[Plasma pharmacokinetics of morphine and morphine-6-glucuronide using high performance liquid chromatography and colorimetric detection].

This pilot study was undertaken in a group of 7 patients receiving morphine either by oral route under a controlled release form (Moscontin tablets), or by subcutaneous route with continuous infusion. Complete pharmacokinetics over 24 h were carried out with blood samples taken every hour. The measurements of morphine and of its metabolite, morphine-6-glucuronide (M6G) were performed by high-performance liquid chromatography (HPLC) with coulometric detection, using nalorphine (NAL) as an internal standard. The morphinics were extracted on a Bond Elut C18 column according to a double liquid-solid extraction. The extract was chromatographed by ion-pairing on a mu Bondapak C18 column, 10 microns (300 x 3.9 mm). The minimal detectable concentrations were respectively 1 and 5 ng/ml for M and M6G. When Moscontin was given at dosages < 1 mg/kg/d, the areas under the curve over 24 h (AUC 24 h) of M were rather close to those of M6G (ratio 1.1 +/- 0.1). However, with dosages > 1 mg/kg/d, a difference appeared and gradually rose to a M/M6G ratio of 1.3 +/- 0.04. With subcutaneous infusion, the plasma levels of M6G were from 2 to 17-fold lower than those of M.


[Hypothalamo-hypophyseal and gastric metastasis of a breast neoplasm. Clinical case and a review of the literature].

The authors report the case of a young woman with advanced breast cancer who developed diabetes insipidus due to pituitary involvement and also gastric metastases. This patient had a normal brain CT scan. Gastric metastases were diagnosed when she was operated for a perforated gastric ulcer. Although very rare, and even if the brain CT scan is normal, pituitary metastases should be diagnosed in the presence of suggestive clinical symptoms. Abdominal pain also warrants investigation in these patients in an early attempt to document any possible gastric metastases.


[Adverse effects of interleukin 2].

Interleukin 2, has frequent and important side effects. Toxic effects observed are systemic (fever, chills, malaise), hemodynamic (capillary leak syndrome, hypotension), cardiac (arrhythmia, infarction), renal (renal dysfunction), infectious (septicemia), cutaneous, hematologic, gastrointestinal, endocrinologic and metabolic. Side effects are dose-dependent, generally reversible, with a mortality from 1 to 3%. Regimens of administration and other cytokine combinations affect interleukin 2 toxicity. If the treatment of these side effects is well known, selection of patients and specialized care unit remain always necessary.


[The hypothesis of the cortical mechanisms of operative memory].

The investigation of neuronal activity of monkey cerebral cortex during delayed spatial choice performance allows to develop a hypothesis about the neuronal networks securing the operative memory. The work of one of them is based on the relay-race and reverberation principles of information transfer. Another neuronal network secures the reliability of the transfer phases of behavioural program. Both of these neuronal networks are represented differently in the prefrontal and parietal associative cortical areas.


[The participation of cortical brain areas in the processes of perceiving and reproducing human emotional states].

New method of mapping intracortical interactions was used to study the participation of cortical brain areas in the processes of perception and of mental reproduction of emotional states in humans. When an emotion was identified, the activity focus was observed in the left temporal cortex. If emotion was not identified, the temporal focus did not appear, but activity foci were seen in frontal regions of both hemispheres. When emotional states were mentally reproduced, activity foci were encountered mostly in the frontal cortical areas.


[The characteristics of motor asymmetry in the ontogeny of calves].

The side of preference (first turn of head) was recorded in calves in situation of free equal probability two-sides choice, and rate of reconstruction of conditioned reflex to food presented from the left or from the right was determined. Initially the calves preferred the left turn, i.e. manifested motor asymmetry. Preference to the left turn changed depending on the calves age with the period of 22-23 days. The rate of conditioned reflexes reconstruction was higher in calves with the left-side preference. Correlation of the motor asymmetry and rate of conditioned reflex reconstruction in calves of different age changed in analogy with age changes of asymmetry. Probably the observed periodical changes of asymmetry and its correlation with the rate of reconstruction reflect formation of interhemispheric interactions in regulation of the organism functions in animals ontogenesis.


[A computer analysis of EEG intersignal reactions during the the acquisition of conditioned motor-food reflexes in dogs].

Background electric activity was studied of different neocortex areas in interstimulus intervals at the stage of generalization during elaboration of motor alimentary conditioned reflexes in dogs. For this stage the appearance is typical of short-term (0.1-0.3 s) packs of high frequencies (above 40 osc./s) significantly exceeding the adjacent initial background by frequency and amplitude (along side with motor interstimulus reactions). The index of specific variation, elaborated by us, allowed to single out this EEG pattern in the initial realizations of the background activity during their input in the computer. With the purpose of further evaluation of the above phenomenon parameters non-standard approaches of computer analyses were used, directed to decomposition of the EEG curve into the system of oscillations and receipt of corresponding amplitudes frequencies distributions (maps). It was shown, the described high frequencies packs were localized on these maps in definite sufficiently compact places.


[The characteristics of probabilistic prognosis and of the orienting reaction in children with learning difficulties].

Middle-aged school-children were examined with learning disabilities, differentiated by the parameters of probabilistic prognosis in two subgroups: with disturbances of attention (1) and memory (2). The first subgroup differed from the norm by intensified reaction of desynchronization of the projection areas of the cortex to irrelevant stimuli. Relevant information evoked an increase of activation of the associative zones, less expressed than in the norm. In the second subgroup a weak involvement of associative cortical areas in the reaction of desynchronization to relevant stimuli correlated with insufficient formation of alpha 2-rhythm and high frequency of meeting the signs of dysfunction of mesodiencephalic brain structure. The results are discussed in the aspect of the role of neurophysiological mechanisms of regulation and trace fixation for the formation of the integrative brain activity in the ontogenesis.


[The effects of intracerebral injections of kynurenine on conditioned reflex activity and on the serotonin level of the blood in dogs].

Higher nervous activity of dogs was studied by classical Pavlovian method of alimentary salivary conditioned reflexes and serotonin content in blood was measured. Kynurenine sulfate in a dose of 300 + 300 mkg (bilaterally) was injected in the dorsal hippocampus region through chemiotrodes. In most cases the injection of the substance led to changes towards excitation (increase of conditioned and unconditioned alimentary salivation in the day of injection and the next day) and also to a rise of serotonin content in animals blood.


[The regulatory effect of the functional status of the cat on the perception of an external afferent stimulus].

Experiments were conducted on cats by conditioned food-procuring method. Behavioural, vegetative reactions and a set of electrophysiological characteristics were recorded. It was found that regulatory influence of an extraneous stimulus and of artificial excitation of the brain was expressed in an increase of reactivity to conditioned and unconditioned sensory stimuli and in disinhibition of effector responses. This influence was realized not only during the development of EEG activation reaction but could be preserved over a long period in conditions of the deactivated brain state. Regulatory influence of interceptive factors is characterized by a decrease of reactivity and by inhibition of effector responses. As in the case of external effects, the realization of this influence begins with a period of brain activation and is preserved for a long time in conditions of deactivated state.


[The effect of the S1A-receptor agonist ipsapirone on behavior types in wild and domesticated rats].

Selective agonist of 1A subtype of serotonine receptors ipsapirone inhibited manifestation of affective kinds of aggression in wild and domesticated rats. Administration of ipsapirone (10 mg/kg) decreased the number of aggressive attacks of wild and domesticated rats in the test of shock-induced aggression and blocked manifestation of defensive reaction to the experimenter in wild rats. Neophobia in wild rats decreased under the influence of ipsapirone. At the same time ipsapirone did not change mouse-killing behaviour either in wild or in domesticated rats. Probably, 5-HT1A receptors the aggressive regulate reaction, which are parts of the complex of defensive behaviour of the wild animals.


[The capacity of ants for multiple alterations in the maze habit].

Ability was shown of ants Myrmica rubra to multiple reconstructions of the habit elaborated in symmetrical multialternative maze under motivation of care for the progeny (transportation of breed of the own species). Reconstruction consisted in the change of reinforcement location on the left or right aim spot. The ants showed the ability to carry out the series of eight reconstructions during one-two days. An improvement took place of the fulfillment of the last reconstructions in comparison with the first ones. Peculiarities of learning and reconstructions were found in two groups of animals differing by conditions of learning: at reinforcement on both ain spors or on one of them. The results obtained are considered as indices of high plasticity of the behaviour of ants of the studied species.


[The participation of the neostriatal cholinergic system in the differentiation of acoustic signals in dogs].

In chronic experiments on six dogs the influence was studied of micro-injections of choline agonist carbocholine (0.05-0.2 mkg) and of blocker of choline receptors atropine (40 mkg) in the caudate nucleus head of the left and right hemispheres on realization of instrumental defensive reflexes, connected with the maintenance of definite posture and on differentiation of signals in defensive situation. It has been shown that the cholinergic system of the neostriatum participated in realization of both the motor and sensory mechanisms in connection with the realization of motor responses to defensive and differentiation signals. Analysis of the obtained results also allowed to make a conclusion that the influence of carbocholine micro-injections into the neostriatum on differentiation depended on a number of factors: it did not take place when the signal was poorly distinguished (judging by the values of motor components to defensive and differentiation signals) or, on the other hand, against the background of stable differentiation reaction in other animals, i.e. in case of complete learning.


[The effect of high-frequency stimulation of the midbrain reticular formation on the interaction of neocortical neurons].

The influence was studied of midbrain reticular formation (NRT) stimulation at the rate of 75-100 Hz by the current of 33-400 mkA upon the neuronal interaction in the visual and somatosensory regions of rabbits neocortex. Histograms of cross- and autocorrelation of impulse trains were plotted. NRT stimulation resulted (as compared with calm wakefulness) in an increase of the number of pairs of neurons with correlated activity and in an increase of the probability of neurons discharges 100-400 ms one after another. Mechanisms of cellular interaction did not change. Comparison with the previously obtained data allowed to conclude that NRT activation can induce certain changes in neuronal interaction observed during pseudoconditioning and early phases of conditioning.


[The intercentral relations of the biopotentials in the rabbit brain during the creation of a blinking dominant].

On rabbits in chronic experiment intercentral relations were studied of biopotentials of the sensorimotor cortical zone (blinking presentation in the cortex), VPM of the thalamus and motor nucleus of the oculomotor nerve at formation of blinking dominant created by serial stimulation of one eye by air jet. By the method of spectral-correlation analysis an increase was revealed of spectrum power and increase of COG of the potentials in delta-range in the structures connected with blinking function of the stimulated eye. At transition of the dominant focus to the inhibitory state and activation of the symmetrical centre of the other eye, in centers constellation of this induced focus a reconstruction of the electrical processes took place typical for the dominant.


[The effect of acetylcholine and atropine on the temporal connection in the neuronal populations of the motor cortex].

On alert non-immobilized rabbits the activity of neurones in the sensorimotor cortex was studied at pair combination of brain structures stimulations. During omission of the reinforcing stimulus at the place of its expected presentation a complicated complex develops of neurones impulses reconstructions, consisting in reproduction of responses and activity changes which by their configuration differ from them and usually appear in later terms. Direct acetylcholine application on the cortex promotes manifestation of both types of neurones activity reconstructions. But atropine application depresses mainly the second type of reconstructions. Besides, acetylcholine increases the general duration of the given conditioned effects, but atropine decreases it.


[The functional testing of the interhemispheric asymmetry in the spatial organization of rabbit cortical potentials].

Interhemispheric asymmetry was studied of spatial-temporal potentials organization (STPO) of the cortex in non-fixated animals in the states of deep rest, behavioural activity and in the transition period between them. Despite the intrahemispheric differences of the STPO in each of these states, interhemispheric divergences in the character of reconstructions of momentary topograms of the cortical potentials, recorded at 24-channels leading, are limited by 35% of the epoch analysis time. Comparison of the dynamics of intrahemispheric changes of topograms of cortical potentials in the left and right hemispheres in the states of rest and activity revealed a narrowing of temporal period of the absence of resemblance in reconstructions of successive topograms of the left and right hemispheres in comparison with transition processes. In the phase of rest the interhemispheric conjugation of spatial reconstructions in topograms became lowered mainly because of the disturbances of monotony of changes of their reliefs in one of the hemispheres in turn. In the active phase, deviations from STPO of the cortex, characteristic of the state of rest, were met more frequently in the right hemisphere; in that case oscillations of the topograms general mean level connected with the activity of non-specific activating subcortical brain system acquired a significant role in regulation of interhemispheric relations. Presence of interhemispheric resemblance of reconstructions of topograms reliefs in the active phase, despite the tendency to its lowering in comparison with the rest, testifies to the contribution also of the intracortical processes to the interhemispheric spatial synchronization of the cortical potentials in this state.


[Cholinergic sensitivity as an index of the functional differences in cortical neurons in young and old rabbits].

Acetylcholine-sensitivity of motor cortex neurons was studied in the young and old rabbits. Muscarinic-type excitation in the neurons of old animals was revealed twice less frequently compared to the young ones. The age-related fall in the number of cholinoceptive neurons may be due to general decrease of neuronal activation in the motor cortex during aging. Changes in functional properties of motor cortex neurons with age may have a result that firing rate of movement related neurons becomes insufficient for the effective control of motor function.


[The capacity for competition in rats raised in isolation].

It is shown, that rats, bred in conditions of intraspecies isolation are able to competition for water in the kin group, having usual experience of intraspecies intercourse. At the same level of drinking motivation in conditions of competition for water the intraspecies activity is significantly higher in rats, bred in isolation in comparison with grouped animals. Rats-isolants significantly more often than the grouped animals use extraordinary tactics of intraspecies behaviour, which increase their competitive ability in conditions of limited access to water.


[Lipoxygenase inhibitors, eicosapolynoic acids, attenuate the short-term plasticity of the cholinoreceptors of snail neurons].

On identified Helix neurones RPa3 and LPa3 with the use of the double-electrode voltage clamp technique on the membrane the influence was studied of three polyacetilenic analogues of natural polyenoic acids which were the inhibitors of their lipoxygenase oxidation on the dynamics of inward current extinction, caused by the repeated iontophoretic applications of acetylcholine to soma. It was found that 5, 8, 11, 14-eicosatetraynoic acid (30-60 microM) and 5, 8, 11, 14, 17-eicosapentaynoic acid (4-5 microM) decreased the amplitude of inward current caused by acetylcholine leading and weakened its extinction at the repeated applications. The third analogue -8, 11, 14-eicosatrynoic acid had no modulating influence on the value of current and on its extinction. The supposition was made that lipoxygenase metabolites of polyenoic acids regulated plasticity of Helix neurones cholinoreceptors. Considering different inhibiting by the used compounds of various lipoxygenases the most probable was participation in regulation of cholinoreceptors plasticity of those eicosanoids which were formed from arachidonic acid under the influence of 5-lipoxygenase. Regulating role of eicosanoids formed at the action of other lipoxygenases was not excluded.


[The characteristics of the change in the catecholamine content of the brain in inbred mouse strains under zoosocial stress].

Noradrenaline (NA) and dopamine (DA) contents in various brain regions and their dependence on genotype, determining predisposition to domination, were studied during 7 days after the formation of artificial micropopulations consisting of 6 male mice of different genotypes. Significant changes of NA level were found in the olfactory bulbs and in the medulla oblongata and of DA in the hypothalamus and the hippocampus. Genotypic differences in NA levels were found in the hypothalamus and in DA levels--in the hippocampus. Reactions of RT males predisposed to domination differed both in noradrenaline and DA systems of the brain from the reactions of the males genetically predisposed to subordinate type of behaviour. Interconnection between the amines content both inside and between catecholamine systems was revealed.


[The intravenous self-administration of narcotics in mice].

Four commonly and largely abused drugs morphine, cocaine, amphetamine, cathinone and sympathomimetic ephedrine were investigated, using intravenous self-administration by naive mice, with special regard to methodological aspects of these techniques. All drugs showed a similar bell-shaped concentration response curves, which are typical of compounds with high addictive potential. A new method of analysis of the reinforcing properties allowing to disregard motor side effects of drugs nas been proposed. Procedure and analysis aspects of described techniques as well as the possibilities of its application for screening of addictive substances are discussed.


[Use of an endoprosthesis in the treatment of bile leakage from the cystic duct following laparoscopic cholecystectomy].

The case is reported of a female aged 32 years in whom, after laparoscopic cholecystectomy performed because of symptomatic gallbladder calculi, leakage from the cystic duct occurred. After percutaneous drainage of the perihepatic bile collection, endoscopic retrograde cholangiopancreatography (ERCP) with papillotomy was performed; since this proved insufficient, an endoprosthesis was inserted into the common bile duct by ERCP, following which the bile leakage ceased.


[The predisposition to catatonic reactions, monoamine oxidase and the delta-sleep peptide in rats].

MAO B/MAO A rations and the influence of delta-sleep inducing peptide (DSIP) on the two forms of MAO and on the predisposition to different types of catatonic reactions were compared in rats of GC strain selected from Wistar for predisposition to catalepsy, and in wild rats. In GC rats, the MAO B/MAO A ratio was increased, as compared to Wistar, in the brain stem and hemispheres, whereas in wild rats predisposed to catatonia it was increased, as compared to normal wild rats, only in the hemispheres. In GC rats, this increase of the MAO B/MAO A ratio was due to a decrease of MAO A and increase of MAO B activity, while in wild catatonic rats only due to heightened MAO B activity. Administration of DSIP abolished the susceptibility to catatonic reactions and normalized the MAO B/MAO A ratio both in GC and in wild catatonic rats. There seems to be a partial similarity of physiological mechanisms of catatonic reactions in laboratory albino and in wild rats.


Differential tissue regulation of the insulin-like growth factors in rats bearing the MStT/W15 pituitary tumor.

The content of insulin-like growth factors, IGF-I and IGF-II, was measured in tissues of rats bearing a transplantable mammosomatotrophic tumor, MStT/W15. Serum IGF-I was elevated in tumor-implanted rats [2,557 +/- (SE) 419 vs. 891 +/- 100 ng/ml], and tumor tissue concentrations of IGF-I were increased (321 +/- 16 ng/g) in comparison to control liver tissue (160 +/- 5 ng/g) or control pituitary (80 +/- 3 ng/g). The IGF-I levels were significantly increased in most peripheral tissues in the tumor-bearing rats with the exception of the liver. In support of this finding, messenger RNA for prepro IGF-I was likewise not increased in the livers of tumor-bearing rats, nor was there an increase in the growth hormone-dependent IGF-binding protein, BP-3, in the liver or serum of these animals. All tumors had detectable levels of prepro IGF-I mRNA which was, however, less than 50% of that noted in normal control liver. The tumors also expressed an IGF-BP which was identified as IGF-BP-2 by immunoblotting. Serum concentrations of IGF-II were similar in control and tumor-bearing animals (approximately 70 ng/ml). IGF-II levels in the tumor (90 +/- 5 ng/g) were significantly higher than levels in control liver (34 +/- 2 ng/g), but similar to those found in normal pituitary (165 +/- 24 ng/g). In peripheral tissues, IGF-II concentrations were selectively increased in skeletal muscle and heart of tumor-bearing rats. These data demonstrate tissue-specific regulation of IGF-I and IGF-II. Paradoxically, the liver does not appear to be stimulated over control levels by high serum growth hormone levels, since neither IGF-I peptide, IGF-I mRNA, nor IGF-BP-3 levels are increased in livers of tumor-bearing rats. This suggests that the increase in serum IGF-I in these animals is due to increased production of IGF-I by the tumors themselves and by nonhepatic peripheral tissues and further that hepatic responsiveness to growth hormone is diminished in these tumor-bearing animals.


Effect of elevated serum prolactin concentrations on cytokine production and natural killer cell activity.

In vitro and in vivo studies in rodents and human suggested an immunostimulatory effect of prolactin. The aim of the present study was to determine the impact of chronically elevated serum prolactin concentrations on the immune system in patients with prolactinomas. For this purpose parameters of the humoral and cellular immune system were studied in seven patients with prolactinomas on two occasions (1) when their serum prolactin concentration had been normalized through treatment with dopamine agonists and (2) when their serum prolactin concentration was high. Serum concentrations of immunoglobulines, interleukin 1, 3 and 6, TNF-alpha, interferon-gamma and the soluble interleukin 2 receptor, leukocyte subsets and the natural killer cell activity were found to be within the normal range on both occasions, i.e. at normal and at high serum prolactin concentrations. The assumption could be made that long-lasting elevation of serum prolactin concentration induces adaptive changes when the acute stimulatory effects of prolactin on several parameters of the immune system have subsided.


Alterations in gonadotropin secretion in middle-aged persistent-estrous rats following LHRH agonist treatment.

During aging female rats enter an anovulatory condition with chronically elevated circulating levels of estrogen described as persistent estrus (PE). Since this endocrine state is dramatically different from the fluctuating steroid milieu of young regularly cycling females, interpretations of altered neuroendocrine responses in aged rats have been difficult to attribute to aging per se. In the present study, young cyclic and middle-aged PE rats were treated with an LHRH agonist, [DTrp6,Pro9-NHEt]-LHRH, continuously (2.5 micrograms/h) for 12 days to suppress gonadotropin and ovarian steroid secretion. On the evening of the first day of LHRH agonist (LHRH-AG) treatment both young cyclic and middle-aged PE rats showed marked (p < 0.01) increases in plasma LH and FSH followed by progressive decreases in gonadotropin secretion which reached significantly (p < 0.05) lower levels than pretreatment values by day 7. LHRH-AG treatment significantly (p < 0.01) reduced circulating 17 beta-estradiol (E2) levels in both young and PE rats while progesterone concentrations did not change. Following LHRH-AG treatment, ovariectomy (OVX) resulted in increases of plasma LH and FSH that were delayed and attenuated in PE rats as compared to those of young females. When compared to nontreated rats, 12 days of LHRH-AG treatment in both young and PE females had a minimal and transient effect on the post-OVX gonadotropin responses, suggesting that the endocrine status immediately prior to OVX does not profoundly influence the post-OVX responses in young cyclic and middle-aged PE rats. Furthermore, LHRH-AG treatment does not appear to have permanent inhibitory effects on the hypothalamic-pituitary axis.(ABSTRACT TRUNCATED AT 250 WORDS)


Early complete maturation of proenkephalin processing induced by dexamethasone in the adrenal gland of neonatal rats.

We have previously found that proenkephalin processing is incomplete in the neonatal rat adrenal medulla and have postulated that immaturity of either the nervous input to the gland or the endocrine hypothalamus-pituitary-adrenal axis might be involved in the failure of the gland to yield free met-enkephalin. Therefore, we investigated whether cholinergic and glucocorticoid agonists may act in vivo on neonatal proenkephalin processing; reserpine, a strong activator of precursor cleavage, was also tested. Acute administration of nicotine, pilocarpine and reserpine to 24-hour-old rats increased the content of enkephalin-containing peptides (ECP) after 72 h (4-day-old rats) and activated the posttranslational processing of proenkephalin to high, intermediate and low molecular weight peptides respectively, although free met-enkephalin was not produced. Chronic treatment with nicotine and pilocarpine neither modified the concentration of ECP nor were able to induce free metenkephalin production. Chronic administration of dexamethasone increased ECP levels in the adrenal of 4-day-old rats and caused proenkephalin processing to intermediate- and low-molecular-weight products including the production of free met-enkephalin. These results indicate that only dexamethasone was able to induce the production of met-enkephalin in the adrenal of neonatal rats, suggesting an involvement of the hypothalamus-pituitary-adrenal axis in the proteolytic maturation of proenkephalin during the ontogeny of rat adrenal medulla.


Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat.

Previous studies have shown that activation of the 5-HT1A receptor subtype enhances rat plasma ACTH concentration. Such receptors have been suggested to be located on CRH neuronal cell bodies in the paraventricular nuclei of the hypothalamus (PVN). In this report, microinjection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT1A agonist, into the PVN increased rat plasma ACTH concentration in a dose-related manner. Similar responses were observed when two other 5-HT1A agonists, busipirone and gepirone, were used. (+/-)-Pindolol, known to have 5-HT1A antagonist properties, blocked the effect induced by an optimal dose of 8-OH-DPAT after injection into the PVN. This same dose of 8-OH-DPAT also induced a decrease of hypothalamic CRH concentration, which was completely antagonized as well by pretreatment injection of (+/-)-pindolol into the PVN. A significant inverse correlation was found between hypothalamic CRH and plasma ACTH levels. These results confirm that elevation of the plasma ACTH concentration induced by 5-HT1A receptor subtype activation is mediated by the release of CRH from the paraventricular nuclei of the hypothalamus in rats, but do not exclude other mechanisms.


Transient hyponatremia after damage to the neurohypophyseal tracts.

Section of the neurohypophyseal stalk classically produces a triphasic response: diabetes insipidus (1st phase), hyponatremia or normonatremia (2nd phase), and diabetes insipidus (3rd phase). Transient hyponatremia without diabetes insipidus has been reported after transsphenoidal pituitary surgery. We report two additional cases of transient hyponatremia which occurred 6-8 days after pituitary surgery. We hypothesize that this outcome may be due to partial section or damage of the hypothalamiconeurohypophyseal tracts. The remaining intact vasopressin neurons function normally to protect against the diabetes insipidus of the first and third phase, but leak of vasopressin from the damaged tracts and posterior pituitary is sufficient to cause what can be described as an isolated second phase. To study this hypothesis in rats, partial damage to the hypothalamicneurohypophyseal tracts was produced by radiofrequency lesions. The lesions did not affect anterior pituitary function. A variety of responses in posterior pituitary function occurred, including classic triphasic response in 2 rats and transient hyponatremia in 20 of 35 lesioned animals. The mean sodium nadir was 128.7 +/- 1.5 mEq/l in comparison to the sham-operated value of 140.0 +/- 0.4 mEq/l. Of the 20 rats exhibiting transient hyponatremia, 12 went on to develop diabetes insipidus, and 8 recovered. In the recovered group, the transient hyponatremia occurred 1-3 days after lesioning and returned to normal by day 7 which corresponds to the timing of the second phase of the triphasic response in rats. Hyponatremia was accompanied by vasopressin levels inappropriate for the plasma sodium level, inappropriately concentrated urine, water retention, and natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)


Immunocytochemical localization of beta endorphin and gonadal steroid regulation of proopiomelanocortin messenger ribonucleic acid in the ewe.

In the ewe, estradiol and progesterone inhibit luteinizing hormone (LH) secretion during the breeding season. Endogenous opioid peptides (EOP) are also inhibitory to LH secretion, and both estrogen and progesterone have been reported to enhance EOP inhibition of LH release. Which EOP are involved in this inhibition is unclear. In this study, we concentrated on beta-endorphin because evidence for its ability to inhibit LH secretion exists in ewes. We first studied the distribution of beta-endorphin-immunoreactive neurons in 4 cycling ewes using immunocytochemistry. Cell bodies were found only within the medial basal hypothalamus (MBH) and were concentrated in arcuate nucleus and mammillary recess of the third ventricle, with a few in the median eminence. Extensive fiber tracts were seen in preoptic area (POA) and median eminence. We next tested the hypothesis that gonadal steroids increase the synthesis of EOP by measuring levels of mRNA for proopiomelanocortin (POMC), the precursor to beta-endorphin. Ovariectomized ewes were treated with no steroids (n = 7) or given subcutaneous Silastic implants containing either estradiol (n = 6) or progesterone (n = 6). After 4 days of treatment, EOP inhibition of LH secretion was measured by determining the LH response to WIN 44,441-3 (WIN), an EOP antagonist. LH pulse frequency and pulse amplitude were determined in blood samples collected at 12-min intervals for 3 h before and after intravenous administration of 12.5 mg WIN. WIN injection increased (p < 0.01) the LH pulse-frequency only in progesterone-treated and pulse amplitude only in estradiol-treated ewes. After blood sampling, the ewes were killed, and POA, MBH, and pituitary gland were removed. Total RNA was extracted from these tissues and dot blotted onto nitrocellulose membranes for hybridization with a DNA probe complementary to the POMC mRNA. The resulting autoradiographs were quantified densitometrically. Levels of POMC mRNA in the MBH were increased (p < 0.01) by both estradiol and progesterone as compared with the no steroid group. There was no detectable POMC mRNA in the POA. These results suggest that estrogen and progesterone enhance EOP inhibition of LH secretion by increasing POMC mRNA levels and thus synthesis of beta-endorphin.


Opioid inhibition of luteinizing hormone secretion compared in developing male and female sheep.

The sheep exhibits a marked sex difference in the timing of the pubertal increase in luteinizing hormone (LH). Male lambs undergo a reduction in sensitivity to inhibitory steroid feedback, leading to an increase in LH by 10 weeks of age, but females remain hypersensitive until 30 weeks of age. Endogenous opioids suppress LH secretion in the female lamb prepubertally and in adult male and female sheep. It has been suggested that a reduction in opioid inhibition of LH secretion is the signal to time puberty. Therefore, if a decrease in opioid tone occurs during sexual maturation, it should begin earlier in the male lamb than in the female. The objective of this study was to compare opioid inhibition of LH secretion in male and female lambs in relation to the timing of puberty. Our approach was to examine the response to the opioid antagonist naloxone at various ages in both sexes. To determine the timing of the pubertal LH rise in the presence of constant inhibitory steroid feedback, male and female lambs (n = 5 each) were gonadectomized at 3 weeks of age and implanted with a Silastic capsule of estradiol. They were then challenged with naloxone at 5, 11, and 23 weeks of age; blood samples were collected every 12 min for 8 hours, and lambs received naloxone (1 mg/kg i.v.) at hours 4, 5, 6, and 7. Mean LH before and during naloxone treatment was compared at each age.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibitory effects of the new bombesin receptor antagonist RC-3095 on the luteinizing hormone release in rats.

The effects of bombesin receptor antagonist RC-3095 and gastrin-releasing peptide [GRP (14-27)] on basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, as well as on the release of LH and FSH in response to LH-releasing hormone, were studied in normal and castrated male rats. We also examined the release of LH and FSH after intracerebroventricular injection of RC-3095 under different types of anesthesia (urethane, sodium pentobarbital, Metofane). Following injection of 10 micrograms RC-3095 into the lateral brain ventricle, serum LH levels were rapidly and significantly (p < 0.001) lowered. This effect lasted for at least 60 min and was not affected by the type of anesthetic used. Serum FSH levels were not affected by intracerebroventricular administration of RC-3095 or GRP (14-27), indicating different central control mechanisms between LH and FSH release. The suppressive effect of RC-3095 on LH release could be completely prevented by prior intracerebroventricular administration of GRP (14-27) at a dose of 1 micrograms, but intravenous administration of either peptide RC-3095 or GRP (14-27) did not change the basal levels of LH, FSH, and testosterone. The pituitary LH response to LH-releasing hormone was also not modified by intravenous administration of RC-3095. These results indicate that bombesin-like peptides might be involved in control of LH release from the pituitary by an action on the CNS which is mediated by specific bombesin receptors.


In vitro glucoregulation of prolactin secretion.

In this study we have examined the direct glucoregulation of prolactin secretion from normal anterior pituitary cells in vitro and have found that changes in medium glucose concentration regulate the amount of prolactin released. Nature and/or degree of this response to glucose was influenced by some effect, long-lived in vitro, which was correlatable to serum insulin levels. When the cells were derived from animals with mean low-normal serum insulin levels, there was a stimulation of prolactin secretion by hypoglycemia, the response was rapid, transient, dose-dependent, and could be duplicated by 2-deoxyglucose. When the cells were derived from animals with a higher mean serum insulin level, the prolactin secretion from the cells was slowly, adversely affected by hypoglycemia. Conversely, elevated glucose caused a depression in prolactin secretion in the first group and a stimulation of prolactin secretion in the second. We conclude (1) that modulation of glucose levels in vitro regulates prolactin release from pituitary mammotrophs and (2) that this glucose regulation of prolactin release is in turn coregulated with or regulated by insulin.


Glucocorticoid receptors in LHRH neurons.

Luteinizing hormone-releasing hormone (LHRH)-producing neurons constitute the final pathway for regulation of reproductive endocrine function by the central nervous system. Chronically elevated levels of glucocorticoids exert an inhibitory effect on reproductive function. Although this is thought to be mediated in part via modulation of classical transmitters and peptides which regulate LHRH synthesis and release, it is also possible that glucocorticoids may regulate LHRH neurons directly. We localized glucocorticoid receptors (GR) in LHRH neurons in the rat central nervous system using immunocytochemistry. In males and randomly cycling females 10-24% of LHRH neurons in the medial septum-diagonal bands of Broca, and preoptic regions colocalized nuclear GR. Ovariectomy increased the percentage of GR/LHRH neurons at the level of the organum vasculosum of the lamina terminalis to 34%, half of which showed both nuclear and cytoplasmic GR. Treatment with estradiol reversed this effect. We suggest that the actions of glucocorticoids on reproductive endocrine function are mediated partly through direct modulation of LHRH gene expression and/or release by activated GR. Moreover, GR in LHRH neurons may provide a mechanism by which the gonadal steroid progesterone can affect LHRH neurons directly, despite a lack of progesterone receptors in these neurons.


Histamine H1 and H2 receptor activation stimulates ACTH and beta-endorphin secretion by increasing corticotropin-releasing hormone in the hypophyseal portal blood.

Histamine (HA) stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END) via activation of central postsynaptic H1 or H2 receptors. The effect of HA is indirect and may involve the hypothalamic regulating factors corticotropin-releasing hormone (CRH), arginine vasopressin, or oxytocin (OT). We studied the effect of specific HA H1 or H2 receptor agonists on the concentration of CRH and OT in hypophyseal portal blood in urethane-anesthetized male rats. In addition we investigated the effect of the agonists on ACTH and beta-END immunoreactivity in peripheral plasma in conscious male rats pretreated with antiserum to CRH. Intracerebroventricular administration of the H1 receptor agonist 2-thiazolylethylamine (2-TEA) or the H2 receptor agonist 4-methylhistamine (4-MeHA) increased the CRH concentration in pituitary portal blood by 80-90% when compared to preinfusion levels (p < 0.05). Central infusion of saline had no effect. The level of OT in the pituitary portal blood was not affected by 2-TEA or 4-MeHA when compared to saline-treated rats. Intracerebroventricular infusion of 2-TEA or 4-MeHA increased the ACTH concentration in peripheral plasma 3- or 4-fold, respectively (p < 0.01). Pretreatment with a specific CRH antiserum (abCRH) inhibited the responses by 50 and 70%, respectively (p < 0.01). Intracerebroventricular administration of 2-TEA or 4-MeHA increased the beta-END immunoreactivity in peripheral plasma 3- or 2-fold, respectively (p < 0.01). These effects were inhibited by 80-90%, when rats were pretreated with abCRH (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Immunocytochemical localization of insulin-like growth factor I in the hypothalamo-hypophyseal system of the adult rat.

Insulin-like growth factor I (IGF-I) is shown to be involved in the regulation of pituitary hormones. High IGF-I concentrations were detected in hypothalamus and pituitary during adulthood. This study was undertaken to analyze the cellular distribution of IGF-I in the hypothalamo-hypophyseal system of the adult rat using immunocytochemical procedures. IGF-I was found to be widely distributed throughout the hypothalamus; it was present in the magnocellular neurons of the supraoptic, paraventricular, and accessory nuclei. Moreover, nerve fibres and puncta containing immunoreactive IGF-I were localized in the median eminence and the posterior lobe of the pituitary. These results support possible IGF-I neuromodulatory or neurohormonal action in the hypothalamus on pituitary hormone regulation.


Differential expression of melatonin receptors in spontaneously hypertensive rats.

Quantitative autoradiography was used to compare melatonin receptors in brain areas and arteries of young (4 weeks old) and adult (14 weeks old) spontaneously hypertensive rats (SHR) to those in age-matched normotensive controls, Wistar-Kyoto (WKY) rats. Age and strain influenced the number of melatonin receptors in an anatomically selective manner, and the most striking changes occurred in arterial receptors. Melatonin receptors were not detectable in the anterior cerebral arteries of adult SHR. In the caudal artery, melatonin receptors decreased with age in both strains, but the decrease was more pronounced in SHR. When compared to age-matched WKY rats, the number of caudal artery receptors was higher in young and lower in adult SHR. The number of melatonin receptors was higher in the area postrema of adult SHR when compared to adult WKY rats, but in the suprachiasmatic nucleus, no such differences between the two strains were present. Alterations in receptor density were not accompanied by changes in binding affinity. Our results indicate that in the rat melatonin receptors show different developmental patterns according to location and that the receptors may be expressed differentially in genetic hypertension.


Influence of dopamine on the altered release of prolactin, luteinizing hormone, and follicle-stimulating hormone induced by interleukin-2 in vitro.

Interleukin-2 (IL-2) alters the release of anterior pituitary hormones at femtomolar concentrations from hemipituitaries incubated in vitro. This cytokine significantly lowered luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and stimulated prolactin (PRL) release, thus demonstrating a reciprocal action of the lymphokine on lactotrophs and gonadotrophs. Since dopamine (DA) is a powerful inhibitor of PRL release, in the present experiments were evaluated possible dose dependent effects of DA on IL-2-induced alterations of the release of PRL, LH, and FSH. Hemipituitaries were incubated with varying concentrations of DA, a combination of IL-2 plus DA, or a combination of haloperidol (1 x 10(-5) M) with DA for 1 h, followed subsequently by incubation with medium containing only high potassium (K+) to study the effects on depolarization-induced hormone release. DA induced a dose-related, significant lowering of the basal PRL release with a minimal effective dose (MED) of less than 19 nM. The depolarization-induced PRL release was also inhibited, but the MED was 100-fold higher than the MED to inhibit basal PRL release. DA at much higher concentrations (30, 60, and 90 microM) significantly reduced pituitary PRL content. The addition of 0.187, 3.75, 15, or 60 microM DA to IL-2-induced PRL release. IL-2 (10(-15) M) produced a significant decrease in LH and FSH release. The combination of 3.75 or 15 microM DA plus IL-2 failed to alter the IL-2 suppressed LH release, whereas the addition of 0.187 microM DA to IL-2 blocked its suppressive influence, and 60 microM DA added to Il-2 produced an additive inhibitory effect. Thus, the interaction of IL-2 and DA is biphasic on LH release. The significant reduction of FSH release induced by IL-2 was blocked in the presence of 0.187, 3.75, 15, or 60 microM DA. DA alone at relatively high concentrations of 30, 60, and 90 microM suppressed basal LH and FSH release. The effects of DA on PRL, LH, and FSH at all doses tested were blocked by the DA receptor blocker, haloperidol which by itself at the concentration tested (1 x 10(-5) M) had no effect. Thus, the actions of DA at all concentrations tested appear to be mediated via DA receptors. In conclusion, DA was capable of blocking the stimulatory action of IL-2 on PRL release and its inhibitory action on FSH release by a DA receptor mediated action.(ABSTRACT TRUNCATED AT 400 WORDS)


Quantitative autoradiographic analyses of the time course and reversibility of corticosterone-induced decreases in binding at 5-HT1A receptors in rat forebrain.

Quantitative autoradiography was used to evaluate the time course and reversibility of corticosterone (CORT)-induced decreases in binding at 5-HT1A receptors in the dorsal hippocampus, cortex and septum of the male rat. Continuous exposure to high levels of CORT decreased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the dentate gyrus and in the oriens and lacunosum moleculare layers of CA4 after 16 to 48 h. CORT-induced decreases in binding were also observed in the dorsal lateral septum after 2-4 days, and in the intermediate lateral septum after 4-8 days of exposure to high levels of CORT. When CORT pellets that had remained in rats for 8 days were removed 3 weeks prior to sacrifice, binding at 5-HT1A receptors increased in comparison to control values in the oriens and lacunosum moleculare layers of CA2, and in layers 4-6 of the parietal/temporal cortex. These increases in binding were associated with very low serum CORT levels, and resembled increases previously observed in those areas in ADX rats. Although removal of CORT reversed the decreases in binding in the septum, no significant increases above control values were observed. Thus, there appear to be differences in the degree of sensitivity in the various brain regions to low and high levels of circulating adrenal steroids.


Trophic effects of estradiol on fetal rat hypothalamic neurons.

Sex steroids play an important role in the development and functioning of the central nervous system (CNS); however, the mechanisms by which such hormones exert these effects are not well understood. We addressed the question as to whether sex steroids affect the development of the hypothalamus, at least in part, by acting as a trophic factor to modulate the number of neurons in the hypothalamus. To this end, primary hypothalamic cultures were prepared from the brains of embryonic (day 15) fetuses. Cultures received either 17 beta-estradiol (10(-12) M) or vehicle 6-h after seeding and everyday throughout the study. As early as 24 h later, cultures receiving 17 beta-estradiol had significantly more neurons (44%, p < 0.001) than the control cultures. This effect not only continued throughout the duration of the study, but the difference between the two groups increased so that after 5 days, 17 beta-estradiol-treated cultures had 209% more neurons than control cultures (p < 0.001). Thus, addition of 17 beta-estradiol to fetal hypothalamic cultures produced a significant increase in the number of neurons surviving in vitro. The presence of glia was not required for this phenomenon, since the number of neurons surviving in glial-free cultures was also significantly increased by the addition of 17 beta-estradiol. The neuron survival promoting effect of 17 beta-estradiol was saturable and could be blocked by the estrogen antagonist tamoxifen (10(-7) M). Testosterone (10(-10) M), but not the nonaromatizable androgen dihydrotestosterone (10(-10) M), could mimic the neuron survival-promoting effects of estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)


Age- and sex-related changes in Tyr-MIF-1-like immunoreactivity in rat plasma.

The concentrations in plasma of the biologically active endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) have not been measured during development or in female rats. By radioimmunoassay, we found that Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was first consistently detectable in plasma when the rat was 5 days old, and then gradually increased to adult concentrations by day 15. In male rats, the levels remained relatively constant for the next 21 months. In female rats, plasma concentrations of Tyr-MIF-1-LI at day 15 were about the same as in male rats. At 6 months of age, however, the concentrations in females decreased by half and by 21 months of life were only about a third of the concentrations found at day 15 or in age-matched males. The differences with age were not due to the length of time of storage of the samples, because another group of rats 1 month old was killed on the same day as 5-day-old rats and still showed several times more Tyr-MIF-1-LI in the plasma; again, no differences were found between male and female rats at either 5 days or 1 month. A single injection of estradiol followed by progesterone lowered the concentrations in 1-month-old male rats. In female rats that were either ovariectomized or sham-ovariectomized, the expected similarity in their plasma concentrations of Tyr-MIF-1-LI was found at 1 month of age.(ABSTRACT TRUNCATED AT 250 WORDS)


delta-Opioid receptors and the secretion of growth hormone in man: effect of opioid delta-receptor agonist deltorphin on GH responses to GH-releasing hormone and insulin-induced hypoglycemia.

To investigate the role of delta-opioid receptors in the modulation of growth hormone (GH) secretion, we compared in normal subjects the effect of the highly selective delta-opioid receptor agonist Deltorphin (DT) on the GH secretion responses to pituitary (GH-releasing hormone, GHRH)- and hypothalamic (insulin-induced hypoglycemia, IIH)-mediated stimuli. DT blunted the GH response to IIH, whereas it had no effect on the GH response to GHRH. It is concluded that in man DT-induced activation of delta-opioid receptors exerts an inhibitory action on hypoglycemia-stimulated GH secretion. Based on the lack of an effect of DT on the GH response to GHRH, we suggest that DT may modulate the secretion of GH through suprapituitary mechanisms.


Short-term starvation decreases POMC mRNA but does not alter GnRH mRNA in the brain of adult male rats.

Dietary restriction reduces circulating gonadotropin and testosterone levels in male rats, an effect thought to be mediated through reduced gonadotropin-releasing hormone (GnRH) secretion; however, the cellular mechanisms subserving this response are still unknown. We reasoned that if dietary restriction reduces GnRH secretion, this would be reflected by a decrease in GnRH synthesis and likewise cellular GnRH mRNA levels. We tested this hypothesis by comparing cellular levels of GnRH mRNA between ad libitum fed (n = 4) and starved (n = 4) adult male rats. Five days of starvation resulted in a 21% decrease in body weight and an 85% decline in serum testosterone levels (fed: 13.9 +/- 2.00 vs. starved: 2.1 +/- 0.70 nmol/l; p < 0.01). In situ hybridization and image analysis demonstrated that short-term starvation influenced neither GnRH cell number (fed: 148 +/- 16 vs. starved: 157 +/- 13 cells) nor cellular GnRH mRNA signal level (fed: 177 +/- 5 vs. starved: 160 +/- 7 grains/cell) in any region of the basal forebrain. Endogenous opioid peptides are known to exert an inhibitory effect on GnRH secretion and have been implicated in having a role in the starvation-induced effects on the reproductive system. We therefore also tested the hypothesis that alterations in proopiomelanocortin (POMC) gene expression are involved in the neuroendocrine response to starvation, by comparing cellular POMC mRNA levels in individual neurons (approximately 160 neurons/animal) of the arcuate and periarcuate nuclei between fed control (n = 4) and starved (n = 4) adult male rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Estradiol enhances the action of neuropeptide Y on in vivo luteinizing hormone-releasing hormone release in the ovariectomized rhesus monkey.

The effect of estrogen on the responsiveness of the luteinizing hormone-releasing hormone (LHRH) neurosecretory system to neuropeptide Y (NPY) stimulation was examined using a push-pull perfusion method in conscious monkeys. NPY, at doses of 10(-6) to 10(-12) M, was infused into the stalk-median eminence (S-ME) of ovariectomized monkeys with or without estrogen, while perfusates were continuously collected. LHRH in perfusates was measured by RIA. The results indicate that in both estrogen-primed and unprimed monkeys, NPY infusion into the S-ME elicited LHRH release in a dose-dependent manner (p < 0.01). Moreover, estrogen priming enhanced the responsiveness of LHRH release to NPY infusion: (1) the minimum NPY dose necessary to elicit a significant LHRH response was reduced, (2) the peak LHRH response to NPY at a dose of 10(-6) to 10(-10) M was increased, and (3) the total release of LHRH in response to NPY at doses of 10(-6) to 10(-12) M was increased. These results suggest that NPY stimulates LHRH release in the S-ME in the presence or absence of estrogen and that estrogen enhances the responsiveness of the LHRH neurosecretory system to NPY stimulation in the rhesus monkey.


Daily rhythm of aspartate aminopeptidase activity in the retina, pineal gland and occipital cortex of the rat.

The levels of specific soluble aspartyl aminopeptidase activity were assayed in retina, occipital cortex, anterior pituitary, posterior pituitary, pineal gland and serum of adult male rats, using Asp-2-naphthylamide as substrate, in a 12:12 h light:dark cycle (7-19 h light). Significant diurnal variations appeared in retina, pineal gland, occipital cortex and serum. In addition, different patterns of diurnal variation of the enzymatic activity were observed in the tissues analyzed. A regular increase of the activity was noticed at the end of the dark period in all the tissues as a common feature, except in serum, in which the enzymatic activity reached a peak in the middle of the light period, decreasing progressively during the dark hours. After the last hours of darkness, the pattern of variation in the activity differed in each tissue. These diurnal variations in aspartyl aminopeptidase activity could reflect the functional status of its putative endogenous substrates, such as angiotensin II, and it may also suggest the existence of differential regulatory mechanisms associated with each location.


Central administration of neuropeptide Y induces precocious puberty in female rats.

To examine the role of neuropeptide Y (NPY) in the regulation of puberty, the effects of various doses of NPY or saline injected into the 3rd ventricle of peripubertal female rats were determined. A single injection of NPY at a dose range of 10-20 micrograms into the 3rd ventricle of 30-day-old female rats advanced the time of vaginal opening (VO) and first ovulation by 4 days, as compared to saline-treated controls. Ova number and ovarian, adrenal and uterine weights at first estrous were similar in all animals regardless of treatment. The NPY-treated precocious animals showed lower body weight than did the VO-matched controls, but showed similar body weight as that of age-matched controls. Determination of plasma luteinizing hormone (LH) levels in the peripubertal female rats revealed that plasma LH was increased transiently immediately after NPY administration. Also, NPY-treated rats which had precocious puberty showed elevated pituitary and plasma LH levels on the day of VO. These results suggest that NPY can activate the hypothalamic-pituitary-gonadal axis to precociously initiate puberty.


Increased circulating interleukin-1 and interleukin-6 after intracerebroventricular injection of lipopolysaccharide.

Recently, it was demonstrated that intracerebroventricular (icv) injection of interleukin-1 (IL-1) stimulated circulating interleukin-6 (IL-6) to a greater degree than intravenous (i.v.) injection of IL-1. The goal of this study was to compare the efficacy of lipopolysaccharide (LPS), injected both icv and i.v., on circulating concentrations of IL-1 and IL-6. Both i.v. and icv injection of LPS stimulated plasma levels of IL-1 to a similar degree. However, i.v. injection of LPS was significantly more efficacious than icv injection of LPS in elevating circulating IL-6. These results demonstrate that like i.v. injection of LPS, icv injection of LPS stimulates plasma levels of IL-1 and IL-6. Increases in circulating cytokines during infectious diseases which are limited to the central nervous system may serve to activate peripheral functions of an acute phase response.


[Retroperitoneal liposarcoma. Disclosure by anemia and prolonged fever].

We report the case of a 79-year old woman with a retroperitoneal liposarcoma. The condition was discovered because of the association, in a woman of that age, of anaemia and persistent fever. The diagnosis was suggested by computed tomography. Treatment was exclusively surgical. Liposarcomas usually affect men in their sixth decade. Postoperative radiotherapy improves the quality of life but does not prolong survival. Metastases are frequent, and death usually occurs in the year that follows discovery.


[Epidemiologic study of myotonic dystrophy on the island of Mallorca].

Myotonic dystrophy (MD) or Steinert's disease is the most frequent hereditary myopathy in the adult. The aim of this study was to determine the rate of prevalence of MD on the island of Mallorca. Patients diagnosed with MD were studied in all public and private surgeries and centres able to diagnose this disease on the island of Mallorca. Therefore, this study included the whole population of Mallorca (551,129 inhabitants). A total of 60 cases were studied representing a prevalence rate of 110 cases per one million inhabitants. The patients were further classified according to the existence of family history and were geographically located into the different towns. The prevalence rate found was much higher than that described in the literature which oscillates between 30 and 50 cases per million inhabitants. Furthermore, there was a concentration of cases in 10 of the 52 towns of the island with the presence of 2 cases in 6 being significant. The rate of prevalence of the disease in the city of Palma (295,136 inhabitants) representing more than half of the population of the island was very similar (120 per million) to that found for the population as a whole.


[Information and support to cancer patients. Experience from a course for young cancer patients at the Montebello Center].

The Montebello Centre offers courses for cancer patients from the whole country. The intention is to improve the patients' quality of life and ability to cope through information, group discussions and various kinds of activities. During Easter 1991 the Centre arranged a course for young people. An oncologist and a psychiatrist served as teachers and group participants, and offered individual consultations. Most of the patients had received insufficient information about their cancer. The period after end of active treatment was experienced as particularly distressing due to psychological reactions. The establishment of more self-help groups, and contact with already established groups, seem to be valuable psychosocial interventions.


Impact of the long term supply of iodized salt to the endemic goitre area.

The study was designed to assess the impact of the supplementation levels of iodine in salt supplied since the last 12 years to Gilgit and Hunza, an endemic goitre area of Pakistan. The overall prevalence of visible goitre is reduced from 61.36% to 4.68%. Results of urinary excretion of iodine (UEI) indicate severe to mild iodine deficiency among 70.41% of the randomly surveyed households. Severely deficient are 3%, moderate 29.54% and mild 37.87%, criteria of UEI being less than 2.0 micrograms/dl, 2-5 micrograms/dl and 5-10 micrograms/dl respectively. Levels of iodine supplementation in 267 iodized salt samples at production (n = 128) and consumption (n = 139) points are compared with a mean +/- SD are 70.86 +/- 29.73 ppm and 37.24 +/- 20.47 ppm respectively, representing 566.8 +/- 237.8 micrograms and 297.9 +/- 163.7 micrograms of iodine per 8.0 gram of salt. It is suggested to replace common salt with iodized salt in the goitre area to ensure the use by all households and quality control measures for iodination of salt should strictly be adhered so that uniform and consistent supply of iodine be ensured. The magnitude of contributory factors other than iodine deficiency, i.e., environmental and hereditary should be monitored and considered when levels of iodine supplementation are adjusted.


Four interfaces for liquid chromatography/atmospheric-pressure-ionization mass spectrometry.

Mixture analyses are demonstrated using the liquid chromatograph/atmospheric-pressure-ionization mass spectrometric system with four modes. These modes are atmospheric-pressure spray with electron ionization, atmospheric-pressure chemical ionization, atmospheric-pressure spray ionization, and electrospray ionization modes. This system can deal with a wide variety of compounds from hydrocarbons with low polarity to proteins with high polarity.


Urological evaluation of sexual partners of women with human papillomavirus (HPV) infection.

Cancer of the uterine cervix has been related to HPV infection, based on clinical and laboratory data. The high recurrence rate in couples undergoing treatment for HPV infection points to a probable viral reservoir, either in subclinical lesions or in male internal genital organs. We have evaluated 31 men, all sexual partners of women with HPV infection. Eleven patients (35.5%) had related lesions: 4 (12.9%) with condyloma acuminatum; 5 (16.1%) with lesions revealed by magnified examination after reaction with 5% acetic acid and 2 (6.5%) with condyloma and subclinical lesions. A short-term follow-up confirmed a successful treatment with podophyllin.


[Systemic scleroderma and scleroderma-like disease after silicone implants].

Systemic sclerosis or clinical patterns indistinguishable from systemic sclerosis have previously been demonstrated in workers in the polyvinylchloride industry and in mine-workers exposed to silica dust. In recent years, an increasing number of cases of systemic sclerosis, localized scleroderma, and scleroderma-like disease have been diagnosed in women after implantation of silicone gel prosthesis either following operations for breast cancer or cosmetic augmentation mammoplasty. We present two cases of systemic sclerosis or scleroderma-like disease appearing after silicone implants. Together with the already reported cases these results should lead to reduced use of silicone for cosmetic augmentation mammoplasty and a search for another material for patients operated on for breast cancer. The cases described, together with the reports concerning industrially provoked scleroderma, are of interest for the continued efforts to clarify the pathogenesis of scleroderma. Other types of exposure than those described here may also be of interest, i.e. occupational exposure to silicone spray.


[Norwegian physicians and referral to chiropractors].

Two comparable surveys were carried out, one in 1979 and one in 1989, to study the practice of medical practitioners as regards referrals to chiropractors. Norway is the only country where reimbursement for chiropractic treatment from the National Health Insurance depends on referral by a medical practitioner. The survey investigated the attitude towards this system of referral, whether or not a uniform standard of practice existed in regard to musculoskeletal disorders, and what types of conditions are referred. A substantial percentage, 41.6, of the patients had not been examined by their medical doctor before the referral, and 23.9% had received their referral after the chiropractic treatment had started. A medical diagnosis was given in 84.3% of all cases, and x-ray findings were communicated to the chiropractors for 35.5% of the x-rayed patients. The surveys indicate that the present system of referrals does not function properly and may not be the best way of organizing the working relationship between medical doctors and chiropractors. The practice of referral had changed during the ten year period. In 1989, chiropractic was the first choice of treatment for patients with musculoskeletal problems more often than in 1979. Low back pain was the reason for the majority of referrals both in 1989 and in 1979. An apparent lack of standardization of diagnostic and therapeutic measures was demonstrated by comparing different regions of Norway. A marked discrepancy was found between rural and urban areas in the use of sick-leave and drug therapy.


[New therapeutic methods in tubal pregnancy].

A world-wide increase in the incidence of extrauterine pregnancy has increased interest in new forms of treatment of this condition. In Denmark, the number of cases of diagnosed tubal pregnancies has doubled from 1980 til 1989. Experience with the spontaneous course of tubal pregnancies is reviewed. In addition, various forms of laparoscopic treatment and systemic and local treatment with methotrexate are described. In Denmark, local treatment with prostaglandin has been employed with good effect. Whether conservative surgical treatment or treatment with methotrexate or prostaglandin are to be employed depends upon the patience of the treating physician as regards control examinations with ultrasonic scanning and measurement of serum human chorion gonadotropin. Repeated tubal pregnancy in the salpinx involved, persisting trophoblastic tissue after treatment and long periods of observation are unintentional side effects of treatment. After conservative treatment of tubal pregnancy, it is important that the patient is given meticulous information.


Protein A columns for the treatment of patients with idiopathic thrombocytopenic purpura and other indications.

ECI using protein A columns has been designed to selectively remove circulating CICs and IgG from the plasma of patients in whom these substances are associated with their disease. The use of protein A columns appears to be a reasonable alternative to plasmapheresis in many autoimmune disorders for which plasma exchange is indicated. Although preliminary evidence suggests efficacy of plasma exchange, there is a paucity of data indicating that ECI would indeed provide comparable efficacious results. Although the role of ECI using protein A columns for the treatment of ITP continues to be poorly defined, its use in urgent and life-threatening situations in both ITP and HUS appears reasonable. The results of any treatment for chronic refractory ITP continue to be unsatisfactory. However, favorable responses have been achieved using protein A columns, suggesting the need for further investigation. The role of ECI in the treatment of other disorders, including AIDS, TTP, and the treatment of malignancies, where clinical effects are transient, continues to be investigational. The true clinical response rates and duration of responses to ECI using protein A in treating any disorder requires definition in studies involving a larger number of patients with longer followup. The demonstration of the ultimate clinical value of this therapy will require clinical trials comparing its efficacy to other therapies. Although more serious reactions have been reported, toxicities associated with the use of protein A columns are generally transient and mild.


Patient selection criteria for electrostimulation of salivary production in the treatment of xerostomia secondary to Sjogren's syndrome.

Electrostimulation has been introduced as a technique for increasing salivary output in the treatment of patients with xerostomia (dry mouth) secondary to Sjogren's syndrome. The procedure uses an electrostimulation device (salivation electrostimulator) to increase salivary production from existing glandular tissue. The device delivers a low-voltage electrical stimulus to the mouth via a probe. Patients with residual salivary tissue in the oral and pharyngeal regions who demonstrate a decrease in the flow rate of saliva are potential candidates for this procedure. It is estimated that more than one million people in the United States, predominantly middle-aged and elderly women, suffer from Sjogren's syndrome. Patients with chronic xerostomia complain of a continual feeling of oral dryness and have difficulty eating dry foods. These patients are susceptible to increased caries, oral pain, infection, and have difficulty speaking, chewing, and swallowing. The approach to the treatment of xerostomia in Sjogren's patients is usually determined by the level of severity of the symptoms. Appropriate management of patients with xerostomia requires that those patients whose salivary flow can be increased by means of sialagogues be distinguished from those patients whose salivary flow is either unaffected or insufficiently stimulated. To alleviate some of the complications due to salivary dysfunction in those patients who respond to stimuli, pharmacologic sialagogues as well as sialagogues that include sugarless gums, mints and candies are prescribed in order to increase salivary flow. Recently, electrostimulation via a hand-held stimulus probe has been introduced as a method of treatment in xerostomia secondary to Sjogren's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)


Cataract risk factors: blood level of antioxidative vitamins, reduced glutathione and malondialdehyde in cataractous patients.

Since many years experimental evidences have suggested an association between nutrition and lens opacities. A dietary deficiency of antioxidants and reactive oxygen scavengers may be involved in the pathogenesis of the "idiopathic" human senile cataract, as it has been demonstrated in some experimental cataracts. We tested the levels of ascorbic acid (vit. C), alpha-tocopherol (vit. E), reduced glutathione (GSH) and malondialdehyde (MDA) in the plasma or in the red blood cells (RBC) of 42 patients who were affected by surgically significant cataract and of 40 age-matched controls. Plasma vit. C mean level was 4.46 gamma/ml in cataracts and 4.62 gamma/ml in controls, while vit. E level was 7.70 and 7.09 gamma/ml respectively. RBC GSH was found to be 342 gamma/ml in cataracts and 346 in controls, while the MDA content was 4.06 picoMol/ml and 4.08 picoMol/ml respectively. The level of each tested nutrient or metabolite was not found to be statistically different between cataractous patients and controls, nor any significant trend was found to be present when the nutrients and metabolites were correlated to each other. Our results do not support the hypothesis of a nutritional deficiency in human senile cataracts. However, a defect in the antioxidative metabolism pathways could be present either systemically or at lens level.


A nation-wide study of myopia prevalence in Israel. Findings in a population of 312,149 young adults.

We conducted a nation-wide survey of the Prevalences of Myopia and other refractive errors in Israel, from data of medical examinations of an unselected population of 312,149 subjects ages 17 to 19 years. 80.47% of the population were emmetropic in both eyes. Myopia in both eyes was found in 16.27% of the population. The prevalence of monocular myopia was 1.69%. Manifest hyperopia in both eyes was found in 0.93% and astigmatism at least in one eye was found in 7.13%. The various errors of refraction (myopia, hyperopia and astigmatism) were more common among females.


Uveitis in patients with Graves' disease.

Uveitis was studied in patients with Graves' Disease. Graves' disease was found in 2.3% of uveitis patients, but no uveitis was found in patients with Graves' disease who visited our clinic with Graves' ophthalmology. Most of the Graves' disease patients with uveitis had had uncontrolled thyroid function before the onset of uveitis. Generally speaking, uveitis was mild. Steroid hormone therapy was very effective. No specific HLA type was found in our patients with uveitis.


Effects of Nd-Yag laser vitreolysis on lens and vitreous prostaglandins in the rabbit eye.

This study concerns the quantitative modifications of the prostaglandins, PGF alpha e PGE2, in the vitreous and in the lens following the application of Nd-Yag Laser. Five minutes after the Yag-laser treatment, an increase of PGF1 alpha concentration of PGE2 decreased in the lens and increased in the vitreous. These changes, similar to those occurring in the aqueous humor, may be related to the activation of specific enzymatic pathways of prostaglandin synthesis.


Morphology of the transplantable colon carcinoma derived from the spontaneous colon carcinoma of WF-Osaka rat strain.

Two lines of the transplantable colon carcinoma were established. They were from the spontaneous colon carcinoma of WF-Osaka rat strain which had been set up in our laboratory. Transplant procedure was carried out mainly by the intraperitoneal implantation, and, in particular, the treating with a specified way of HIBITANE for disinfection against colonic flora at the primary transplant was quite effective. The growth speed of the transplanted colon carcinoma was slow at first and gradually increased its speed. Histology of the transplanted tumor altered gradually from the glandular pattern at first to the medullary pattern in the late stage of the transplant generation. Each tumor node in the late stage of transplant generation was composed of numerous small nodules separated by thin stromal tissue. Squamous metaplasia and central necrosis were seen in the center of the small nodules. Two lines of the transplantable colon carcinoma were named C1 and C2 and the former is at now the 101th generation and the latter is at the 107th generation.


Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain.

The effects of zonisamide on [3H]flunitrazepam binding and [3H]muscimol binding were studied in Sprague-Dawley rat brain. Specific [3H]flunitrazepam bound was decreased to 64.6 +/- 5.6% (mean +/- SD, n = 5, p < 0.002) and 91.9 +/- 4.0% (p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Scatchard plot analysis of [3H]flunitrazepam binding with 10(-3) M of zonisamide revealed an increased Kd value with no change in Bmax. No inhibitory effect of zonisamide was seen on the enhancement of specific [3H]flunitrazepam binding by GABA. As for the effects on GABA receptors, specific [3H]muscimol bound was decreased to 27.7 +/- 10.4% (mean +/- SD, n = 4, p < 0.005) and 68.3 +/- 3.7% (mean +/- SD, n = 4, p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Since therapeutic serum level of zonisamide are around 10(-4) M, these results suggest that zonisamide neuropharmacologically interacts with the GABA/benzodiazepine receptor ionophore complex in a manner similar to phenytoin.


[3H]zonisamide binding in rat brain.

We previously reported that zonisamide inhibits both [3H]flunitrazepam and [3H]muscimol binding in rat brain. In the present study, [3H]zonisamide was found to bind in a saturable fashion to the crude synaptosomal fraction of whole rat brain. Linear regression analysis of the binding data in the Scatchard plot indicated a Kd of 90 nM, and a maximal binding capacity of 1.40 x 10(3) fmol/mg protein. Displacement studies revealed an inhibitory effect of clonazepam and an enhancement effect of GABA on specific [3H]zonisamide binding. These results suggest that specific [3H]zonisamide binding sites may have a tight correlationship with benzodiazepine receptors in rat brain.


Adenocarcinoma in the ascending colon of ACI strain rat foster bred by WF-Osaka female rat.

We now keep HFRSV free WF-Osaka rats and ACI rats together in the separate three animal rooms (animal room 1, 2 and 3) and the incidence of colon carcinoma is still high on the WF-Osaka rats in animal room 1 with the high humidity. Two female ACI rats developed colon carcinomas in the ascending colon. The gross and the histological appearance of the colon carcinoma were completely the same as those of WF-Osaka rats. ACI and WF-Osaka rat strain together have been kept bred in neighborhood of each other in different racks in the identical animal room 1. To obtain HFRSV free ACI rat strain, Antecedents born by cesarean section of ACI female pregnant rat were foster-bred by WF-Osaka female nursing rat incidentally, and at the fourth mating generation after the start of foster-breeding, they developed colon carcinomas at the age of four months. Before five out of eight F1 hybrids by WF-Osaka cancer carrying female rat x male ACI rat had developed the same colon carcinoma, but none of F1 hybrids by the contrary mating had developed colon carcinomas in this same animal room 1. Animal room 1 and 2 where there was a high incidence of colon carcinomas, had happened to be kept moistened. However, after disinfection of these animal rooms, the animal room 2 and 3 occurred to be kept dried, and rats of WF-Osaka strain ceased to develop colon carcinomas in the animal room 2. Thereafter, animal room 2 and 3 were adjusted to be kept moistened again. Subsequently WF-Osaka rats in the animal room 2 began to have colon carcinomas in the ascending colon as before, but none of rats developed colon carcinomas in the animal room 3. Based on these findings, we consider that milk factor at the time of foster-breeding played an important role first and high moistened condition of the animal room resulted in promoting effect on colon carcinogenesis on ACI rats and WF-Osaka rats as well.


Polymorphonuclear leukocyte induced vasoconstriction in isolated canine coronary arteries.

To assess how polymorphonuclear leukocytes act on coronary vasomotion, we measured the changes in isometric tension of isolated canine coronary arterial rings by adding autologous polymorphonuclear leukocytes to the organ chamber. Ring preparations of the left circumflex coronary artery developed isometric tension with a maximum of 80 +/- 21% of PGF2 alpha (5 muM)-induced contraction at the addition of polymorphonuclear leukocytes (5 x 10(5) cells/ml) isolated by the Percoll gradient method. This increase in tension was dependent on the amount of added polymorphonuclear leukocytes (10(4)-5 x 10(6) cells/ml). The integrity of endothelial cells was not disrupted after the addition of polymorphonuclear leukocytes, because the developed tension was reversed by the addition of acetylcholine in an endothelium-dependent manner. The mechanical rubbing of endothelium completely abolished this polymorphonuclear leukocyte-induced vasoconstriction, which was regained by placing an endothelium-unrubbed ring inside the rubbed ring ("sandwich preparation"). The supernatant of either polymorphonuclear leukocyte suspension or polymorphonuclear leukocyte incubation medium with A23187 could not induce the development of vascular tension. Lipoxygenase inhibitors partially suppressed polymorphonuclear leukocyte-induced vasoconstriction. These findings indicate that polymorphonuclear leukocytes and endothelial cells. This polymorphonuclear leukocyte-induced vasoconstriction is not an increase in resting tension due to endothelial injury caused by added polymorphonuclear leukocytes, but the development of active tension. Lipoxygenase product(s) of arachidonate may partially mediate this contraction.


Initial appearance of an ill-defined shadow on a chest roentgenogram in a patient with aortitis syndrome.

A 20-years-old woman with fever and an abnormal shadow on a chest roentgenogram was admitted to our hospital. High grade fever continued even after gradual disappearance of the ill-defined shadow on the right upper lobe (S3) with minor fissure deviation upward, while neck pain and bruit gradually developed. She was diagnosed as aortitis syndrome from a digital subtraction angiography. The initial appearance of an ill-defined shadow on a chest roentgenogram, considered as pulmonary infarction, is rare in the aortitis syndrome and this kind of onset is interesting in relation to the pathogenesis and diagnosis of this syndrome.


In vivo evaluation of fixation of metal implants coated by melt-sprayed alumina--experiments in rabbit.

Skeletal fixation characteristics of the stainless steel implants coated by 60 microns thick porous alumina layer using a flame spray method were evaluated in vivo for the duration of up to 12 weeks. Surface roughness of the implants appeared to be the determining factor for the fixation characteristics, irrespective of the implant materials.


Prediction of contractile reversibility in impaired left ventricular wall motion following coronary artery bypass grafting.

Interventional left vertriculograms (LVGs) using postextrasystolic potentiation (PESP), nitroglycerin (TNG) and a combination of both were analyzed in order to decide the degree of efficacy of each intervention as a predictor of reversibility in impaired left ventricular segments. Segmental wall motion (SWM) in less severely impaired segments increased to the normal range and SWM in severely impaired segments increased but remained in the abnormal range after CABG. The effects of both PESP and TNG on SWM in impaired segments correlated (r = 0.78 and 0.78) with that of CABG. The increase in SWM due to TNG + PESP was significantly (p < 0.01) greater than that due to either PESP or TNG alone or that of CABG. Either PESP or TNG was clinically reliable for prediction of contractile reversibility in the segments with impaired wall motion prior to CABG. Including the global left ventricular function, PESP reflected the efficacy of CABG more sufficiently than TNG. TNG + PESP provoked more contractile reserve and exaggerated the results of CABG, but may predict reversibility in severely reduced wall motion.


Ultrasonographic monitoring of pancreatic pseudocyst during delivery.

A case of pancreatic pseudocyst complicating with pregnancy and delivery was reported. This primipara patient with pancreatic pseudocyst was able to achieve a full-term, transvaginal delivery of a mature baby. The usefulness of ultrasonic monitoring of the pseudocyst during labor was clinically demonstrated. When intra-abdominal pressure increased, pancreatic pseudocyst was deformed.


Effects of injection interval on pentylenetetrazol (PTZ) kindled seizures in rats.

We investigated the effects of different injection intervals, (24 hr, 48 hr, and 72 hr) on the development of kindled seizures induced by repetitive pentylenetetrazol (PTZ) injections (30 mg/kg) in rats. Regardless of injection interval, kindled seizures were obtained 1 week after the completion of consecutive PTZ injections. This PTZ kindled seizure model appears to mimick generalized seizure and be useful in the investigation of seizure phenomenon. With 48 and 72 hr injection interval, the seizure responses gradually increased with consecutive injections. The convulsive severity of 24 hr interval group showed a transient increased and then stabilized at a low score (2/6). This difference between these injection interval might reflect the appearance of some short of inhibition during the more closely spaced (24 hr) repeated injections.


Induced adenocarcinoma of the ascending colon on LE and Wistar/Shhi rats and virus like particles in the serum of colon cancer carrying WF rats.

Intraperitoneal injection of the serum of colon cancer carrying WF rats induced, within two months, colon carcinomas in the ascending colon of LE and Wistar/Shi rats when they were given it during their suckling. We had also induced colon carcinomas in the ascending colon of ACI rats by the same methods. Therefore, it is supported that this serum derived from colon cancer carrying WF rats must have some transmissible agent in itself. In addition, we ultracentrifuged the serum of cancer carrying WF rats and we found, in the sediment, numerous round or oval virus like corpuscles by electron microscopy studies. Negatively stained corpuscles by phosphotungstic acid staining clearly revealed fine spike appearance on their surface. We believe that these virus like corpuscles are the etiological agent for the transmissible colon carcinoma of WF rat strain.


Histopathology of the temporal bones in thanatophoric dysplasia.

The pathological findings of temporal bone in two cases of thanatophoric dysplasia were reported. Thanatophoric dysplasia is classified into type 1 and type 2, each of which has been reported to show specific clinical and radiographic-findings. The present study revealed that each type also showed specific characteristic in the structure of the temporal bones. The developmental mechanisms of hearing impairment in this disease were also discussed on the basis of the pertinent literature.


Recurrence after incompletely resected acousticus neurinomas.

It is known that the recurrence rate is high when an acoustic neurinoma is incompletely excised, but the details of the process of recurrence are still unclear. We reviewed the recurrence of acoustic neurinomas, as evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), in 51 consecutive patients over the past 10 years who underwent tumor resection and had postoperative follow-up by CT or MRI. The factors promoting recurrence related to incomplete excision of tumor were analyzed. Total resection of the tumor was performed in 22 patients (43%), nearly total resection in 17 patients (33%) and subtotal resection in 12 patients (24%). The recurrence rates were 29% (5 of 17 patients) and 25% (2 of 8 patients) for nearly total and subtotal resection, respectively, whereas no recurrence occurred following total resection. Of the patients having nearly total resection, all recurrences arose from residual tumor in the internal auditory meatus (5 of 12 patients). In contrast, there were no recurrences from residual tumor at the site of the brain stem (none of 4 patients). Acoustic neurinomas should be totally removed through neurosurgical and neuro-otological approaches whenever possible. If a small fragment of tumor is left in the internal auditory meatus due to fear of damaging the facial or cochlear nerves, it should be strictly followed up by CT or MRI.


Demonstration of islet cell antibodies in apparently non-insulin dependent diabetic patients; a marker for the later development of insulin dependency.

One hundred and ten diabetic patients who were apparently non-insulin dependent at 1984 were followed up for 5 years from 1984 to 1989. Islet cell antibodies (ICA) of the patients were tested in 1987. Eleven patients were positive for ICA and 99 were negative. There was no significant difference in age, sex, duration of diabetes, and HbA1c levels between ICA-positive and negative groups. Six of 11 (54.5%) patients in ICA-positive group developed insulin-requiring state in the period from 1984 to 1989, while only 5 of 99 (5.1%) patients in ICA negative group became insulin-requiring. Glucagon tolerance test (1 mg i.v.) was performed on 8 patients who developed insulin-requiring state; among them 4 patients were ICA-positive and other 4 patients were ICA negative. The serum C-peptide response to intravenous glucagon injection was markedly decreased in 3 of the 4 ICA-positive patients, and only mildly decreased in all the 4 ICA-negative patients. The markedly decreased C-peptide response indicates that these ICA-positive subjects had developed insulin-dependency. We conclude that the presence of ICA in apparently non-insulin dependent diabetics indicates a high risk for developing insulin-dependency.


Clinical and histologic study of endoscopic duodenitis.

Duodenitis was investigated by endoscopy in 93 cases from among 1242 subjects. Endoscopic duodenitis was classified into three types endoscopically--reddening type, erosive type and nodular type. There was a relatively high correlation between the endoscopic and the histological diagnosis of duodenitis. Severely inflamed cases were found histologically more frequently in erosive- or nodular-type duodenitis than in reddening-type duodenitis. During the follow-up period, changes in endoscopic findings were observed more frequently, from the erosive type to the reddening type, and from the reddening type to normal. There were no cases which subsequently developed duodenal ulcers. We found a significantly high incidence of "endoscopic duodenitis" in uremic patients who had been given regular dialysis, and not in hepatic cirrhosis patients.


Discriminative stimulus properties of nicotine: mechanisms of transduction.

Our thinking about how nicotine might be inducing DS control of behavior has changed drastically in the past 25 years. Our first inclination was that nicotine was mimicking ACh at a variety of specific and select n-AChRs. Then several nicotine researchers suggested that nicotine might be acting via specific and select noncholinergic receptors. At present, we seem to have returned to the view that nicotine may have pronounced effects at the n-AChR (figure 1), at least in some specific cases such as in the development of tolerance and in rats trained to discriminate nicotine (figure 6). The endogenous ligand has not changed, but the mechanism of how it affects presynaptic and postsynaptic receptors appears to have been rediscovered. The concept of rapid ACh-induced desensitization at the n-AChR is not new and appears basic to cholinergic neuronal function (figure 5). The desensitization concept has been revitalized by several investigators who also consider this mechanism important to how nicotine might act in protecting DA neurons from neurotoxicity of chemicals such as 6-OHDA or MPTP (Janson et al. 1988). The overall concept suggests that n-AChR desensitization at presynaptic DA sites may reduce neuronal accessibility to select exogenous neurotoxins and thus attenuate neuronal destruction. This hypothesis has also been partially validated in relation to the cholinergic neuron by providing preliminary evidence that nicotine was able to reduce cholinergic neuron destruction (measured by brain ACh levels) via the intraventricular administration of the neurotoxin AF64A, an ACh nitrogen mustard (Villanueva et al. 1990). Thus, nicotine or compounds acting like nicotine could possibly be beneficial to patients exhibiting the select neurological problems observed in Parkinson's and Alzheimer's diseases. The process of desensitization might also be useful to understanding why humans choose to smoke tobacco products. Perhaps the ability of nicotine to induce such neuronal effects at a specific n-AChR makes it reinforcing (or aversive) to behavior. Such a mechanism of action might explain why nicotine appears to both increase and decrease arousal levels in animals (or humans) exhibiting differential basal level of excitability (Hendry and Rosecrans 1982), or why some people never become dependent on nicotine. How nicotine alters the n-AChR may also be beneficial to our understanding of the subtle nature of cholinergic neuronal function in learning, memory, and other behavioral states. The ability of ACh (or nicotine) to induce an activation or attenuation of some cholinergic or noncholinergic neuron or both may be important to these brain processes.(ABSTRACT TRUNCATED AT 400 WORDS)


Tolerance to drugs acting as discriminative stimuli.

The experiments described above highlight the ways behavioral and pharmacodynamic processes interact to modulate the development of tolerance to the discriminative stimulus effects of drugs. These studies suggest that frequent drug exposure does not lead inevitably to the development of tolerance to a drug's discriminative effects. Rather, the interplay between a drug stimulus and reinforcement opportunities shapes the sensitivity of discriminative performances over successive episodes of drug exposure. Maintaining a discriminative relation between a drug and behavior strengthens the likelihood that an initially effective dose will maintain discriminative control. Development of tolerance requires exposure to both treatment regimens appropriate to the agent under study and behavioral contingencies that limit an individual's ability to learn a new discrimination. When both requirements are met, tolerance does develop to drugs acting as discriminative stimuli. When training is suspended during a period of chronic drug treatment, the dose of drug required to evoke stimulus control can be increased by treatment with appropriate maintenance doses of the training drug or a closely related drug. Tolerance is proportional to maintenance dose, develops relatively slowly, and disappears after termination of repeated drug treatment. Tolerance appears pharmacologically specific and can be accompanied by cross-tolerance to other drugs that evoke cross-generalization with the training drug. Finally, tolerance can be diminished markedly by continuing training with the original training dose. Taken together, these patterns suggest that development of tolerance to drugs acting as discriminative stimuli is the result of joint actions of conditioning and pharmacodynamic processes.


Discriminative stimulus properties of hallucinogens and related designer drugs.

Animals trained to discriminate classical hallucinogens from saline have been used in the past decade to examine other hallucinogenic agents. Time course (onset, duration of action) and locus of action have been studied, SARs have been formulated, and mechanism of action has been investigated in detail. On the basis of DD studies in animals, it was proposed that hallucinogenic agents may produce their actions in humans via a 5-HT2 agonist mechanism and that certain phenalkylamine hallucinogens such as DOM and DOB might constitute the first known examples of 5-HT2 agonists. This led to the development of [3]HDOB and [125I]DOI for use in radioligand binding and autoradiographic studies and to the use of hallucinogen-trained animals as a functional behavioral model of 5-HT2 receptor activation. Animals trained to classical hallucinogens are more recently being used to evaluate novel designer drugs. It can be seen, then, that this paradigm, using hallucinogenic agents as training drugs, has proven to be quite useful for the investigation of hallucinogens and nonhallucinogens alike.


Discriminative stimulus properties of amphetamine, cathinone, and related agents.

Although the AMPH and CATH cues have been studied extensively, inconsistent findings remain that need to be investigated. It is not known to what extent, if at all, AMPH and CATH cues differ and how they differ from the cocaine cue. The extent to which D1 and D2 receptor systems are coupled in AMPH DD assays requires further investigation. The inconsistent findings in substitution studies with nisoxetine need to be addressed in parametric studies in various species. Finally, the possibility that the AMPH cue may generate false positives in screening for drug abuse potential needs to be evaluated.


Neurite growth-promoting protein (amphoterin, p30) binds syndecan.

A new ligand for syndecan (a cell surface heparan sulfate-rich proteoglycan) has been discovered. In the solid-phase binding assay utilizing small nitrocellulose discs to immobilize matrix molecules, binding of syndecan to neurite growth-promoting protein, p30/amphoterin, was observed. This binding was strongly dependent on the concentration of amphoterin used to coat the discs, but was saturable with an excess amount of syndecan. The interaction was inhibitable with heparan sulfate and heparin but less effectively with chondroitin sulfate, indicating that heparan sulfate chains of syndecan were involved in the binding. Anti-amphoterin antibodies inhibited the binding partially. Mouse mammary epithelial cells were shown to bind amphoterin directly but not after trypsin treatment or in the presence of heparin and to produce amphoterin in the extracellular space. Both syndecan and amphoterin were found to localize on lateral surfaces of newly adhered mammary epithelial cells. Toward confluency amphoterin amounts decreased. Because amphoterin can be localized to the same sites with syndecan and because of their interaction, amphoterin is a new putative pericellular ligand for syndecan. These interactions may be involved in the regulation of cell behavior.


Virostatic in vivo effect of elliptinium on Friend's retrovirus (a model for HIV infection).

As we had discovered the virostatic effects of some analogues of acriflavine, a non-oncostatic intercalating agent, on HIV1 and on its best murine model, Friend's virus [7], we then studied other non- or poorly oncostatic intercalating agents, in particular ellipticins (whose negligible cytostatic effect with methoxy-9-ellipticin we first published. We report in this paper the in vivo virostatic effect of 2-methyl-9-hydroxy-ellipticinium (elliptinium) on Friend's virus.