Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “selective sweeps”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources

Creative productivity in women analysts.

A pilot study of female analyst creative productivity finds that women authors are well represented in numbers in two leading analytic journals, The Journal of The American Academy of Psychoanalysis and Journal of the American Psychoanalytic Association, for 1980-81. However, women analyst members of the journals' parent organizations are very poorly represented compared with male analyst members. This has led to an exploration of factors affecting female analyst productivity, encompassing a broad sweep from the sociological to the personal, dynamic level. Differential opportunities for women analysts may be inherent in the educational processes. There is evidence for an "accumulation of disadvantage" for women in the field of psychiatry, as well as the impression of gender bias and feelings of stigmatization in psychoanalysis. The question of whether academic research career paths for women are adequately encouraged is raised. Mentorship patterns are also discussed. Whether gender bias affects journal publications and the nature of psychoanalytic thinking is questioned. Women's lessened productivity is sometimes ascribed to practical aspects of feminine role. This myth is debunked for women in science, where married women with children are equally productive. The author suggests that women analysts, however, may be a select group and may be more subject to role conformity pressures. Feminine role conflicts and their effects are discussed. Dynamic issues related to creative productivity are explored in two major areas. The author suggests that female preoedipal object relations may play a part in females devaluing of their own creative efforts in a competitive arena. The oedipal situation is also discussed, especially with regard to very high-achieving women. It is suggested that though competition with the maternal-nurturant rival may be worked through, often there is incomplete resolution of the surpassing and separation from the protective, loving, but dominant oedipal father, thus limiting true professional autonomy.

Clinical Competence↗

A cohort study on mortality among long-time employed Swedish chimney sweeps.

A cohort study on mortality among all members of the Swedish Chimney Sweeps Union who were active in 1950 or later and have been members for at least 10 a has been performed; 2,071 chimney sweeps fulfilled the criteria and the loss in the follow-up was less than 1 %. The observed numbers of death before the age of 80 were compared with sex-, calendar year-, and age class specific expectancy values from the national statistics of 1951-1979. Two hundred and thirty deaths were observed versus 197.6 expected. This result was due to a significant excess of deaths from tumors, particularly lung and esophageal cancer, and from nonmalignant chronic respiratory diseases. The multifold increased risk from these diseases could hardly be explained by extreme smoking or alcohol habits but rather by exposure to polycyclic aromatic hydrocarbons, nitrogen compounds, arsenic, and asbestos in combination with exposure to sulfur dioxide. The excess mortality had occurred in spite of favorable selection factors as demonstrated in different subcohorts. Preventive actions to diminish inhalation of soot and combustion gases should be taken.

Adult↗

A review of recent trends in cholera research and control. With an annex on the isolation and identification of cholera vibrios.

Since 1961 cholera El Tor has been sweeping through the Far East, and this dissemination of the disease has stimulated research not only in the countries afflicted but also in Europe and the Americas. New laboratories and workers have entered the field and many fresh ideas and concepts have emerged. The time seemed ripe, therefore, to survey the most important papers published since 1959, when the literature on cholera was thoroughly reviewed by Pollitzer, for the benefit both of those engaged in research and of those concerned with public health practice.This review covers history and incidence, causative agents (including the "classical", "El Tor" and "incomplete" forms), pathophysiology, diagnosis, treatment, mode of spreading and control measures (with particular reference to public health education and the International Sanitary Regulations). An annex, intended for laboratory use, contains selected procedures for the isolation and identification of cholera vibrios.

Cholera↗

Prediction of response speed by anticipatory high-frequency (gamma band) oscillations in the human brain.

Response to a stimulus is faster when a subject is attending and knows beforehand how to respond. It has been suggested recently that this occurs because ongoing neuronal activity is spatially and temporally structured during states of expectancy preceding a stimulus. This mechanism is believed to mediate top-down processing, facilitating the early grouping and selection of distributed neuronal ensembles implicated in ensuing sensory-motor processing. To validate this model, it must be shown that some features of this early ongoing neural activity are correlated with subsequent perceptual decisions or behavioral events. We investigated this hypothesis in an electrophysiologic study in 12 subjects carrying out a simple visuomotor reaction-time task. Local field potentials (LFP) at each brain voxel were estimated using a linear distributed inverse solution termed "ELECTRA" for each single trial of each subject. The energy of oscillations for different frequency bands was computed for the period between the warning cue and visual stimuli by applying a time-frequency decomposition to the estimated LFP. A nonparametric correlation coefficient was then calculated between energy of oscillations and reaction times for each single sweep. Gamma band oscillatory activity in a frontoparietal network before stimulus onset significantly correlated with reaction time for a significant amount of subjects. These results provide direct evidence for the role of neural oscillations as a top-down attentional control mechanism that mediates the speed of motor actions.

Adult↗

Effect of the leaving group on the electrodic reduction mechanism of anti-Helicobacter pylori metronidazole derivatives, in aprotic and protic media.

Because redox properties are central to bioreductive drug activity and selectivity, six 2-methyl-5-nitroimidazole, substituted at the N1-ethyl side chain with I, Br, Cl, OAc, OMs and NH(3)(+) were synthesized and submitted to cyclic voltammetry and electrolyses, in order to define their electrodic reduction mechanism, in aprotic [dimethylsulphoxide (DMSO)+0.1 mol l(-1) tetrabuthylammonium perchlorate (TBAP)] and phosphate-buffered media, on glassy carbon electrode, in comparison with metronidazole. Three of these compounds, namely, the iodo, bromo and ammonium salt derivatives showed significant anti-Helicobacter pylori (strain resistant to metronidazole) activity. All the cyclic voltammograms (CV), in aprotic medium, are similar to the one for metronidazole, except for -I, -Br and -NH(3)(+) derivatives. The CV of the N1-ethylhalide (-I, -Br) 5-nitroimidazole showed more intense and irreversible first waves, even at faster sweep rates (nu<2 V s(-1)). The absence of the first wave anodic counterpart, along with analysis of the dependence of E(p), I(p) and other parameters with nu, and results from electrolysis (consumption of two electrons) showed the process to be an ECE system, with halide release, after uptake of two electrons. This behaviour represents a case of dissociative electron transfer (ET). For the ammonium salt, self-protonation mechanism was evident. The facility of reduction represented by the first wave potential and concerning the substituents is NH(3)(+)>Br>I>Cl>OMs>OH>OAc. In aqueous phosphate-buffered medium, the electrochemical behaviour of all the compounds is similar to the one of metronidazole, represented by a unique and irreversible 4e(-)/4H(+) wave. The order of reduction ease is NH(3)(+)>Br approximately OMs>I>OH>OAc. Aprotic medium allows a better discrimination between the substituents. Concerning biological activity, despite the impossibility of establishing a correlation, it has been observed that the more electrophilic compounds showed better anti-H. pylori activity.

Anti-Bacterial Agents↗

Use of ground-penetrating radar to study tree roots in the southeastern United States.

The objectives of our study were to assess the feasibility of using ground-penetrating radar (GPR) to study roots over a broad range of soil conditions in the southeastern United States. Study sites were located in the Southern Piedmont, Carolina Sandhills and Atlantic Coast Flatwoods. At each site, we tested for selection of the appropriate antenna (400 MHz versus 1.5 GHz), determined the ability of GPR to resolve roots and buried organic debris, assessed root size, estimated root biomass, and gauged the practicality of using GPR. Resolution of roots was best in sandy, excessively drained soils, whereas soils with high soil water and clay contents seriously degraded resolution and observation depth. In the Carolina Sandhills, 16 1 x 1-m plots were scanned with the 1.5 GHz antenna using overlapping grids. Plots were subsequently excavated, larger roots (> 0.5 cm diameter) sketched on graph paper before removal, and all roots oven-dried, classified by size and weighed. Roots as small as 0.5 cm in diameter were detected with GPR. We were able to size roots (0.5 to 6.5 cm in diameter) that were oriented perpendicular to the radar sweep (r(2) = 0.81, P = 0.0004). Use of image analysis software to relate the magnitude of radar parabolas to actual root biomass resulted in significant correlations (r(2) = 0.55, P = 0.0274). Orientation and geometry of the reflective surface seemed to have a greater influence on parabola dimensions than did root size. We conclude that the utility of current GPR technology for estimating root biomass is site-specific, and that GPR is ineffective in soils with high clay or water content and at sites with rough terrain (most forests). Under particular soil and site conditions, GPR appears to be useful for augmenting traditional biomass sampling.

Biomass↗

Hearing and hunting in red bats (Lasiurus borealis, Vespertilionidae): audiogram and ear properties.

We examined aspects of hearing in the red bat (Lasiurus borealis) related to its use of biosonar. Evoked potential audiograms, obtained from volume-conducted auditory brainstem responses, were obtained in two bats, and the sound pressure transformation of the pinna was measured in three specimens. Field-recorded echolocation signals were analysed for comparison. The fundamental sonar search calls sweep from 45 to 30 kHz (peak energy at 35 kHz), approach-phase calls sweep from 65 to 35 kHz (peak 40 kHz) and terminal calls sweep from 70 to 30 kHz (peak 45 kHz). The most sensitive region of the audiogram extended from 10 kHz to 45-55 kHz, with maximum sensitivity as low as 20 dB SPL occurring between 25 and 30 kHz. A relative threshold minimum occurred between 40 and 50 kHz. With increasing frequency, the acoustic axis of the pinna moves upwards and medially. The sound pressure transformation was noteworthy near 40-45 kHz; the acoustic axis was closest to the midline, the -3 dB acceptance angles showed local minima, and the pinna gain and interaural intensity difference were maximal. These results are related to the known echolocation and foraging behavior of this species and match the spectral components of approach- and final-phase calls. We conclude that co-evolution with hearing prey has put a higher selective pressure on optimizing localization and tracking of prey than on improving detection performance.

Animals↗

Efficacy...what's that??

We need to develop techniques for measuring the usefulness of medical services. If resources are limited, and we cannot do all the diagnostic tests we would like to do, we must be able to select those that are most useful. To do this we need to known how to weigh benefits against risks and how to measure the worth of a given outcome. This article discusses efficacy, in diagnosis, management, and outcome. Diagnostic efficacy of a test is measured by its ability to change the probability of disease (pre- versus post-test likelihood). Management efficacy is a measure of how the test changes patient management. Outcome efficacy, which may take years to evaluate, is the ultimate yardstick of usefulness. Even though there are many problems in estimating the likelihood of a disease (subjectivity, varying terminology, etc.), physicians can make reasonably close estimates, as shown by the American College of Radiology's Efficacy Study, which analyzed the diagnostic process in 9000 cases. Efficacy studies may be a mixed blessing, however, as they may result in overly strict criteria and sweeping economic changes. They may be ignored because of the difficulty in following the "perfect" protocol for a given clinical situation, and it remains to be shown that they themselves are efficacious. Nevertheless, we are finally coming to grips with the question of how useful our tests are in patient management.

Cost-Benefit Analysis↗

[Towards a better health status in pig farming].

UNLABELLED: The Dutch pig-farming industry is on the verge of sweeping changes due to national and European legislation and changes towards a buyers market. An improved health-status is a necessity. Such improvements must fall in line with changes in the industry. This paper presents the characteristics of primary, secondary and tertiary infectious disease, and methods by which improvements can be achieved. These are: stamping out; systematic vaccinations; systematic pre-medications; improved husbandry; in-line production; breeding for improved disease-resistance; the SPF system; and Early Medicated Weaning. In the Dutch pig-farming industry the number of farms will decrease to approx. 10,000. These farms will be organised in vertically integrated production systems. IN CONCLUSION: improvement of the national pig-health status is acquired through vertically integrated production systems under improved husbandry conditions. Particular infectious microorganisms will be banned through EEC regulations; other diseases will be minimised by vaccination. Selection for disease-resistance will contribute to some extent to an improved health-status in the future.

Animal Husbandry↗

Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channel currents in differentiated PC12 cells.

Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channels (Cav2 channels) were investigated in cell-attached patches of nerve growth factor (NGF)-differentiated PC12 cells. Cav2 channels, mainly composed of N-type channel in our experimental condition, were defined in this study as high voltage-activated Ca2+ channels obtained after selection of patches without L-type channel "mode 2" activity in the presence of 1 microM BayK8644, or L-type channel block by 5 microM nifedipine. At a test potential of +20 mV, they had a unitary current amplitude of approximately 0.5 pA and open time constants of approximately 0.4 ms and approximately 1.1 ms when fit assuming double exponential components. As bath application of amlodipine was ineffective to modify Cav2 channels in the sealed patch, we analyzed the channel activity when giga-seal formation was obtained in the presence of amlodipine (10 microM both in the pipette and bath solution). Amlodipine did not modify the unitary current amplitude but suppressed the channel open probability (NPo) when holding potential was depolarized, shifting the voltage-dependent inactivation curve towards negative potentials by 25mV. Amlodipine-induced suppression of NPo was mainly due to the decreased ratio of sweeps with channel openings (availability) and was not associated with changes in open time constants. These results were consistent with the view that amlodipine prevented channel openings through the high-affinity binding to the inactivated state, as often observed when dihydropyridines block L-type Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology.

Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.

Animals↗

Mercury vapor as an atmospheric contaminant of dental offices.

Airborne mercury from dental offices was selectively trapped by silber gauze elements in borosilicate glass obsorbers, followed by heat-desorption and spectrophotometric measurement at 2537A. As little as 0.4 ng of Hg could be accurately determined, which is equivalent to 49 ppt in a wone-L air sample on a v/v basis. Over 860 air samples were taken over a range of locations and working conditions at 88 different dental offices, and at the Dental Training Clinic of the University of Manitoba. The Hg vapor concentrations at the dental facilities ranged from 0.45 to 742 mug/m3 of air, 29% of the samples were within 0.45 to 5 mug; 37.8 were within 5.1 to 25mug;and 33.2% were above 25 mug. Mercury concentrations varied during the working day, depending on the time of sampling, the number of amalgams placed, and the interval between placements. The lowest concentrations were obtained in the morning. Disturbance of residual mercury droplets on floors or working areas by sweeping or dusting, or immediately after attempted clean-up of a mercury spill, sharply increased the amount of airborne mercury.

Air Pollutants↗

Prevalence of and risk factors for shedding of Cryptosporidium parvum in Holstein Freisian dairy calves in central México.

A total of 31 dairy farms from three states in central México were selected for this study in order to determine the prevalence of and risk factors for Cryptosporidium parvum shedding in young Holstein Freisian calves. Fecal samples were obtained once from each calf for acid-fast staining for detection of C. parvum oocysts. Information on each calf and on each dairy's management practices regarding the maternity pen, calf hutches and calf feeding was obtained by personal interview using a standardized questionnaire. Of the 31 dairies, 29 had one or more calves shedding C. parvum oocysts. The overall point prevalence was 25% (128/512). Dairy calves from the states of Hidalgo, Jalisco, and México had overall point prevalences of 28% (51/185), 29% (33/112) and 20% (44/215), respectively. Day of age was strongly associated with the risk of shedding C. parvum oocysts, with a maximum risk of shedding at approximately 15 days of age. Using mixed-effects logistic regression with herd as the random effect, feeding starter grain to calves, sweeping out the maternity pen, and using hay bedding in the maternity pen were significantly associated with increased odds of shedding C. parvum oocysts. We speculate that the association between feeding starter grain to calves and the higher odds of shedding C. parvum is linked to an increased duration rather than a higher incidence density of shedding. In addition, the association between sweeping the maternity pen and the increased odds of shedding C. parvum may be attributable to dairy personnel using the same broom for cleaning calf hutches and the maternity pen, thereby cross-contaminating oocysts from infected to newborn calves.

Animal Feed↗

Silica dust exposures during selected construction activities.

This study characterized exposure for dust-producing construction tasks. Eight common construction tasks were evaluated for quartz and respirable dust exposure by collecting 113 personal task period samples for cleanup; demolition with handheld tools; concrete cutting; concrete mixing; tuck-point grinding; surface grinding; sacking and patching concrete; and concrete floor sanding using both time-integrating filter samples and direct-reading respirable dust monitors. The geometric mean quartz concentration was 0.10 mg/m(3) (geometric standard deviation [GSD]=4.88) for all run time samples, with 71% exceeding the threshold limit value. Activities with the highest exposures were surface grinding, tuck-point grinding, and concrete demolition (GM[GSD] of 0.63[4.12], 0.22[1.94], and 0.10[2.60], respectively). Factors recorded each minute were task, tool, work area, respiratory protection and controls used, estimated cross draft, and whether anyone nearby was making dust. Factors important to exposure included tool used, work area configuration, controls employed, cross draft, and in some cases nearby dust. More protective respirators were employed as quartz concentration increased, although respiratory protection was found to be inadequate for 42% of exposures. Controls were employed for only 12% of samples. Exposures were reduced with three controls: box fan for surface grinding and floor sanding, and vacuum/shroud for surface grinding, with reductions of 57, 50, and 71%, respectively. Exposures were higher for sweeping compound, box fan for cleanup, ducted fan dilution, and wetted substrate. Construction masons and laborers are frequently overexposed to silica. The usual protection method, respirators, was not always adequate, and engineering control use was infrequent and often ineffective.

Air Pollutants, Occupational↗

The selective gating of the N30 cortical component of the somatosensory evoked potentials of median nerve is different in the mesial and dorsolateral frontal cortex: evidence from intracerebral recordings.

OBJECTIVE: The somatosensory evoked potentials of the median nerve (SEP) were registered intracerebrally in 12 subjects to elucidate the origin of N30 component and its behavior in the motor 'gating' tasks. METHODS: The recordings were done from the electrodes which were inserted within the cortex of frontal lobe in the pre-surgical phase of epilepsy surgery. The registrations focused on the precentral N30 SEP component and its behaviour under the 'gating' paradigms. Two different 'gating' paradigms, motor and mental, were used and the SEP then were recorded in 3 conditions: (1) normal (N) paradigm, during which the subjects were instructed not to perform any movement by the stimulated hand, or to mentally simulate the movement; (2) active movement (AM) paradigm, during which the subjects were instructed to perform the active movement as the internal motor sequence test by the fingers of the hand of the stimulated limb; (3) mental movement simulation (MMS), during which the subjects were instructed to only mentally simulate the movements performed in the previous paradigm, and this 'virtual' movement also involved the hand of the stimulated limb. The recordings were done at least twice in each paradigm and averaged runs of 2000 artefact-free sweeps were used for the analysis. RESULTS: The results demonstrated that the precentral N30 component of SEP is generated only in the pre-motor area, either dorsolaterally or mesially, which consists of Brodmann's areas 6 and 8, and their borders. Only the N30 potentials recorded there in 7 subjects had a shape and character of 'near-field' potential. The behaviour of the N30 component when recorded in the AM and MMS paradigms was different depending on the fact of whether they were recorded dorsolaterally or mesially. When there was a clear 'near-field' N30 potential recorded mesially, there was a certain gating present during the AM paradigm, i.e. during the performance of movement. However, the gating caused by the mental movement simulation in the MMS paradigm was substantially more expressed, and the N30 wave practically disappeared in some cases. On the contrary, the gating of the N30 wave, recorded in the frontal dorsolateral premotor cortex (DLPC), was almost complete when the AM (active movement) paradigm was employed, and it was only partial when the MMS paradigm (mental movement simulation) was employed. CONCLUSIONS: The results of N30 registrations in our group of patients strongly support the theory of separate generator (or generators) of the N30 wave within the premotor cortex. They also brought forward evidence that the dorsolateral premotor cortex (Brodmann's areas 6 and 8) serves as the substrate of the 'motor execution' process, and the mesial frontal cortex (Brodmann's area 6) serves as the substrate of the 'motor planning' process. Further research should focus on the mutual registration of neurophysiological phenomena and imaging phenomena to obtain new data, which will be able to more precisely elucidate the workings of the premotor cortex during the whole process of motor performance.

Adult↗

Vision abnormalities in young children exposed prenatally to organic solvents.

Despite an accumulating body of evidence demonstrating that the visual system is an important target for organic solvent toxicity in adults, little attention has been paid to the visual functioning of children with prenatal exposure to organic solvents. The present study aimed to: (1) determine prospectively whether prenatal solvent exposure increases the risk of visual deficits in infants and (2) assess the relationship between estimates of exposure level and integrity of visual responses. A sample of 21 infants born to women who were occupationally exposed to solvents during pregnancy was compared with 27 non-exposed age-matched control infants. All mothers were recruited from Motherisk, an antenatal counseling service in Toronto, Canada. Contrast sensitivity and grating acuity were assessed using a sweep visual evoked potential (VEP) technique whereas chromatic- and achromatic mechanisms were assessed using a transient VEP technique. Exposure level was estimated from questionnaire data obtained during pregnancy. Testers were masked to exposure status. Results showed a significant reduction in contrast sensitivity in the low and intermediate spatial frequency range in solvent-exposed infants compared to controls (p<0.001). With respect to grating acuity, there was a significant effect of exposure level, with children in the high exposed having reduced grating acuity compared with children in the low exposed group (p<0.025) and controls (p=0.02). Regarding color vision, 26.3% of infants in the exposed group versus 0% of the controls produced abnormal VEP responses to the red-green onset stimulus (p<0.01), but not to either blue-yellow or achromatic stimuli. No differences were found with respect to latency or amplitude of chromatic and achromatic response. These findings suggest that prenatal solvent exposure is associated with selective visual deficits, including reduced contrast sensitivity and abnormal red-green vision. Increasing levels of exposure may lead to further visual deficits affecting grating acuity. These findings support the need for a re-evaluation of current occupational exposure standards for pregnant women.

Adult↗

Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects.

GR79236 is a highly potent and selective adenosine A1 receptor agonist that has analgesic and anti-inflammatory actions in humans and animals. In animal models it inhibits trigeminal nerve firing and calcitonin gene-related peptide release which play a pivotal role in migraine pathophysiology. Thus GR79236 may have therapeutic potential in migraine. Although there are no validated human models of migraine, the trigeminal nociceptive pathways may be studied with a novel electrode to elicit nociception-specific blink reflex responses. Twelve healthy female volunteers were randomized in a double-blind, placebo-controlled, cross-over trial to investigate the effect of GR79236 on trigeminal nociceptive pathways, as measured by the blink reflex. A secondary objective was to compare the use of two types of electrode, the standard (SE) and nociception-specific electrodes (NE), to investigate human trigeminal pharmacology. Blink reflexes were elicited with SE and NE before and 30 min after GR79236 (10 microg/kg i.v.) or placebo. The median area under the curve of repeated sweeps of the R2 component of the blink reflex was analysed using analysis of covariance with baseline as covariate. Using NE, GR79236 produced a non-significant reduction of the ipsilateral R2 compared with placebo (P = 0.097) and a significant reduction contralaterally (P = 0.008). No significant changes were observed using SE. There were no significant adverse events. The results suggest that NE is more sensitive than SE to detect pharmacological effects in the trigeminal nociceptive system. Furthermore, the adenosine A1 receptor agonist GR79236 inhibits trigeminal nociception in humans. These results support a possible therapeutic role for GR79236 in primary headache disorders.

Adenosine↗

Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation.

Activation of the sympathetic nervous system inhibits insulin-stimulated glucose uptake. However, the underlying mechanisms are incompletely understood. Therefore, we studied the effects of catecholamines on insulin-stimulated glucose uptake and insulin-stimulated translocation of GLUT4 to the plasma membrane in 3T3-L1 adipocytes. We found that epinephrine (1 microM) nearly halved insulin-stimulated 2-deoxyglucose uptake. The beta-adrenoceptor antagonist propranolol (0.3 microM) completely antagonized the inhibitory effect of epinephrine on insulin-stimulated glucose uptake, whereas the alpha-adrenoceptor antagonist phentolamine (10 microM) had no effect. When norepinephrine was used instead of epinephrine, the results were identical. None of the individual selective beta-adrenoceptor antagonists (1 microM, beta(1): metoprolol, beta(2): ICI-118551, beta(3): SR-59230A) could counteract the inhibitory effect of epinephrine. Combination of ICI-118551 and SR-59230A, as well as combination of all three selective beta-adrenoceptor antagonists, abolished the effect of epinephrine on insulin-stimulated glucose uptake. After differential centrifugation, we measured the amount of GLUT1 and GLUT4 in the plasma membrane and in intracellular vesicles by means of Western blotting. Both epinephrine and norepinephrine reduced insulin-stimulated GLUT4 translocation to the plasma membrane. These results show that beta-adrenergic (but not alpha-adrenergic) stimulation inhibits insulin-induced glucose uptake in 3T3-L1 adipocytes, most likely via the beta(2)- and beta(3)-adrenoceptor by interfering with GLUT4 translocation from intracellular vesicles to the plasma membrane.

3T3-L1 Cells↗