contrast, no inhibitory influences occurred from caudate nucleus stimulation upon pyramidal tract induced flexor responses in either the intact or decorticate preparation. Inhibitory loci were distributed toward the rostral portion of the caudate nucleus, whereas facilitatory loci were distributed throughout; this distribution was statistically significant (chi2; P less than 0.01). Only enhancement or no influence upon cortical induced or pyramidal tract induced responses were obtained by conditioning stimuli to the globus pallidus. In the unanesthetized but immobilized cat, trains of shocks delivered to the caudate nucleus enhanced, reduced or had no influence upon the cortically evoked direct (D) and indirect (I) potentials recorded in the bulbar pyramidal tract. The distribution of facilitatory and inhibitory loci was organized in a similar fashion as in theanesthetized preparation. From these observations, a model was proposed in which the output of the caudate nucleus exerts both facilitatory or inhibitory modulation of the tonically active globus pallidus cells. The latter in turn predominantly or exclusively facilitate output of pyramidal tract neurons as well as the output of subcortical structures; both effects facilitate motor responses at the spinal level.

Animals↗

Phase-dependent modulation of dorsal root potentials evoked by peripheral nerve stimulation during fictive locomotion in the cat.

To help elucidate the role of presynaptic mechanisms in the control of locomotor movements, the transmission of PAD pathways was investigated by recording dorsal root potentials (DRPs) evoked by electrical stimulation of cutaneous and muscle nerves of both hindlimbs at various phases of the fictive step cycle. Fictive locomotion occurred spontaneously in decorticate cats or by stimulating the mesencephalic locomotor region (MLR) as well as in low spinal cats injected with nialamide and L-DOPA. Evoked DRPs were superimposed on a fluctuating DRP accompanying the fictive locomotor rhythm (locomotor DRP) which typically consisted of two peaks of depolarization per cycle, the largest peak occurring during the flexor phase. The amplitude of evoked DRPs was substantially modulated throughout the locomotor cycle and followed a similar modulation pattern for all stimulated nerves whether ipsilateral (i-) or contralateral (co-). The amplitude of evoked DRPs decreased at the beginning of the flexor phase, dropped to a minimum later in the flexor phase and then increased during the extensor phase where it became maximum. Results were comparable in decorticate and spinal preparations and for L6 and L7 rootlets with cutaneous and muscle nerve stimulation. It is noteworthy that the modulation pattern for a given rootlet was similar for i- and co- stimulation, even though the bilateral locomotor DRPs fluctuate out-of-phase with each other, subjecting the stimulated fibres to opposite presynaptic polarization changes. This suggests that the modulation may depend more on the presynaptic mechanisms of the receiving fibres than on those of the stimulated fibres. These results demonstrate that the transmission in spinal pathways involved in primary afferent depolarization (PAD) is phasically modulated by the activity in the spinal locomotor network. It is further suggested that the presynaptic inhibition associated with PAD evoked by movement-related sensory feedback during real locomotion could be modulated in a similar way.

Animals↗

Interhemispheric relationships of reponses to sine wave modulated light in normal subjects and patients.

(1) The interhemispheric amplitude correlations of the fundamental (A1) and second harmonic (A2) components of responses to sine wave modulated light were determined in the occipital, parietal and temporal scalp areas of a group of normal subjects and a group of patients with unilateral irritative EEG phenomena. The interhemispheric amplitude correlation was computed at 10- and 16-c/sec stimulation frequencies and under 3 conditions: no modulation and no attention (M-, A-), modulation 30%, and no attention (M+, A-) and modulation 30% and attention (M+, A+). The correlations wre expressed in the rank correlation coefficient of Kendall (rK). (2) Analysis of variance revealed that the interhemispheric amplitude correlation of A1 in the normal group was significantly larger than that in the patient group at a stimulation frequency of 10 c/sec and under the conditions (M-, A-) and (M+, A-). (3) Both groups presented the largest correlation coefficients in the occipital scalp area. (4) In the normal group a significant increase of rK occurred under the influence of modulation. Attention caused a decrease of the correlation coefficient of A1. In the group of patients this influence was not clear. (5) The standard deviation of the mean interhemispheric phase differences was considered as a measure of synchrony of the response components between the two hemispheres. The smallest values of standard deviation were found in the occipital scalp area of the normal group at 10 c/sec stimulation frequency. Considerable variations between individuals were observed in both groups. (6) The correlation between the interhemispheric amplitude correlation (rK) and the interhemispheric synchrony was influenced by changing modulation depth from 0 to 30% and by introduction of attention, mostly in the group of normal subjects. This phenomenon was considered to support the theory that in patients with unilateral EEG disturbances the interhemispheric relations are different from those in normal subjects. (7) The findings as to amplitude correlation (rK) were the same under the condition (M-, A-) as under the condition (M+, A-).

Attention↗

Modulation of the mutagenic response in prokaryotes.

Short-term tests investigating genetic end-points in prokaryotes have been extensively used worldwide not only for risk assessment purposes but also for evaluating the modulation of the mutagenic response. In spite of some intrinsic limitations, such as the lack of cell compartmentalization or the need for an exogenous metabolic system working extracellularly, experimental systems in bacteria can provide useful preliminary indications and some information on the mechanisms involved. In the large majority of studies the putative modulator is mixed with a known mutagen and then assayed in target bacteria, with suitable controls. However, under natural conditions exposure of target cells to modulators may either precede, co-exist with, or follow exposure to mutagens. Therefore, a variety of methodological variations, involving pre-treatment, co-treatment, or post-treatment of bacteria with the putative modulator, have been designed. Application of these procedures showed that the effects of modulators can be completely upset, from inhibition to enhancement, or vice versa, by changing the experimental conditions. Use of methodological variations may provide more complete information on the spectrum of possible effects in bacteria as well as a better insight into modulation mechanisms. Several examples illustrating the flexibility of the Salmonella test in this field of research are available. On the other hand, the widespread use of these relatively simple techniques, yet requiring skillfulness and experience, may lead to some misuse or oversimplifications. A rather common inadequacy is to use excessive amounts of test mutagens, or to express the results in terms of revertants/survivors, rather than revertants/plate. In fact, in the Salmonella test the number of revertants is rather unrelated to the initial number of plated bacteria, provided a normal background lawn of bacterial growth is formed. Thus, a 50% killing of bacteria will not appreciably influence the number of revertants/plate, but expressed as revertants/survivors the effect will look twice as large.

Antimutagenic Agents↗

Metabotropic glutamate receptor modulation of synaptic transmission in corticostriatal co-cultures: role of calcium influx.

Modulation of excitatory glutamatergic transmission at corticostriatal synapses by a metabotropic glutamate receptor (mGluR) was examined using a newly developed cell culture preparation in which small explants of cortical tissue are grown in co-culture with isolated striatal neurons. Electrical stimulation of cortical tissue evoked excitatory postsynaptic currents (eEPSCs) observed during tight-seal, whole-cell recordings from striatal neurons. Transmission was mediated by activation of AMPA/kainate-type glutamate receptors. The mGluR agonists, 1SR,3RS-ACPD and DCG-IV, reduced eEPSC amplitude. The effect of 1SR,3RS-ACPD increased in a concentration-dependent manner. Application of phorbol diacetate (PDAc) potentiated eEPSC amplitude and reduced the inhibitory effect of mGluR activation. Pretreatment with pertussis toxin (PTX) also reduced inhibition by 1SR,3RS-ACPD. Under conditions in which transmission was independent of the function of voltage-gated calcium channels, mGluR activation reduced the frequency of occurrence of miniature EPSCs (mEPSCs), but did not alter mEPSC amplitude. This effect of mGluR activation was reduced by PDAc treatment. mGluR activation modulates glutamatergic transmission via a presynaptic autoreceptor at corticostriatal synapses in this newly-developed corticostriatal co-culture preparation as in striatal slices. Modulation of transmission occurs whether or not transmission involves activation of voltage-gated calcium channels. Furthermore, many of the characteristics of mGluR modulation of eEPSCs are shared by mGluR modulation of mEPSCs. These findings indicate that mechanisms downstream from calcium entry may contribute to modulation of synaptic transmission by mGluR autoreceptors.

Animals↗

Visual sensitivity to spatially sampled modulation in human observers.

Thresholds were measured for detecting spatial luminance modulation in regular lattices of visually discrete dots. Thresholds for modulation of a lattice are generally higher than the corresponding threshold for modulation of a continuous field, and the size of the threshold elevation, which depends on the spacing of the lattice elements, can be as large as a one log unit. The largest threshold elevations are seen when the sample spacing is 12 min arc or greater. These results are similar to those observed by Burr, Ross and Morrone [Vision Research, 25, 717-727 (1985)], who proposed an explanation based on a compressive point nonlinearity. Although their explanation is not consistent with the present data, the results may be explained in terms of nonlinear saturation of a spatially opponent stage early in the visual pathway. Theories based on response compression cannot explain the further observation that the threshold elevations due to spatial sampling are also dependent on modulation frequency: the greatest elevations occur with higher modulation frequencies. The idea that this is due to masking of the modulation frequency by the spatial frequencies in the sampling lattice is considered.

Contrast Sensitivity↗

Effects of flicker modulation depth on the detection of changes in target location.

Response times to a change in location of a small, low contrast target in a uniform flickering field were investigated under a range of flicker modulation depths. Increasing depth of modulation gave an increased response time for modulation depths from 0% (no flicker, to approx. 35%. Further increases in modulation depth had only a marginal effect on response time. It is shown that this effect is not due to flicker adaptation. The functional form of the modulation dependence is qualitatively similar to that reported by Badcock and Smith (1989, Vision Research, 29, 803-808), but shows a large difference in the modulation at which a levelling of performance occurred. It is shown that this difference is consistent with the presence of a third temporal filter, as proposed by Mandler and Makous (1984, Vision Research, 24, 1881-1887).

Adult↗

Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance.

Multidrug resistance is mediated by a membrane-bound protein, P-gp, that functions as an energy dependent efflux system to reduce the intracellular concentration of anticancer drugs by binding to these drugs and actively exporting them from the cell. Compounds that interact with P-gp and compete with anticancer drug binding modulate the degree of drug resistance and therefore enhance the cytotoxicity of anticancer drugs against the resistant cell. Effective modulators share certain physical and chemical properties including octanol/water partitioning and molecular size, but the physical properties of size and shape seem to correlate best with modulator effectiveness. Using a photoactivatable analog of vinblastine as a probe, together with a semi-synthetic series of structurally homologous reserpine and yohimbine analogs, the need for two planar aromatic domains and a basic nitrogen atom was established within the structural context of these compounds. The use of three-dimensional comparisons was extended to examine important structural features in other modulator types such as the condensed-ring aromatics. This approach indicates that structural similarities between different classes of compounds are present in compounds recognized by the MDR phenotype. These studies emphasize the importance of a ligand-receptor relationship for modulators of MDR, and begin to define the P-gp-binding pharmacophore. It is likely that this approach will be useful in directing the de novo synthesis of compounds that modulate MDR and help to further define the requirements for molecular recognition by this system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗