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PubMed1985

Role of intrinsic muscles and tracheal motion in modulating laryngeal receptors.

Recording from the superior laryngeal nerve discloses a respiratory modulated activity even in the absence of airflow and pressure changes in the larynx. The present study evaluates the relative contribution of intrinsic laryngeal muscle activity and transmitted tracheal movement on the respiratory modulation of laryngeal mechanoreceptors. Seventy-four receptors were studied in 22 anesthetized spontaneously breathing dogs. The modulation of 31 receptors depended solely on laryngeal muscle activity since it was abolished by cold block of laryngeal nerves. Twelve receptors were primarily activated by tracheal movement since tracheal stabilization alone reduced or abolished their modulation. The respiratory modulation of the remaining 31 receptors was found to be dependent on both laryngeal muscle activity and tracheal movements. Lidocaine (2%) was applied to the receptor field of 13 endings; the results indicate that while some receptors are located superficially (blocked within 1 min) others are located in deeper structures (not affected in 30 min). These receptors may be involved in the precise coordination of laryngeal muscle activity and could play a role in the regulation of breathing pattern and airway patency due to their pressure sensitivity.

Animals↗
PubMed1991

The modulation of rat liver carcinogenesis by perfluorooctanoic acid, a peroxisome proliferator.

Perfluorooctanoic acid (PFOA) is a peroxisome proliferator. The aim of this study was to test for its ability to act as a positive modulator of hepatocarcinogenesis, in the so-called biphasic (initiation by diethylnitrosamine 200 mg/kg ip followed by treatment with the suspected modulators) and triphasic (initiation by the same dose of diethylnitrosamine followed by a selection procedure for 2 weeks consisting of giving 2-acetylaminofluorene and in the middle of this treatment a single dose of CCl4 followed by treatment with the suspected modulators) protocols of liver carcinogenesis. In both protocols treatment with PFOA increased the incidence of malignant hepatocellular carcinoma (HCC). As compared to phenobarbital, the modulating effect of PFOA is more pronounced in a biphasic than in the triphasic protocol. In parallel with positive modulation of HCC, PFOA also selectively induced the peroxisomal acyl-CoA oxidase activity and, to a lesser extent, catalase activity.

Acyl-CoA Oxidase↗
PubMed1987

Duration of visual afterimages on modulated backgrounds: postreceptoral processes.

A foveal afterimage produced by a small photoflash increases in duration when the luminance of a 5.8 degrees diameter background on which it is seen is temporally modulated. At a modulation frequency of 1 Hz and a depth of modulation of 52%, the duration of the afterimage is prolonged by 335% compared to the duration obtained on a steady background. This increase has been attributed to the functional border resulting from the difference in excitability between bleached and unbleached photoreceptors. Afterimage duration is also prolonged, although only by 20%, when the luminance of the background is kept constant, while the luminance of an annular surround is modulated. This finding suggests a weak effect of neural lateral interaction (via area contrast). If the background luminance is modulated only in the contralateral eye (dichoptic presentation), afterimage duration increases by as much as 54% compared to the unmodulated state. This result indicates that afterimages, in part, are sustained by processes mediated by the visual cortex.

Adult↗
PubMed1989

Biochemical modulation of cisplatin toxicity.

The biochemical modulation of cisplatin toxicity has contributed substantially to the safe and effective administration of cisplatin in the clinic. In most cases, however, the demonstration of clinical efficacy has preceded the understanding of mechanisms by which these agents provide protection to normal tissues. A number of protocols are now available to ameliorate cisplatin-induced nephrotoxicity; these approaches have been so successful that renal toxicity is rarely of clinical significance today. However, the dramatic escalation in cisplatin dose engendered by the use of modulators has resulted in new dose-limiting toxicities involving the nervous system and the bone marrow. Although preliminary data suggests that certain modulators may reduce these toxicities, extensive clinical trials will be necessary to substantiate the beneficial effects in the clinic. Further clinical studies will also be necessary to determine the optimum scheduling for the newer agents and to provide convincing evidence of efficacy in man. Finally, modulator combinations (i.e. DDTC and hypertonic saline) have the potential to provide the broadest coverage of normal tissue protection and appear to merit more extensive clinical investigation. Cisplatin has demonstrated remarkable clinical efficacy at currently tolerated doses; further advances in the biochemical modulation of cisplatin toxicity should provide significant therapeutic gains for this important drug in the future.

Animals↗
PubMed1984

Resolution of multiple fluorescence lifetimes in heterogeneous systems by phase-modulation fluorometry.

Procedures are described for the treatment of phase and modulation lifetime data in fluorescent systems having multiexponential decay. All computer procedures (called FIT programs) arise from the lifetime resolution theory for phase-modulation measurements (Weber, G. (1981) J. Phys. Chem. 85, 949-953). The programs most successful in resolving heterogeneous lifetimes use a Monte Carlo approach in which phase and modulation lifetime data at three modulation frequencies are simultaneously utilized. These programs are shown to have more utility than the final closed form procedure presented by Weber (1981). The FIT routines are simple and require little computer time while yielding excellent results. To illustrate the applicability of these programs, defined binary (carbazole and pyrene) and ternary systems (carbazole, pyrene and POPOP) were examined. In most cases, the resolved lifetimes were within 5% of the independently measured value and the fractional fluorescence contributions were within 10% of that expected. These results demonstrate that phase-modulation measurements analyzed by appropriate computer programs are capable of solving for lifetimes in both binary and, in selected cases, ternary systems. An example is given from the recent literature (Dalbey, R., Weiel, J. and Yount, R.G. (1983) Biochemistry 22, 4696-4706) in which the above programs allowed the resolution of both binary and ternary lifetimes of a dansyl label on myosin, where Förster energy transfer was occurring. These lifetimes were used to quantify changes in distances between two activity-related thiols on myosin upon the addition of Mg-ATP or its analogs.

Computers↗
PubMed1990

A statistical test for demonstrating a presynaptic site of action for a modulator of synaptic amplitude.

A statistical technique for demonstrating a presynaptic site of action for a modulator of synaptic amplitude was developed and tested. It requires that multiple measurements of peak synaptic amplitude be made under control and test conditions. The ratio of the coefficients of variation (CV) obtained under test and control conditions is calculated. A method was developed for determining the confidence interval for the CV ratio (CVR) statistic based on the null hypothesis that the synaptic modulation is purely postsynaptic. If the measured CVR falls outside the confidence interval, this implies that the modulator of synaptic amplitude is, at least in part, acting at a presynaptic site. The effectiveness of the technique and its limitations were investigated using Monte Carlo simulations. It was found to be sensitive and reliable under a variety of realistic recording conditions. The test was effective even in the presence of simulated presynaptic rundown of the synaptic response. Conventional deconvolution analysis was also applied to the Monte Carlo simulations and was found to be an inadequate indicator of the site of synaptic modulation when the discrete amplitude components were not well resolved. The CVR technique was applied to excitatory postsynaptic currents (epsc) recorded between pairs of cultured hippocampal neurones in control and test media containing 1 mM Ca2+ and 2 mM Ca2+, respectively. Test conditions increased the average synaptic amplitude, and the statistical analysis indicated that this modulation was produced by an action at a presynaptic site.

Animals↗
PubMedDate not supplied

Dietary modulation of experimental neoplastic development: role of fat and fiber content and calorie intake.

Cancer is still one of the major causes of death in the industrialized countries but locally prevailing lifestyles may dictate the kinds of cancer seen among populations of different geographical areas. Dietary habits and, in particular, the nature and/or the amount of fat, calorie and/or vegetable fiber which are consumed in these countries are among the most frequently quoted etiological factors which may account for this situation. Epidemiological and experimental evidence has accumulated which, even though it can be used to support these conclusions, is still a matter of considerable debate. Modulation of neoplastic development is a concept which has been elaborated to overcome the fact that many experimental observations are not really taken into consideration by the classical 2-step theory of carcinogenesis. It is defined as the effect of any treatment which given before, during or after the initiation of a full carcinogenic process modifies the pattern of neoplastic development as evaluated by the kinetics of appearance, the incidence and/or the yield of histologically characterized malignant tumors. It is said to be positive or negative depending on whether it accelerates or slows down the process and increases or decreases the yield of malignant tumors respectively. From a review of the available experimental data, it is concluded that fat per se has, most probably, no modulating effect but that unbalanced diets rich in lipids could act as a positive modulator of chemically induced carcinogenesis by virtue of their capacity to cause a break in metabolic and proliferative homeostasis; that vegetable fibers as well as restriction in calorie intake could act as negative modulators of the same process because they could restore or help restore this homeostasis. It is thus proposed that to maintain dietary balance either by increasing fiber and/or by reducing total calorie intake is the most effective way to negatively modulate chemically induced carcinogenesis in experimental animals. To make the same recommendation to humans could most probably help preventing major cancers like breast and colon cancers.

Animals↗
PubMed1995

Modulation of muscle sympathetic activity during spontaneous and artificial ventilation and apnoea in humans.

Respiratory modulation of muscle sympathetic activity was compared in relaxed subjects breathing spontaneously and in anaesthetized and non-anaesthetized subjects ventilated artificially with intermittent positive pressure. Muscle sympathetic activity was recorded directly from the peroneal nerve using the microneurographic technique. Arterial pressure was monitored continuously either by finger-pulse photoplethysmography (Finapres) or intraarterially. Respiratory modulation of sympathetic activity, heart rate and arterial pressure was measured by averaging consecutive breaths to the ECG R-wave closest to the onset of inspiration. In relaxed subjects (n = 15) breathing quietly the averaged sympathetic activity was greatest during late expiration and the first half of inspiration and minimal after the peak of inspiration, after correcting for delays within the baroreflex loop. Systolic and diastolic pressures fell during inspiration. In anaesthetized or awake subjects ventilated artificially at normal tidal volumes the pattern of respiratory modulation of sympathetic activity was preserved but the changes in arterial pressure were reversed and respiratory sinus arrhythmia abolished. Ventilation with positive end-expiratory pressure (20 cmH2O) increased the overall level of sympathetic activity and enhanced the breath-to-breath modulation. We conclude that, although baroreceptors provide potent modulation of muscle sympathetic activity in humans, the inspiratory inhibition of sympathetic activity does not depend on an increase in arterial pressure and hence an increase in baroreceptor input.

Adult↗
PubMedDate not supplied

Substance P modulation of DAMGO binding in the brain of CXBK and Swiss-Webster mice.

The effects of substance P (SP) on the binding of the selective mu opioid agonist [3H]DAMGO to brain membranes of CXBK and Swiss-Webster (SW) mice were compared. We have previously shown that subnanomolar concentrations of SP and N-terminal fragments of SP modulate DAMGO binding in SW brain membranes and hypothesized that modulation occurs via SP interaction with mu 1 sites. In the present study, binding assays using CXBK mice, a strain deficient in mu receptors including mu 1 sites, were performed to assess the effect of mu receptor deficiency on SP-induced modulation of DAMGO binding. Whereas the addition of 0.1 nM SP to the binding mixtures produced up to 30% increase in the values of Kd and maximum binding capacity (R) for the SW strain, SP produced little or no change in the case of CXBK strain. Maximum binding capacity for DAMGO was 43% less in the brain of CXBK mice than in SW mice. No difference was observed in the estimated binding parameters of the spinal cord for the two strains. Whereas pretreatment of brain membranes of SW mice using beta-funaltrexamine (beta-FNA) increased from 2- to 10-fold the modulatory effect of SP, CXBK brain membranes pretreated with beta-FNA remained nearly insensitive to modulation by SP. The effect of SP on the affinity of DAMGO binding in SW mice, but not in CXBK mice, was reversed by the addition of GTP. It is concluded that mu receptor deficiency can markedly influence SP-induced modulation of DAMGO binding.

Animals↗
PubMed1982

Platelet activating factor (PAF) causes human platelet aggregation through the mechanism of membrane modulation.

Recent investigations have shown that human and canine platelets possess a new pathway for securing irreversible platelet aggregation independent of ADP secretion and prostaglandin synthesis. Platelet activating factor (PAF) is a potent aggregating agent for rabbit platelets and is also reputed to stimulate the cells by a completely independent pathway. Since the newly recognized mechanism in human and dog cells, termed membrane modulation, might be mediated by PAF, we evaluated the influence of this agent on human cells. Results of that study demonstrated that PAF did not activate platelets through an independent pathway and was not involved in the mechanism of membrane modulation. In the present investigation we have examined the possibility that PAF might act on human platelets through the mechanism of membrane modulation. Human platelets were made refractory to amounts of PAF routinely causing irreversible aggregation by prolonged incubation of C-PRP at 37 degrees C, by exposure to PGI2 or aspirin, or by aggregation-disaggregation of control or aspirin treated cells. Epinephrine at concentrations which did not cause aggregation turned on the mechanism of membrane modulation in refractory platelets and restored their sensitivity to PAF. Thus, PAF does not appear to activate human platelets through a unique, independent pathway. Rather, it usually causes irreversible aggregation of human cells through the mechanisms of ADP secretion and thromboxane synthesis or, as shown in this study, can be dependent on membrane modulation.

Adenosine Diphosphate↗
PubMed1991

Simple spike modulation of Purkinje cells in the cerebellar nodulus of the pigmented rabbit to optokinetic stimulation.

In immobilized pigmented rabbit anesthetized with N2O (70%) and halothane (2-4%), simple and complex spike responses of Purkinje cells in the cerebellar nodulus to large field optokinetic stimulation (OKS) was studied. About half of the cells showed significant simple spike modulation to OKS delivered to ipsilateral (25/57) or contralateral (18/31) eye. The preferred direction and the amplitude of modulation of simple spike responses did not necessarily correlate with those of complex spike responses, suggesting that the simple spike modulation is not secondary to complex spike modulation but due to modulation of mossy fiber activity to OKS.

Action Potentials↗
PubMed1980

Mechanism of activation of cyclic GMP-dependent protein kinase from rat liver by multiple modulators.

A number of polyanionic compounds, including DNA, RNA and polyglutamate, were shown to exhibit protein kinase stimulatory modulator activity as they were required for cyclic GMP to stimulate the phosphorylation of various cationic substrates by rat liver cyclic GMP-dependent protein kinase. Anionic proteins (casein, phosvitin) were phosphorylated poorly by the enzyme and their phosphorylation was not stimulated by the stimulatory modulators. Studies of the mechanism of action suggest that the modulators interact directly with the substrates to form a complex which is a better substrate than free histone. The observed effect of modulator is complex as it depends on the ratio of modulator to histone and the resultant state of the complex formed (better or poorer substrate than free histone). The observed effect is also dependent on the properties of the histone substrate as Michaelis-Menten kinetics are not observed in the phosphorylation of arginine-rich histone in the absence or presence of cyclic GMP.

Animals↗
PubMed1996

Lateral hypothalamus: site involved in pain modulation.

The present study is an attempt to examine the neuronal circuitry of a supraspinal site engaged in pain modulation. Five physiological measures were postulated as the criteria for defining a central nervous system site engaged in the circuitry of pain modulation. The lateral hypothalamus met these five measures: (i) 81% of the lateral hypothalamus neurons (247/304) responded to noxious stimuli using a single cell recording procedure; (ii) stimulation of the periaqueductal gray-dorsal raphe area or the habenula modulated 98% and 87% of the lateral hypothalamus noxious-evoked activity; (iii) microiontophoretically applied morphine modulated 77% of the lateral hypothalamus noxious evoked activity; (iv) electrical stimulation of the lateral hypothalamus produced behavioral analgesia proportional to the stimulus intensity as assessed by the tail flick assay; and (v) morphine application into the lateral hypothalamus produced behavioral analgesia in a dose-response manner using the tail flick assay. In conclusion, the lateral hypothalamus can be considered one of the pain modulation sites.

Animals↗
PubMed1994

Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation.

PURPOSE: To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo. MATERIALS AND METHODS IN VITRO STUDIES: an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined. RESULTS: In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. CONCLUSION: These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.

Animals↗
PubMed1994

The dorsal raphe: an important nucleus in pain modulation.

The dorsal raphe nucleus (DRN) is an important nucleus in pain modulation. It has abundant 5-HT neurons and many other neurotransmitter and/or neuromodulator containing neurons. Its vast fiber connections to other parts of the central nervous system provide a morphological basis for its pain modulating function. Its descending projections, via the nucleus raphe magnus or directly, modulate the responses caused by noxious stimulation of the spinal dorsal horn neurons. In ascending projections, it directly modulates the responses of pain sensitive neurons in the thalamus. It can also be involved in analgesia effects induced by the arcuate nucleus of the hypothalamus. Neurophysiologic and neuropharmacologic results suggest that 5-HT neurons and ENKergic neurons in the DRN are pain inhibitory, and GABA neurons are the opposite. The studies of the intrinsic synapses between ENKergic neurons, GABAergic neurons, and 5-HT neurons within the DRN throw light on their relations in pain modulation functions, and further explain their functions in pain mediation.

Animals↗
PubMed1984

Detection of amplitude-modulated tones by frogs: implications for temporal processing mechanisms.

The whole nerve action potential (AP) from the auditory nerve and midbrain averaged evoked potential (AEP) were recorded in Hyla chrysoscelis and H. versicolor in response to synthesized amplitude-modulated stimuli with variable modulation frequencies (Fm). The AP from these frogs is similar to the potential described for mammals and showed a bandpass characteristic in its ability to follow sinusoidally amplitude-modulated (AM) sound stimuli. A lesioning study suggests that the midbrain AEP is a localized neural response of neurons near the ventral border of the torus semicircularis. The AEP is a complex waveform consisting of fast and slow components. The fast component encodes the temporal structure of acoustic stimuli and is used to measure temporal sensitivity in these two species. The AEP behaves like a low-pass filter with a cutoff frequency of 250 Hz when tracking AM signals. Threshold for detection requires a modulation depth of 8-12% of the total stimulus amplitude (delta I = 1.5-2.0 dB). Relative to the eighth nerve AP, the AEP displays an enhanced coding of AM signals when Fm less than 100 Hz, and a slightly inferior ability to code Fm above 250 Hz. The AEP reflects only that portion of the neural response that encodes amplitude fluctuations. In comparison to the range of amplitude fluctuations coded by single units in the rat inferior colliculus or by human evoked potential, the frog AEP codes higher rates of Fm. The proposal that these frogs process AM stimuli solely on the basis of amplitude fluctuations, and do not use spectral cues at higher modulation frequencies is considered. The AM sensitivity of the AEP, which encompasses most biologically relevant rates of amplitude fluctuation for the animal, and the limited frequency resolution of the periphery, lend support to this proposal. However, convergent spectral processing at higher auditory centers cannot be excluded by this study. Psychophysical tests will be required to determine whether both of these mechanisms may be operating during temporal information processing in anurans.

Action Potentials↗
PubMed1986

Scalp potentials of normal and hearing-impaired subjects in response to sinusoidally amplitude-modulated tones.

None of the current electrical audiometric procedures, alone or in combination, has yet achieved the precision of conventional audiometric testing that is used to assess hearing in verbally capable children and adults. The reason for this, in part, lies in the use of stimuli which have a wide frequency content. We have measured scalp potentials which follow the envelopes of sinusoidally amplitude-modulated tones: a frequency-specific stimulus. In normal subjects such amplitude-modulation following responses (AMFRs) appear to be generated by two sources. One source has a latency of about 30 ms, generates large responses and is only observed at modulations below 55 Hz, while the other source has a latency of 7-9 ms, generates smaller responses, and is only observed at modulations from 100-350 Hz. The latencies of these two sources are consistent with origins in the cortex and midbrain, respectively. We examined AMFRs to low frequency (50 Hz) modulations as a possible audiometric tool. In normal subjects, the amplitude of the AMFR increased as a function of intensity, decreased as a function of carrier frequency, and could be evoked across the whole audiometric range (250-8000 Hz). In hearing-impaired subjects, the AMFR amplitudes as a function of carrier frequency accurately reflected the pattern of hearing loss on a frequency-by-frequency basis. In most subjects, the threshold for evoking the AMFR was within 0-25 dB of hearing threshold. It therefore appears that the AMFR may be a potentially useful tool to assess hearing in those unable to undergo conventional audiometric testing.

Acoustic Stimulation↗
PubMed1986

Representation of amplitude modulation in the auditory cortex of the cat. I. The anterior auditory field (AAF).

The ability of cortical neurons to follow amplitude modulation (AM) of tones was examined in the anterior auditory cortical field (AAF) of anesthetized cats using multiple-unit recording techniques. Sinusoidal and rectangular modulations (100%) of a monaural carrier tone at the characteristic frequency of each location were presented to study the degree of response synchronization and changes in firing rate as a function of the modulation frequency. All investigated locations were tuned to a 'best modulation frequency' (BMF) as determined by synchronization measures. Almost all locations (94%) were tuned to a BMF as determined by spike rate. Maximal binaural-interaction strength was observed for modulation frequencies close to the BMF of neurons. For sinusoidal AM, a correlation (r = 0.63, P less than 0.01) between BMF and CF of neurons in AAF could be demonstrated for the synchronization of the response.

Acoustic Stimulation↗