Time-frequency visualization of alcohol withdrawal tremors.

In this paper, we propose a signal processing method of assessing the severity tremors caused by alcohol withdrawal (AW) syndrome. We have developed an iOS application to calculate the Clinical Institute Withdrawal Assessment (CIWA) score which captures iPod movements using the built-in accelerometer in order to reliably estimate the tremor severity component of the score. We report on the characteristics of AW tremor, the accuracy of electronic assessment of tremor compared to expert clinician assessment, and the potential for using signal processing assessment to differentiate factitious from real tremor in patients seen in the emergency department, as well as in nurses mimicking a tremor. Our preliminary results are based on 84 recordings from 61 subjects (49 patients, 12 nurses). In general we found a linear relationship between energy measured by the accelerometer (in the 4.4-10 Hz range) and the expert rating of tremor severity. Additionally, we demonstrate that 75% of the recordings from patients with actual AW syndrome had a mean peak frequency higher than 7 Hz whereas only 17% of the nurses' factitious tremors were above 7 Hz, suggesting that tremor above 7 Hz could be a potential discriminator of real versus factitious tremors.

Dopamine receptor activation inhibits estrogen-stimulated transforming growth factor-alpha gene expression and growth in anterior pituitary, but not in uterus.

Transforming growth factor-alpha (TGF alpha) has been localized to the anterior pituitary, specifically to the lactotroph and somatotroph cell populations, by our previous studies. Since pituitary lactotrophs are known to undergo growth in response to estrogens, we have used an estradiol-induced pituitary hyperplasia/adenoma model. Estradiol treatment resulted in induction of TGF alpha mRNA in anterior pituitary, evident by 48 h, preceding actual macroscopic growth, which attained a maximum greater than 500% by 12 weeks. This rapid effect of estradiol also enhanced PRL mRNA, but did not affect other species of mRNA encoding for proenkephalin, D2 receptor mRNA, or hexosaminidase-A. TGF alpha mRNA remained elevated for the duration of rapid pituitary growth. D2 receptor activation by its agonist bromocriptine resulted in marked attenuation of TGF alpha mRNA preceding regression of growth. Coadministration of bromocriptine with estradiol resulted in an involution of pituitary size, indicating the overriding influence of dopamine in spite of a continued estrogenic stimulus. Epidermal growth factor receptor mRNA was not affected by any of these manipulations, suggesting that the receptor was not coregulated in this tissue similarly to TGF alpha. Estradiol also induced uterine TGF alpha mRNA and marked growth of the organ, but TGF alpha in this location was not regulated by dopamine. These results indicate that TGF alpha in the anterior pituitary is rapidly induced by estrogen in a time course preceding the growth of the gland. Estrogen-induced TGF alpha is rapidly attenuated by D2 dopamine receptor activation and is accompanied by a regression of pituitary growth. Interaction between these opposing hormonal/transmitter responses will determine the growth potential of the anterior pituitary.

Estrogen regulation of rat anterior pituitary adenylate cyclase.

The effect of chronic estrogen treatment on the stimulation and dopamine inhibition of anterior pituitary (AP) adenylate cyclase (AC) activity was examined. Treatment of ovariectomized female rats with estradiol for 21 days resulted in a 450% increase in AP weight compared to ovariectomized controls. Stimulation of AC by guanine nucleotides (GN) (1 nM-0.1 mM) and vasoactive intestinal peptide (1 microM) was reduced by 50%. Stimulation of AC by fluoride ions was unchanged by estradiol treatment. Stimulation above basal by forskolin was reduced by variable amounts (23-50%), and depended on the concentration of forskolin used. Inhibition of AC mediated by D2-dopamine receptors was decreased by 45%. Estrogen treatment had no effect on the toxin-catalyzed incorporation of [32P]ADP into stimulatory and inhibitory GN regulatory proteins. These results indicate that the effect of estrogen on the anterior pituitary include modulation of stimulated, dopamine-inhibited and basal AC activity.

Hypothalamic corticotropin-releasing factor immunoreactivity is reduced during induction of pituitary tumors by chronic estrogen treatment.

The role that estrogen plays in the regulation of corticotropin-releasing factor (CRF) is not known. A radioimmunoassay specific for rat CRF was utilized to measure the CRF-like immunoreactivity (CRF-ir) in the hypothalamus of ovariectomized rats treated with estradiol for periods up to 12 weeks. Compared to ovariectomized controls, estradiol treatment resulted in significantly reduced CRF-ir after 3 and 12 weeks, although no significant change was seen after 8 weeks. Anterior pituitary (AP) weight was greatly increased by estradiol treatment at all time points studied. Bromocriptine treatment for the last 3 weeks of the 12-week period, or removal of estradiol for 3 weeks after 9 weeks of treatment did not reverse the changes in CRF-ir even though significant regression of tumor size was achieved. There was no correlation between AP weight and CRF-ir in individual animals. These data show that chronic treatment with estrogen reduced hypothalamic CRF-ir content. Neither a direct estrogenic effect or an indirect effect mediated through alterations in the adenohypophysis could be ruled out.

Dopamine inhibition of anterior pituitary adenylate cyclase is mediated through the high-affinity state of the D2 receptor.

The diterpenoid forskolin stimulated adenylate cyclase activity (measured by conversion of [3H]-ATP to [3H]-cAMP) in anterior pituitary from male and female rats. Inhibition of stimulated adenylate cyclase activity by potent dopaminergic agonists was demonstrable only in female anterior pituitary. The inhibition of adenylate cyclase activity displayed a typically dopaminergic rank order of agonist potencies and could be completely reversed by a specific dopamine receptor antagonist. The IC50 values of dopamine agonist inhibition of adenylate cyclase activity correlated with equal molarity with the dissociation constant of the high-affinity dopamine agonist-detected receptor binding site and with the IC50 values for inhibition of prolactin secretion. These findings support the hypothesis that it is the high-affinity form of the D2 dopamine receptor in anterior pituitary which is responsible for mediating the dopaminergic function of attenuating adenylate cyclase activity.

Alpha 1 adrenergic receptors in the porcine pituitary neurointermediate lobe: detection with [3H]ketanserin.

[3H]Ketanserin, a serotonin receptor antagonist, labelled high affinity, saturable sites in homogenates of porcine neurointermediate lobe tissue. Cinanserin, a potent and selective serotonin receptor antagonist, inhibited the specific binding of 5 X 10(-10)M [3H]ketanserin with a high affinity component representing 20% of the total binding. Prazosin, a potent and selective alpha 1 adrenergic antagonist, inhibited [3H]ketanserin binding with a high affinity component representing 60% of total binding. The prazosin-specific component was demonstrated to be distinct from the cinanserin-specific component. 10(-7)M cinanserin was co-incubated with [3H]ketanserin to eliminate the serotonergic component of the binding and allow pharmacological characterization of the remaining prazosin-specific component. The prazosin-specific binding of [3H]ketanserin binding closely resembled the results of experiments using [3H]prazosin to label alpha 1 receptors in neurointermediate lobe tissue homogenates. Ketanserin was found to be seven-fold more potent in inhibiting [3H]prazosin binding to alpha 1 adrenergic receptors in the neurointermediate lobe tissue than in brain tissue. This observation explains why low concentrations of [3H]ketanserin can selectively label serotonin receptors in the brain but will label both adrenergic and serotonin receptors in the neurointermediate lobe.

pH-dependent modulation of agonist interactions with [3H]-ketanserin-labelled S2 serotonin receptors.

The effects of varying the pH on the properties of S2 serotonin receptors labelled by [3H]-ketanserin were examined. Between pH 7.0 and 8.2 the agonist affinities, as determined by competition experiments, increased dramatically. Serotonin, 5-methoxytryptamine, tryptamine, bufotenine and quipazine, demonstrated 15,16,8,6 and 5-fold increases in apparent affinity between pH 7.0 and 8.2. On the other hand the antagonists, ketanserin, cinanserin, and spiperone demonstrated little or no affinity changes between pH 7.0 and 8.2. The largest shift in affinity for an antagonist occurred with spiperone, which displayed a two-fold shift. Although changing pH is a rather non-specific manipulation, the selective affect on agonist interaction with S2 receptors indicates further investigation of this pH effect may aid in discovering the difference in receptor interactions between serotonin agonists and antagonists.

Properties of [3H]prazosin-labeled alpha 1-adrenergic receptors in rat brain and porcine neurointermediate lobe tissue.

[3H]Prazosin binding to alpha 1 receptors in homogenates of rat prefrontal cortical tissue and porcine pituitary neurointermediate lobe tissue was investigated. Competition curves produced by coincubating adrenergic agonists and antagonists with 0.5 nM [3H]prazosin and tissue revealed some anomalous binding properties. In the brain and pituitary tissue, agonist competition curves produced "shallow" slopes, with Hill coefficients significantly lower than unity. The IC50 of the agonists epinephrine, norepinephrine, and clonidine for inhibition of 0.5 nM [3H]prazosin binding were significantly lower in the porcine pituitary than in the rat brain. Most antagonists, such as prazosin, chlorpromazine, and piperoxan, produced "steep" competition curves with Hill coefficients close to unity, with two notable exceptions. WB-4101 and phentolamine produced competition curves with Hill coefficients significantly less than unity in the rat brain preparation. Ketanserin, an antagonist, displayed a sevenfold higher affinity for the alpha 1 sites in the pituitary tissue than in the brain tissue. These anomalies in the binding results may indicate the presence of an endogenous modulatory factor affecting agonist and antagonist affinities for the alpha 1 receptor.