Orexin A suppresses in vivo GH secretion.
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BACKGROUND/AIMS: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. METHODS: We administered OX-A (10 microg, i.c.v.) or vehicle (10 microl, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. RESULTS: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means+/-s.e.m. 4.2+/-1.7 ng/ml vs 9.4+/-2.2 ng/ml; P<0.05), mean GH amplitude (3.6+/-0.5 ng/ml vs 20.8+/-5.6 ng/ml; P<0.01) and area under the curve (848+/-379 ng/ml per 4 h vs 1957+/-458 ng/ml per 4 h; P<0.05). In contrast, OX-A failed to modify in vivo GH responses to GHRH (10 microg/kg, i.v.) although it markedly blunted GH responses to ghrelin (40 microg/kg, i.v.) (mean peak GH levels: 331+/-71 ng/ml, vehicle, vs 43+/-11 ng/ml in OX-A-treated rats; P<0.01). Finally, OX-A infusion (10(-7), 10(-8) or 10(-9) M) failed to modify in vitro basal GH secretion or GH responses to GHRH, ghrelin and KCl. CONCLUSIONS: These data indicate that OX-A plays an inhibitory role in GH secretion and may act as a bridge among the regulatory signals that are involved in the control of growth, nutritional status and sleep regulation. (+info)
Forward and backward arm cycling are regulated by equivalent neural mechanisms.
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It was shown some time ago that cutaneous reflexes were phase-reversed when comparing forward and backward treadmill walking. Activity of central-pattern-generating networks (CPG) regulating neural activity for locomotion was suggested as a mechanism involved in this "program reversal." We have been investigating the neural control of arm movements and the role for CPG mechanisms in regulating rhythmic arm cycling. The purpose of this study was to evaluate the pattern of muscle activity and reflex modulation when comparing forward and backward arm cycling. During rhythmic arm cycling (forward and backward), cutaneous reflexes were evoked with trains (5 x 1.0 ms pulses at 300 Hz) of electrical stimulation delivered to the superficial radial (SR) nerve at the wrist. Electromyographic (EMG) recordings were made bilaterally from muscles acting at the shoulder, elbow, and wrist. Analysis was conducted on specific sections of the movement cycle after phase-averaging contingent on the timing of stimulation in the movement cycle. EMG patterns for rhythmic arm cycling are similar during both forward and backward motion. Cutaneous reflex amplitudes were similarly modulated at both early and middle latency irrespective of arm cycling direction. That is, at similar phases in the movement cycle, responses of corresponding sign and amplitude were seen regardless of movement direction. The results are generally parallel to the observations seen in leg muscles after stimulation of cutaneous nerves in the foot during forward and backward walking and provide further evidence for CPG activity contributing to neural activation and reflex modulation during rhythmic arm movement. (+info)
Dynamics of fever and serum levels of tumor necrosis factor are closely associated during clinical paroxysms in Plasmodium vivax malaria.
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Paroxysms are sharp episodes of high fever accompanied by chills and rigors that occur periodically, once in every 48 hr in Plasmodium vivax infections. We have measured the changing levels of serum tumor necrosis factor (TNF) during paroxysms in non-immune patients infected with P. vivax malaria. The changes in TNF levels closely paralleled the rise and fall in temperature during the paroxysms but tended to precede them by 30-60 min. These observations suggest that the rise and fall in temperature during P. vivax paroxysm may be directly related to the periodic changes in TNF levels induced during these infections. The peak TNF levels reached during P. vivax infections were much higher than even those which have been recorded during severe and fatal P. falciparum infections in which TNF has been postulated to contribute to the severe manifestations of this disease. (+info)
Treatment enhances ultradian rhythms of CSF monoamine metabolites in patients with major depressive episodes.
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Unipolar and bipolar depressions show abnormal behavioral manifestations of ultradian (less than 24 h) rhythms, but abnormal rhythms of the central neurotransmitters thought to be important for depression pathophysiology (eg dopamine (DA) and serotonin (5-HT)) have not been shown in this time frame. Since antidepressant treatments normalize disrupted rhythms in depression (eg rapid-eye-movement sleep and hormonal rhythms), we hypothesized that depression-related changes in ultradian oscillations of DA and 5-HT might be revealed during antidepressant treatment. Cerebrospinal fluid (CSF) samples collected q10 min for 24 h in 13 patients experiencing major depressive episodes (MDE) before and after treatment for 5 weeks with sertraline or bupropion were assayed for levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and their ratio was calculated. Data were analyzed in the frequency domain using Fourier transforms and multivariate permutation testing. Antidepressant treatments were associated with decreased variance for 5-HIAA, increased variance for HVA, and markedly increased variance for the HVA : 5-HIAA ratio (p<0.05, p<0.02, and p<0.003, respectively). With treatment, the correlations between 5-HIAA and HVA weakened (p=0.06). Power spectral density (PSD-the Fourier magnitude squared) of the 5-HIAA signals at periods of 1.75 and 3.7 h (both p<0.05) decreased, while circadian cycling of HVA levels (p<0.05) and of the ratio (p<0.005) increased after treatment. The PSD of the full-length HVA : 5-HIAA ratio series after treatment increased in rapid variability (20-103 min periods, p<0.05). Spectrographic windowing demonstrated a focal span of enhanced HVA : 5-HIAA ratio variability following antidepressant treatment, in an approximately 84-min period through the evening (p<0.05). Periodic neurotransmitter relationships in depressed patients were altered by treatment in this analysis of a small data set. This may represent a baseline abnormality in the regulation of periodic functions involved in the depression pathophysiology, but it could also be due to an unrelated antidepressant effect. Further studies including comparisons with healthy subject data are in progress. (+info)
Morning rise in blood pressure is a predictor of left ventricular hypertrophy in treated hypertensive patients.
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To assess the relationship between home blood pressure and left ventricular mass, we evaluated cardiac echocardiography in 297 hypertensive subjects (188 men and 109 women; mean age, 62.8+/-10.3 years) who were treated with amlodipine monotherapy over 1 year (mean dose, 5.5+/-2.3 mg/day). The morning hypertension group (n=57; 19.2%), who had a morning home systolic blood pressure (HSBP) > or =135 mmHg and an evening HSBP <135 mmHg, had a significantly greater left ventricular mass index (LVMI) concomitant with an increase in the homeostasis model assessment insulin resistance index (HOMA-IR) compared to the good control group (n=174; 58.6%), whose morning and evening HSBP were both <135 mmHg, and had a LVMI roughly equivalent to that of the poor control group (n=63; 21.2%), whose morning and evening HSBP were both > or =135 mmHg. By grouping of subjects according to the difference between morning and evening HSBP (delta HSBP), subjects with a delta HSBP> or =10 mmHg had a significantly greater LVMI than subjects with a delta HSBP <10 mmHg. Increases in LVMI in these patients were still significant after adjustment for age, gender, dose of amlodipine, alcohol consumption, body mass index, office systolic blood pressure, and morning and evening HSBP. In a stepwise multivariate regression analysis, delta HSBP (r2=36.2%, p <0.001), morning HSBP (r2=5.5%, p <0.001), HOMA-IR (r2=1.4%, p=0.016) and age (r2=1.0%, p=0.026) were determined to be significant contributing factors for LVMI. This regression model could explain 44.1% of LVMI variability. These results suggest that morning rise in blood pressure is a dominant predictor of left ventricular hypertrophy. (+info)
Variability of swallowing performance in intact, freely feeding aplysia.
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Variability in nervous systems is often taken to be merely "noise." Yet in some cases it may play a positive, active role in the production of behavior. The central pattern generator (CPG) that drives the consummatory feeding behaviors of Aplysia generates large, quasi-random variability in the parameters of the feeding motor programs from one cycle to the next; the variability then propagates through the firing patterns of the motor neurons to the contractions of the feeding muscles. We have proposed that, when the animal is faced with a new, imperfectly known feeding task in each cycle, the variability implements a trial-and-error search through the space of possible feeding movements. Although this strategy will not be successful in every cycle, over many cycles it may be the optimal strategy for feeding in an uncertain and changing environment. To play this role, however, the variability must actually appear in the feeding movements and, presumably, in the functional performance of the feeding behavior. Here we have tested this critical prediction. We have developed a technique to measure, in intact, freely feeding animals, the performance of Aplysia swallowing behavior, by continuously recording with a length transducer the movement of the seaweed strip being swallowed. Simultaneously, we have recorded with implanted electrodes activity at each of the internal levels, the CPG, motor neurons, and muscles, of the feeding neuromusculature. Statistical analysis of a large data set of these recordings suggests that functional performance is not determined strongly by one or a few parameters of the internal activity, but weakly by many. Most important, the internal variability does emerge in the behavior and its functional performance. Even when the animal is swallowing a long, perfectly regular seaweed strip, remarkably, the length swallowed from cycle to cycle is extremely variable, as variable as the parameters of the activity of the CPG, motor neurons, and muscles. (+info)
Effects of time of day of treatment on ambulatory blood pressure pattern of patients with resistant hypertension.
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Patients with resistant hypertension present high prevalence of a non-dipper blood pressure pattern. Recent results indicate that non-dipping is related partly to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. Accordingly, we investigated the impact of treatment time on the blood pressure pattern in 700 patients with resistant hypertension on the basis of clinic measurements who were studied by 48-hour ambulatory monitoring. Among them, 299 patients received all their medication on awakening, and 401 were taking > or =1 antihypertensive drug at bedtime. The percentage of patients with controlled ambulatory blood pressure was double in patients taking 1 drug at bedtime (P=0.008). Among the 578 patients with true resistant hypertension, subjects receiving 1 drug at bedtime showed a significant reduction in the 24-hour mean of systolic and diastolic blood pressure (3.1 and 1.6 mm Hg, respectively; P<0.011). This reduction was much more prominent during nighttime (5.1 and 3.0 mm Hg; P<0.001). Accordingly, the diurnal/nocturnal blood pressure ratio was significantly increased by 2.7 and the prevalence on non-dipping reduced (56.9 versus 81.9%; P<0.001) in patients taking 1 drug at bedtime. Compared with patients receiving all drugs on awakening, subjects with 1 drug at bedtime also showed significant reductions in the average values of glucose, cholesterol, fibrinogen, and urinary albumin excretion (P<0.011). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each patient to improve control and to avoid the non-dipper pattern associated to higher cardiovascular risk. (+info)
Circadian pattern of spontaneous behavior in monarthritic rats: a novel global approach to evaluation of chronic pain and treatment effectiveness.
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OBJECTIVE: Preclinical evaluation is an essential step in the assessment of new antiinflammatory or analgesic drugs. This study was undertaken to develop a new mode of evaluation of drug effectiveness based on behavior indicating well-being in a rat model of chronic inflammatory pain. We chose to examine the circadian pattern of spontaneous behavior. METHODS: The work was performed with a model of chronic monarthritis induced by Freund's complete adjuvant. Variations in behavioral patterns during the time course of arthritis were analyzed. In a second phase, the impact of acetaminophen and 2 nonsteroidal antiinflammatory drugs (aspirin and celecoxib), which are currently used in clinical practice to treat chronic inflammation, was studied after 7 days of treatment. RESULTS: The nocturnal pattern of activity of healthy rats comprised 3 main bursts. Chronic painful monarthritis altered this spontaneous pattern of nocturnal behavior (normal period of activity). Monarthritic rats showed a decrease in the total time spent in activity during the night, and lost their pattern of activity. These behavioral disturbances were reversed after long-term treatment with acetaminophen or celecoxib, with celecoxib appearing to be more effective. Aspirin was ineffective. CONCLUSION: These results enabled us to test this new procedure as a means of assessing well-being or ill- being during stages of chronic inflammatory pain in rats, and the effectiveness of repeated pharmacologic treatments. (+info)