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Caffeine potentiates the discriminative-stimulus effects of nicotine in rats.

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.

Animals↗

Discharge variability and physiological properties of human masseter motor units.

Intramuscular electrodes were used to study discharge variability in motor units of human masseter whose physiological properties were determined using spike-triggered averaging. Subjects voluntarily controlled the mean firing rate of a selected motor unit at 10 Hz for 15 min of continuous activation. Discharge variability was assessed at the beginning and end of this period. In 81% of units, the discharge variability at a mean interspike interval (ISI) of 100 ms increased after 15 min of continuous activity. There was a wide range of discharge variability within the population of masseter units studied, but no significant correlations were found between initial discharge variability and recruitment threshold, twitch tension or time-to-peak tension (TTP). There was, however, a significant correlation between motor unit fatigability and its initial discharge variability. This represents a link between the motoneuron and the functional properties of the muscle fibers in innervates.

Adolescent↗

Contrast discrimination in the cat.

Cats were trained to discriminate between two sinusoidal grating patterns differing only in contrast. The smallest discriminable contrast difference was determined for a number of different baseline contrast levels, and the resulting contrast increment thresholds plotted in the form of a contrast discrimination function. The resulting function was linear when plotted on log/log coordinates and the slope of this function varied with spatial frequency. These behavioural results are compared to the contrast/response properties of retinal and cortical neurones.

Animals↗

DCG-IV, a potent metabotropic glutamate receptor agonist, as an NMDA receptor agonist in the rat cortical slice.

The depolarization induced by DCG-IV, a potent agonist for Group II metabotropic glutamate receptors (Group II mGluRs), was depressed by selective antagonists for NMDA receptors in the rat cortical slice, but was not affected even by a high concentration of a selective antagonist for Group II mGluRs. DCG-IV caused depolarization more effective than NMDA in a dose-dependent manner with a threshold concentration of 3 microM in rat cortical slices, while DCG-IV was less active than NMDA in rat spinal cords. These actions should be carefully considered particularly when DCG-IV is used as an agonist for mGluRs in vivo.

Animals↗

Acceptability of shade differences in metal ceramic crowns.

STATEMENT OF PROBLEM: Application of technology that quantify color and color differences is currently used in esthetic restorative materials research. However, parameters for the size of perceptible and acceptable color differences in metal ceramic crowns have not been determined. PURPOSE: The CIELAB colorimetric system was used to study the relationship between instrumentally measured color differences (delta E) and human observer assessment of color differences in metal ceramic crowns. MATERIAL AND METHODS: Subjects were shown pairs of metal ceramic crowns whose color difference varied from indistinguishable to obvious. The subjects attempted to discern a difference in each pair's color and indicated the clinical acceptability of the shade difference between the crown pairs. RESULTS: Correlations between instrumental and visual assessment of color differences in these crown pairs did not agree in all dimensions of color space. Thresholds acceptability of color differences were 1.1 delta E units for red-varying crowns and 2.1 delta E units for yellow-varying crowns. Thresholds for perceptibility judgments were significantly lower than thresholds for acceptability judgments. CONCLUSIONS: Acceptability thresholds were found to be dependent on chromaticity. Observers were more sensitive and critical of crowns whose color differed in redness as opposed to crowns whose color differed to the same extent in yellowness.

Chi-Square Distribution↗

Normative values for female genital sensation.

OBJECTIVES: Neurologic disorders might be responsible for many cases of female sexual dysfunction. Yet, they are currently undiagnosed because of the lack of measurement tools to assess genital neural function. Therefore, our objective is to provide norms for sensory thresholds in the vagina and clitoris, for a wide range of patient ages. METHODS: Vaginal and clitoral warm, cold, and vibratory sensory thresholds were measured in 89 healthy paid volunteers by the method of limits. Normograms were derived from this group of healthy volunteers. An additional 61 patients were also tested, for a total of 150 individuals. Sixty-two individuals (42 healthy volunteers and 20 patients) from the total group were tested twice to provide test-to-test repeatability data across the range of clinical (normal and abnormal) responses. RESULTS: Normograms are presented, providing age-corrected upper and lower normal values, expressed as 95% confidence limits for warm, cold, and vibratory thresholds. Intertest repeatability is also reported. CONCLUSIONS: Thermal and vibratory thresholds of both the vaginal and clitoral region are clinically feasible, valid, and repeatable. These can be applied as a valuable diagnostic tool to assess neural dysfunction through sensory assessment of the female genitalia.

Adolescent↗

Electrical stimulation of the auditory nerve: II. Effect of stimulus waveshape on single fibre response properties.

To investigate the generation of action potentials by electrical stimulation we studied the response of auditory nerve fibres (ANFs) to a variety of stimulus waveforms. Current pulses were presented to longitudinal bipolar scala tympani electrodes implanted in normal and deafened cochleae. Capacitively coupled monophasic current pulses evoked single ANF responses that were more sensitive to one phase (the 'excitatory' phase) than the other. Anodic pulses produced a significantly shorter mean latency compared with cathodic pulses, indicating that their site for spike initiation is located more centrally along the ANF. The fine temporal structure of ANF responses to biphasic pulses appeared similar to that evoked by monophasic pulses. An excitatory monophasic pulse evoked a significantly lower threshold than a biphasic current pulse having the same polarity and duration leading phase, i.e. the addition of a second phase leads to an increase in threshold. Increasing the temporal separation of the two phases of a biphasic pulse resulted in a moderate reduction in threshold which approached that of an excitatory monophasic pulse for interphase gaps > 100 micros. Greater threshold reductions were observed with narrower current pulses. There was a systematic reduction in threshold with increasing pulse width for biphasic current pulses, reflecting the general charge-dependent properties of ANFs for narrow pulse widths. Chopped biphasic current pulses, which uniformly delivered multiple packets of charge (2 x 30 micros, 3 x 20 micros or 6 x 10 micros) with the same polarity over a 120 micros period, followed by a similar series in the reverse polarity, demonstrated the ability of the neural membrane to integrate sub-threshold packets of charge to achieve depolarisation. Moreover, thresholds for these current pulses were approximately 1.5 dB lower than 60 micros/phase biphasic current pulses with no interphase gap. Finally, stimulation using charge-balanced triphasic and asymmetric current pulses produced systematic changes in threshold and latency consistent with the charge-dependent properties of ANFs. These findings provide insight into the mechanisms underlying the generation of action potentials using electrical stimuli. Moreover, a number of these novel stimuli may have potential clinical application.

Animals↗

Threshold effects in synaptosomal and nonsynaptic mitochondria from hippocampal CA1 and paramedian neocortex brain regions.

After a brief period of global ischemia, the hippocampal CA1 region is more susceptible to irreversible damage than the paramedian neocortex. To test whether primary differences in bioenergetic parameters may be present between these regions, respiration rates and respiratory control activities were measured. In synaptosomal and nonsynaptic mitochondria isolated from the hippocampal CA1 region, state 3 respiration rates and complex IV activities were significantly lower than those present in synaptosomal and nonsynaptic mitochondria from the paramedian neocortex. These results suggest that mitochondria from the CA1 hippocampal area differ in some properties of metabolism compared with the neocortex area, which may render them more susceptible to a toxic insult such as that of ischemia. In addition, when complex I and IV activities were titrated with specific inhibitors, thresholds in ATP synthesis and oxygen respiration became apparent. Complex I and IV activities were decreased by 60% in nonsynaptic mitochondria from the hippocampal CA1 region and paramedian neocortex before oxidative phosphorylation was severely compromised; however, in synaptosomes from these regions, complex I activities had a threshold of 25%, indicating heterogenous behaviour for brain mitochondria. Reduced complex I thresholds in mitochondria, in association with other constitutive defects in energy metabolism, may induce a decreased ATP supply in the synaptic region. The implications of these findings are discussed in relation to delayed neuronal death and processes of neurodegeneration.

Animals↗

Abatement of cockroach allergen (Bla g 1) in low-income, urban housing: A randomized controlled trial.

BACKGROUND: Clinically relevant reductions in exposure to cockroach allergen, an important risk factor for asthma in inner-city households, have proven difficult to achieve in intervention trials. OBJECTIVE: This study investigated a method for the abatement of cockroach allergen in low-income, urban homes. The goal was to reduce mean Bla g 1 concentrations below the previously proposed thresholds for allergic sensitization and asthma morbidity. METHODS: A prerandomized, nonmasked trial with 16 intervention and 15 control homes was conducted. Study inclusion was based on 50 to 500 cockroaches trapped in a 3-day period. The interventions consisted of occupant education, placement of insecticide bait, and professional cleaning. Vacuumed dust and multiple swab samples were collected at 0, 1, 2, 4, and 6 months in intervention homes and at 0 and 6 months in control homes. Room maps containing cockroach and allergen data were used to guide and monitor the interventions. RESULTS: From 0 to 6 months among intervention homes, geometric mean Bla g 1 concentrations (U/g dust) decreased from 633 to 24 on kitchen floors (96% reduction), from 25 to 4.3 on living room floors/sofas (83% reduction), from 46 to 7.3 on bedroom floors (84% reduction), and from 6.1 to 1.0 in bedroom beds (84% reduction). These reductions, with the exception of that on the bedroom floor (P =.06), were statistically significant relative to changes in control homes. CONCLUSIONS: Substantial reductions in cockroach allergen levels can be achieved in inner-city homes. In this study, allergen levels were reduced below the sensitization threshold (2 U/g) in beds, arguably the most relevant site for exposure, and below the asthma morbidity threshold (8 U/g) on bedroom floors and living room floors/sofas. The level on kitchen floors, although reduced 96%, remained above the asthma morbidity threshold. Future studies will test the intervention's effectiveness in asthma prevention trials.

Allergens↗

Frequency and amplitude discrimination along the kinestheticcutaneous continuum in the presence of masking stimuli.

Frequency and amplitude discrimination thresholds along the kinesthetic to cutaneous continuum were evaluated on the left index fingerpad using a multifinger tactual display. Target stimuli were presented either in isolation (no-masker condition) or in the presence of masking stimuli (one- or two-masker conditions). Six reference target signals in the frequency range 2-300 Hz (two each from low-, medium-, and high-frequency regions) and at an amplitude of either 20 or 35 dB sensation levels (SL) were used. In the no-masker condition, the range of frequency Weber fraction was 0.13-0.38 and 0.14-0.28, and the range of amplitude discrimination threshold was 1.82-2.98 dB and 1.65-2.71 dB, at 20 and 35 dB SL, respectively. In the masking conditions, average frequency Weber fractions rose to 0.60 and 0.46, and average amplitude thresholds rose to 3.63 and 3.72 dB, at 20 and 35 dB SL, respectively. In general, thresholds were largest in the two-masker condition and lowest in the no-masker condition. Although the frequency and amplitude thresholds generally increased in the presence of masking stimuli, there was some indication of channel independence for low- and high-frequency target stimuli. The implications of the results for tactual communication of speech are discussed.

Acoustic Stimulation↗

Physiological increments in epinephrine stimulate metabolic rate in humans.

Markedly elevated plasma epinephrine is known to increase metabolic rate (MR), but such levels of epinephrine are encountered infrequently in normal free-living subjects. We studied whether epinephrine levels common in usual daily activities can affect MR and thus possibly regulate caloric expenditure. To aid definition of a MR threshold, we first measured the hourly and daily variation in MR within individuals by measuring the MR of four individuals by indirect calorimetry for 6 h on six separate occasions without any intervention. We found that hour-to-hour variation (2.0 +/- 0.9%) and the day-to-day variation (2.7 +/- 0.9%) were low, thus allowing confident detection of small increments in metabolic rate during epinephrine infusion. To define a threshold for epinephrine's effect to increase MR, we studied five normal-weight postabsorptive young men on four separate occasions. During the 1st h of each 5-h study period, saline was infused intravenously. Then, during the subsequent 4 h, subjects received intravenous infusion of saline or epinephrine at 0.1, 0.5, and 1.0 microgram/min (randomized). A significant increase in MR (3.6 +/- 1.0% SE) was measured with the lowest epinephrine infusion rate (venous plasma concentration, 94 +/- 32 pg/ml). The increases in MR correlated (r = 0.85, P less than 0.001) with increases in plasma epinephrine. The threshold concentration (upper 95% confidence limit) of epinephrine to affect MR was 90 pg/ml, a concentration frequently occurring in daily life. Thus epinephrine may play an important role in weight maintenance by affecting energy expenditure.

Adult↗

Is there a threshold duration of vascular occlusion for hindlimb reactive hyperemia?

Relatively brief changes in perfusion pressure and flow through arterioles occur in a number of conditions, such as in the flying environment and during such common everyday activities such as bending forward at the waist. Also, brief periods of negative vertical acceleration (G(z)) stress, which reduces perfusion in the lower body, has been shown to impair the regulation of arterial pressure during subsequent positive G(z) stress. To examine the contribution that reactive hyperemia makes in these settings, studies on the hindlimb circulation of anesthetized rats (n = 8) were carried out by imposing graded duration vascular occlusion (1, 2, 4, 10, and 30 s) to test the hypothesis that there is a threshold duration of reduction in perfusion that must be exceeded for reactive hyperemia to be triggered. Vascular conductance responses to 1 s of terminal aortic occlusion were no different before and after myogenic responses were blocked with nifedipine, indicating that 1 s of occlusion failed to elicit reactive hyperemia. Two seconds of occlusion elicited a small but significant elevation in hindlimb vascular conductance. The magnitude of the reactive hyperemia was graded in direct relation to the duration of occlusion for the 2-, 4-, and 10-s periods of occlusion and appeared to be approaching a plateau for the 30-s occlusion. Thus there is a threshold duration of terminal aortic occlusion (approximately 2 s) required to elicit reactive hyperemia in the hindlimbs of anesthetized rats, and the reactive hyperemia that results possesses a threat to the regulation of arterial pressure.

Animals↗

Does a unique type of CA3 pyramidal cell in primates bypass the dentate gate?

The predominant excitatory synaptic input to the hippocampus arises from entorhinal cortical axons that synapse with dentate granule cells, which in turn synapse with CA3 pyramidal cells. Thus two highly excitable brain areas--the entorhinal cortex and the CA3 field--are separated by dentate granule cells, which have been proposed to function as a gate or filter. However, unlike rats, primates have "dentate" CA3 pyramidal cells with an apical dendrite that extends into the molecular layer of the dentate gyrus, where they could receive strong, monosynaptic, excitatory synaptic input from the entorhinal cortex. To test this possibility, the dentate gyrus molecular layer was stimulated while intracellular recordings were obtained from CA3 pyramidal cells in hippocampal slices from neurologically normal macaque monkeys. Stimulus intensity of the outer molecular layer of the dentate gyrus was standardized by the threshold intensity for evoking a dentate gyrus field potential population spike. Recorded proximal CA3 pyramidal cells were labeled with biocytin, processed with diaminobenzidine for visualization, and classified according to their dendritic morphology. In response to stimulation of the dentate gyrus molecular layer, action potential thresholds were similar in proximal CA3 pyramidal cells with different dendritic morphologies. These findings do not support the hypothesis that dentate CA3 pyramidal cells receive stronger synaptic input from the entorhinal cortex than do other proximal CA3 pyramidal cells.

Action Potentials↗

Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy.

BACKGROUND: We performed a comparative study on Ca2+ release activity of the sarcoplasmic reticulum and calcium sensitivity of contractile apparatus of chemically skinned myocardial fibers obtained from four nonfailing human hearts and 13 excised hearts from patients with idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Ca2+ sensitivity of contractile apparatus was studied by following the isometric tension developed by chemically skinned myocardial fibers challenged with solutions of decreasing pCa. Ca2+ release from sarcoplasmic reticulum was monitored indirectly by measurement of the isometric tension developed by skinned fibers challenged with caffeine. We observed no significant difference of Ca2+ sensitivity and cooperativity between normal myocardium (pCa50 = 6.00 +/- 0.05; Hill coefficient, nHill = 2.07 +/- 0.10) and dilated cardiomyopathy (pCa50 = 6.03 +/- 0.07; nHill = 2.72 +/- 0.30) when the fibers were stretched to 130% of the resting length. We also found that both in normal myocardium and dilated cardiomyopathy, stretching to 150% of the resting length increased the Ca2+ sensitivity of the contractile system; pCa50 = 6.21 +/- 0.01 and 6.13 +/- 0.04 in normal and dilated cardiomyopathy, respectively, whereas in dilated cardiomyopathy there was a decrease of Hill coefficient with stretching that was not observed in the control group. The caffeine threshold in idiopathic dilated cardiomyopathy was markedly increased compared with the control group, 1.94 +/- 0.27 mmol/l and 0.29 +/- 0.04 mmol/l caffeine, respectively, whereas there were no significant differences in the extent and rate of caffeine-induced Ca2+ release. CONCLUSIONS: These results indicate that in idiopathic dilated cardiomyopathy there is no alteration of contractile and regulatory proteins; on the contrary, the gating mechanism of the Ca2+ release channel of sarcoplasmic reticulum is abnormal, suggesting a possible involvement of the excitation-contraction coupling in the pathogenesis of this disease. It should also be taken into account, however, that the increased caffeine threshold in dilated cardiomyopathy would be a result of the enhanced resistance to the skinning procedure secondary to the modification of lipid species and/or content in sarcoplasmic reticulum membrane.

Adolescent↗

Contrast-enhanced MR angiography: the effects of k-space truncation on luminal representation in a carotid artery phantom model.

Using carotid bifurcation phantom models with different degrees of stenoses, we evaluated the accuracy of vessel lumen representation on MR images obtained from the inverse Fourier transform of different k-space percentages. Our results show that the lower thresholds of truncated k-space sampling are dictated by the severity of luminal narrowing. The defined thresholds may help improve efficiency of 3D MR imaging of the carotid arteries while maintaining adequate luminal representation.

Carotid Arteries↗

Histamine threshold and nasal hyperreactivity in non specific allergic rhinopathy.

The authors studied the histamine threshold (endpoint concentration for a 100% pressure gradient increase at a flow of 0.25 liter/second) in a group of 29 patients suffering from non specific allergic rhinopathy and a control group of 15 normal subjects. The result of the nasal challenge was measured with two different methods of rhinomanometry: the passive anterior rhinomanometry (P.A.R.) and the active anterior rhinomanometry (A.A.R.). There existed a slightly significant difference (P less than or equal to 0.05) in histamine threshold between the patient and the control group. The 21 in duplo performed histamine challenges showed the very good reproducebility of the method. Finally, the A.A.R. method turned out to be slightly more sensitive than the P.A.R.-method.

Aerosols↗

Test-retest variability in glaucomatous visual fields.

We measured test-retest variations in computerized visual fields from glaucomatous eyes. Fifty-one patients were tested four times within a four-week period; the severity of disease varied from incipient to advanced. We determined the dependence of threshold variability on defect depth and test point location. In areas of the visual field initially found to have moderate loss of sensitivity, variation in follow-up measurements ranged from normal sensitivity to absolute defect, with little dependence on distance from fixation. Conversely, large changes were considerably more unusual in locations initially showing normal or near-normal sensitivities, and variability was lowest in the most central portion of the field. Our findings suggest that differentiation between true progression and random variation will be facilitated if these factors are taken into account, as well as if comparisons are based on more than two tests. The complex nature of interest variation in glaucoma makes it natural to approach this problem with the help of computer-assisted analyses.

Adult↗

Linear-no-threshold is a radiation-protection standard rather than a mechanistic effect model.

The linear-no-threshold (LNT) controversy covers much more than the mere discussion whether or not "the LNT hypothesis is valid". It is shown that one cannot expect to find only one or even the only one dose-effect relationship. Each element within the biological reaction chain that is affected by ionizing radiation contributes in a specific way to the final biological endpoint of interest. The resulting dose-response relationship represents the superposition of all these effects. Till now there is neither a closed and clear picture of the entirety of radiation action for doses below some 10 mSv, nor does clear epidemiological evidence exist for an increase of risk for stochastic effects, in this dose range. On the other hand, radiation protection demands for quantitative risk estimates as well as for practicable dose concepts. In this respect, the LNT concept is preferred against any alternative concept. However, the LNT concept does not necessarily mean that the mechanism of cancer induction is intrinsically linear. It could hold even if the underlying multi-step mechanisms act in a non-linear way. In this case it would express a certain "attenuation" of non-linearities. Favouring LNT against threshold-, hyper-, or sub-linear models for radiation-protection purposes on the one hand, but preferring one of these models (e.g. for a specific effect) because of biological considerations for scientific purposes on the other hand, does not mean a contradiction.

Body Burden↗