Comparison of hyperparathyroidism types and utility of dual radiopharmaceutical acquisition with Tc99m sestamibi and 123I for localization of rapid washout parathyroid adenomas.

Tc99m-sestamibi dual-time imaging is a standard tool for localization of adenomas/hyperplasia in hyperparathyroidism. We investigated the degree and causes of localization failure among different types of hyperparathyroidism. Pre-operative parathyroid hormone levels and size of the gland were major determinants of Tc99m-sestamibi positivity; 123I scan may be helpful in localization failures. INTRODUCTION: Tc99m-sestamibi dual-time imaging is a standard tool for localization of adenomas/hyperplasia in hyperparathyroidism. However, parathyroid adenomas/hyperplasia has been reported to washout as fast as normal thyroid tissue ("rapid washout") which may lead to diagnostic failure. We aimed to evaluate the determinants of rapid washout and to determine the role of subtraction imaging for detection of parathyroid adenomas/hyperplasia with rapid washout. METHODS: Retrospective analysis of patients with hyperparathyroidism who have undergone Tc99m-sestamibi dual-time imaging and parathyroid surgery. Rapid washout was correlated to the type of hyperparathyroidism in surgically confirmed cases. Biochemical and pathological data were reviewed. RESULTS: A total of 135 hyperparathyroidism patients met the inclusion criteria. Ninety-six (72%), 29 (21%), and 10 (7%) had primary, secondary, and tertiary hyperparathyroidisms, respectively. Rapid washout was identified in 28/87 glands (32%), 14/53 glands (26%), and 1/16 glands (6%) with primary, secondary, and tertiary hyperparathyroidisms, respectively. Glands that were positive on late-phase Tc99m-sestamibi scans were significantly large being 1.7 (IQR 1.4-2.3) vs. 1.45 (IQR 1-2) cm (p = 0.003). High parathyroid hormone levels (PTH) were associated with early-phase Tc99m-sestamibi positivity in both primary (p = 0.01) and secondary hyperparathyroidism (p = 0.03) but not with last phase (p = 0.11, p = 0.37, respectively). Correlative imaging with subtraction scintigraphy was positive in 14/16 (87.5%) parathyroid adenomas. CONCLUSION: Pre-operative PTH levels and size of the gland were major determinants of Tc99m-sestamibi positivity on early-phase Tc99m-sestamibi scans, whereas size is an independent predictor of late-phase Tc99m-sestamibi positivity. Subtraction scintigraphy might be a useful tool in suspected cases of rapid washout adenomas/hyperplasia.

[Policies, operational framework and guidelines of the Inter-American Committee on Aquatic Animal Health]. / Políticas, marco de trabajo y lineamientos del Comité Interamericano de Sanidad de los Animales Acuáticos.

The Americas are home to a large population of aquatic animals, most of which are used in aquaculture. Production systems are diverse and are distributed over a wide and varied geographical area. This presents a challenge for the region, which must be able to meet food safety requirements for aquatic animals traded in the international market. The authors describe the creation of the Inter-American Committee on Aquatic Animal Health (IAC-AAH), as well as its composition, operation, objectives, the activities of the groups that form the Committee and the various activities conducted so far.

Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles.

The synthesis of novel 4beta-aryl-1-methyl-3alpha-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT, NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4beta-(4-Chlorophenyl)-1-methyl-3alpha-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1.

Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors.

Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.

Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.

1. In addition to inhibiting the dopamine transporter, cocaine affects a variety of other neurotransmitter systems. In the present study, the involvement of both dopaminergic and the nondopaminergic systems in the behavioral effects of cocaine was studied using an intravenous drug discrimination procedure. 2. One group (Group 1) of rats were trained to discriminate cocaine (1 mg/kg, i.v.) from saline, while a second group (Group 2) of rats were trained to discriminate the same dose of cocaine from both GBR-12909 (1 mg/kg i.v.), a dopamine-selective uptake inhibitor, and saline. 3. Following training, substitution tests with different doses of cocaine and several drugs pharmacologically related to cocaine were conducted. When cocaine dose was varied, there was a dose-dependent generalization to the cocaine-training stimulus in both groups of rats. Conversely, GBR-12909 and GBR-12935, another dopamine-selective uptake inhibitor, generalized to the cocaine-training stimulus in Group 1, but there was minimal or no generalization in Group 2 4. The norepinephrine-selective uptake inhibitors, desipramine and nisoxetine, and the serotonin-selective uptake inhibitor, zimeldine, produced little or no generalization to the cocaine-training stimulus in either group of rats. The sodium channel blocker, dimethocaine which has a relatively high affinity for the dopamine transporter fully generalized to the cocaine stimulus in both groups of rats, while procaine which has a low affinity for the dopamine transporters only partially generalized to the cocaine-training stimulus in both groups of rats 5. Finally, lidocaine, which has negligible affinity for the dopamine transporter, did not generalize to the cocaine-training stimulus in either group of rats. The findings suggest similarities as well as subtle, but important, differences between the discriminative stimulus effects of cocaine and the dopamine uptake inhibitors, GBR-12909 and GBR12935.

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors.

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.

Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies.

A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K(i) values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure-activity relationships and molecular modeling studies, we found that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, K(i) values of 11 and 55 nM in binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse.

Cardiovascular responses to cocaine self-administration: acute and chronic tolerance.

The nature and the mechanism of tolerance to the cardiovascular responses to cocaine self-administration were studied in rats implanted with telemetric devices. The first infusion of cocaine (1 mg/kg/infusion) on day 1 of testing produced rapid and brief increases in mean arterial blood pressure and in heart rate. Subsequent infusions in the same session produced minimal effects. With chronic testing, there were gradual reductions in cardiovascular responses to the first infusion in the daily session and enhancements in the daily cocaine intake, with significant changes occurring by the fourth week of the testing. Following saline extinction testing (for 5 days), reinstatement of cocaine during week 6 led to a partial and short lasting (

Monoamine transporter and sodium channel mechanisms in the rapid pressor response to cocaine.

Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine.

Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine.

Inhibition of dopamine (DA) transporter function is thought to be the principal mechanism underlying cocaine's addictive effects. In contrast to cocaine, several other inhibitors of DA transporter function are not considered to possess abuse liability. One of the neuroadaptive changes to chronic cocaine self-administration is the up-regulation of DA transporters. In the present study, we investigated the reinforcing and neuroadaptive effects of two other DA reuptake inhibitors, namely bupropion and nomifensine. Drug-naive rats readily acquired and subsequently maintained consistent self-administration of 3 and 1 mg/kg/infusion doses of bupropion and nomifensine, respectively, during 2-hr daily sessions over a prolonged period. Similarly, self-administration responding at low doses of bupropion (0.75 and 1.5 mg/kg/infusion) and nomifensine (0.1 and 0.3 mg/kg/infusion) showed some consistency during the initial weeks of testing which gradually declined or tended to decline to levels similar to that of the water control group during the later weeks of testing. Bupropion self-administration dose-dependently up-regulated DA transporters in caudate putamen and nucleus accumbens. In contrast, nomifensine self-administration did not alter DA transporter levels. These data provide evidence for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response.

Differential reinforcing effects of cocaine and GBR-12909: biochemical evidence for divergent neuroadaptive changes in the mesolimbic dopaminergic system.

The dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure, in vitro autoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 +/- 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.

Cardiovascular effects of cocaine during operant cocaine self-administration.

The aim of this study was to investigate the acute and chronic effects of cocaine self-administration behavior on cardiovascular function. Mean blood pressure and heart rate were measured by radio-telemetry during several experimental conditions. Initial control studies eliminated possible confounds related to the effects of saline injections and operant responding on heart rate and blood pressure. When rats were first allowed to self-administer 0.5-mg/kg injections of cocaine (FR(fixed ratio)10:TO 30 s), there was a significant increase in blood pressure. Tolerance developed to this effect within 3 daily sessions. A significant decrease in blood pressure and heart rate was observed during saline-substitution sessions. Increasing the injection dose of cocaine (1.0, 2.0 and 4.0 mg/kg per injection) did not produce a dramatic increase in blood pressure or heart rate despite significant cumulative cocaine intake (20-27 mg/kg). The cardiovascular effects of cocaine administration did not approach magnitudes previously reported. The results of the current study suggest that operant-conditioned behaviour and/or the direct reinforcing effects of cocaine modulates the cardiovascular effects of cocaine.

Possible novel pharmacodynamic action of cocaine: cardiovascular and behavioral evidence.

Intravenous cocaine (0.03-3 mg/kg) produced two distinct and temporally separable effects in rats. One is an initial, large, and brief increase in blood pressure (BP) and heart rate (HR) of a rapid onset (abrupt hemodynamic stimulation). A rapid, brief, and intense behavioral arousal accompanied this abrupt hemodynamic stimulation. The other effect of cocaine is a prolonged locomotor activation of a relatively slower onset. Prolonged increases in BP and HR accompanied this locomotor effect. The threshold doses of cocaine to produce abrupt hemodynamic stimulation and locomotion are 0.03 and 0.3 mg/kg, respectively. Dopamine receptor antagonists, SCH 23390 or eticlopride, at a 0.03 mg/kg dose antagonized the locomotion and the parallel prolonged increases in BP and HR, but not the initial brief behavioral arousal and abrupt hemodynamic stimulation responses to cocaine. Peripheral dopamine receptor antagonist, domperidone, altered neither behavioral nor cardiovascular effects of cocaine. Chlorisondamine (1 mg/kg), an autonomic ganglionic blocker, did not alter either the initial brief behavioral arousal or the locomotor responses to cocaine, but it prevented the cardiovascular changes that accompanied both these behavioral responses. Norepinephrine, a direct adrenergic vasoconstrictor, although produced rapid and large increase in BP, did not cause abrupt behavioral arousal or locomotor activation. Unlike cocaine, monoamine reuptake inhibitors that are selective for norepinephrine (nisoxetine, 0.1-1 mg/kg) or serotonin (fluoxetine, 0.3-3 mg/kg) produced neither brief behavioral arousal and abrupt hemodynamic stimulation nor locomotor activation. Dopamine-selective reuptake inhibitor, GBR 12,909, also did not elicit the initial brief behavioral arousal and abrupt hemodynamic stimulation. But, GBR 12,909, like cocaine, produced a prolonged locomotor effect and parallel increases in BP and HR. These effects of GBR 12,909 were prevented by SCH 23,390 and eticlopride, but not by domperidone. Similar to cocaine, cardiovascular, but not the locomotor effects of GBR 12,909 were prevented by chlorisondamine. Lidocaine (0.3-3 mg/kg), a sodium channel blocker and local anesthetic, produced neither behavioral nor physiological changes. Both cocaine (3 mg/kg) and GBR 12,909 (1 mg/kg) increased plasma norepinephrine and epinephrine concentrations. These increases were antagonized by both eticlopride and SCH 23,390. These results indicate that behavioral and cardiovascular effects of cocaine are intricately related with respect to the molecular mechanisms involved. Two pharmacodynamic actions of cocaine appear to mediate these effects. One is a dopamine-dependent while the other is a monoamine- and sodium channel-independent novel action. The former mediates cocaine's locomotor effect and the accompanying prolonged increases in BP and HR, while the latter mediates the initial brief behavioral arousal and the accompanying abrupt hemodynamic stimulation.

Effects of monoamine reuptake inhibitors on cocaine self-administration in rats.

The objective of this study was to investigate the effects of acute administration of monoamine reuptake inhibitors on cocaine self-administration in rats. Pretreatment with GBR 12909 (1-5.6 mg/kg, IV), a dopamine-selective reuptake inhibitor, produced a dose-dependent and large reduction in the self-administration of cocaine (1 mg/kg/infusion). The 3- and 5.6-mg/kg doses of GBR 12909 produced downward shifts in the dose-response curves for cocaine (0.3-3 mg/kg/infusion) self-administration. Unlike GBR 12909, the norepinephrine-selective reuptake inhibitors, desipramine and nisoxetine, at a 10-mg/kg dose produced small, but significant, reductions in the self-administration of cocaine (1 mg/kg/infusion). The 10-mg/kg dose of fluoxetine, a serotonin-selective reuptake inhibitor, produced a small, but not significant, reduction in the self-administration of cocaine. The 10-mg/kg dose of desipramine, nisoxetine, or fluoxetine produced brief respiratory distress and motor abnormalities immediately following IV injections, thereby suggesting that this dose is close to the toxic range for all three drugs. Desipramine, nisoxetine, or fluoxetine at nontoxic doses of 1 and 3 mg/kg had no significant effects on cocaine self-administration. These data indicate that the acute enhancement of endogenous dopaminergic activity by pretreatment with dopamine reuptake inhibitor reduces the total intake of cocaine, thus supporting the hypothesis that the dopamine is critically involved in the reinforcing properties of cocaine. The data also suggest that the acute enhancements in the endogenous norepinephrine or serotonin systems by nontoxic doses of norepinephrine- or serotonin-selective reuptake inhibitors do not appear to alter the reinforcing properties of cocaine.

Pharmacological mechanisms in cocaine's cardiovascular effects.

The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human response to cocaine; low to moderate doses of cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of alpha-1 and beta-1 adrenoceptor mechanisms in mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanisms in the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observed hours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore these differing effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggest a role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanisms involved in the cardiovascular effects of cocaine are not the same as those involved in its behavioral effects.

Calcium channel blockers antagonize some of cocaine's cardiovascular effects, but fail to alter cocaine's behavioral effects.

The effects of cocaine alone and in combination with the calcium channel blockers nimodipine, verapamil and diltiazem were determined for different groups of squirrel monkeys on cardiovascular function, schedule-controlled behavior and drug self-administration. Cocaine alone (0.3 mg/kg) produced increases in both blood pressure and heart rate. All three calcium channel blockers antagonized the pressor effect, but were ineffective against the tachycardiac effect of cocaine. Nimodipine was the most potent agent in antagonizing the pressor effect of cocaine. Response rates for monkeys responding on a second-order schedule of food presentation were increased by intermediate doses of cocaine (0.1-1.0 mg/kg) and were primarily decreased at a higher dose (3.0 mg/kg). Quarter-life values, an index of response patterning, were only decreased by cocaine. None of the calcium channel blockers altered cocaine's effects on either response rate or response patterning. In the self-administration experiments, the training dose of 56 micrograms/kg cocaine maintained high rates of responding on a simple fixed-ratio schedule. As with schedule-controlled behavior, none of the calcium channel blockers altered cocaine self-administration even when administered before self-administration sessions during 5 consecutive days. These results suggest that the calcium channel blockers may be useful in treating cardiovascular-related complications after cocaine use, but they would not be effective as long-term treatment agents for cocaine abuse.

[Integrated imaging of the breast. Use of a hypermedia program and multimedia archives for teaching purposes]. / Imaging integrato della mammella. Utilizzazione a scopo didattico di un programma ipermediale e di un archivio multimediale.

This paper deals with the results obtained with a computerized senology system developed at the Institute of Radiology of "La Sapienza" University in Rome. The system combines a hypermedia program with a multimedia didactic archive integrated with the radiologic information system. These programs have been developed on Macintosh computers: the hypermedia one on a Macintosh IIfx with 160-Mb hard disk and 8-Mb RAM and a Supercard software, the multimedia archive on Macintosh IIvx, IIvi and Quadra 650 units, connected with an Ethernet network to a server Quadra 950 (RAM: 20 Megabytes; optical disk: 1 Giga) and using the 4th Dimension as software. The basics of breast anatomy, radiologic semiology and breast diseases are illustrated with the hypermedia program: such a system has many advantages to teach the basics requiring just a process of learning by heart. The multimedia archive allows to classify a large number of difficult and uncommon clinical cases, according to the ACR code. Thus, it is useful also to teachers to study particular subjects, including anatomical variants and uncommon conditions. In conclusion, we believe these systems to be valuable tools in the formation and update of the physicians devoted to the study of breast diseases.

Differential blockade of chronic versus acute effects of intravenous cocaine by dopamine receptor antagonists.

The objectives of this study were to investigate behavioral sensitization to repeated once daily IV injections of cocaine, and to determine whether dopamine receptor antagonists differentially block chronic versus acute cocaine effects. Acute cocaine (0.3-3.0 mg/kg) produced a dose-dependent increase in both horizontal and stereotypic movements in male Sprague-Dawley rats. Repeated once daily injections of 1 or 3 mg/kg of cocaine augmented these effects. Pretreatment with either the D2 dopamine receptor antagonist haloperidol (0.03-0.3 mg/kg) or the D1 dopamine receptor antagonist R(+)-SCH-23390 (0.003-0.1 mg/kg) dose dependently attenuated cocaine's behavioral effects in both sensitized and cocaine-naive animals. There was a rightward shift in the dose-effect relationship of these antagonists in blocking the expression of behavioral sensitization as compared to their ability to block the acute behavioral effects of cocaine. These results indicate that repeated once daily IV injections of cocaine produced behavioral sensitization and both D1 and D2 dopamine receptor antagonists attenuated the expression of this sensitization. The data also suggest that dopamine receptor antagonists were more potent in blocking cocaine's effects in cocaine-naive animals than in cocaine-sensitized animals.

[Metachronous tumors of the breast. Mammographic findings]. / Tumori metacroni della mammella. Rilievi mammografici.

In breast carcinoma patients the risk to develop a second lesion in the contralateral breast is two to six times higher than in control subjects. The second lesion is called metachronous and classified among bilateral breast cancers. This kind of lesion affects the patients who were mastectomized for breast carcinoma; it may be a primary lesion, when the histologic type is different from that of the first breast cancer or secondary, when the histologic type is the same as that of the first tumor and the second lesion is therefore a metastasis. This study was made to assess the incidence of metachronous lesions and the average time between the first and the second tumor and to investigate the value of mammographic followup. We selected 375 patients who had undergone mastectomy for different histologic types of breast carcinoma and examined the contralateral breast with mammography 6 months after surgery and then every 12 months, January 1990 through January 1992. Mammography showed metachronous lesions in 23 cases: 15 infiltrating ductal carcinomas, 6 infiltrating lobular carcinomas and 2 in situ carcinomas, the latter with histologic confirmation in the patients operated on for benign breast lesions. The incidence of metachronous tumors was 6%, including both the primary and the metastatic lesions; the average time between the first and the second tumors was 20 months. Mammography allowed metachronous lesions to be diagnosed in a very early stage, much earlier than in other studies not including mammography. Prognosis is definitely improved by the early diagnosis of primary breast cancer, when no metastatic spread is present, and also in case of primary metachronous lesions, which are very uncommon.

Cocaine: cardiovascular effects in relation to inhibition of peripheral neuronal monoamine uptake and central stimulation of the sympathoadrenal system.

Cocaine (0.03-5.6 mg/kg i.v.) produced a dose-dependent and prolonged increase in mean arterial blood pressure and heart rate in conscious rats. The 0.3 and 1 mg/kg doses of cocaine potentiated the pressor response to exogenous norepinephrine (0.2 microgram/kg), whereas lower (0.03 and 0.1 mg/kg) and higher (3 and 5.6 mg/kg) doses were ineffective. Desipramine (0.03-1 mg/kg), a prototype norepinephrine uptake blocker, did not alter blood pressure or heart rate. Nisoxetine (0.01-1 mg/kg), another norepinephrine selective uptake blocker, produced a small and brief (< 5 min) pressor response, but not tachycardiac response. Unlike cocaine, both desipramine and nisoxetine produced a dose-dependent potentiation of the pressor response to norepinephrine with the maximal potentiation exceeding that of cocaine. Plasma norepinephrine and epinephrine levels were increased by cocaine (3 mg/kg), but not by nisoxetine (1 mg/kg). Chemical sympathectomy by 6-hydroxydopamine selectively antagonized cocaine-induced increases in both blood pressure and plasma norepinephrine levels, but did not alter cocaine-induced increases in heart rate or plasma epinephrine levels; the converse was the case with adrenal demedullation. Both the combination of chemical sympathectomy and adrenal demedullation and pretreatment with chlorisondamine (10 mg/kg) antagonized cocaine-induced pressor and tachycardiac effects and cocaine-induced increases in plasma epinephrine and norepinephrine levels. In the control group, cocaine (3 mg/kg) produced a biphasic increase in blood pressure consisting of an early peak increase of 52 +/- 2.5 mm Hg 15 sec after its injection followed by a quick and partial recovery to an increase of 20.5 +/- 3.3 mm Hg at 1 min which gradually declined to base-line values in about 30 min. Prazosin (1 mg/kg) pretreatment decreased the magnitude of the initial peak pressor response produced by cocaine and reversed the sustained pressor response to cocaine to a depressor response; the reversal of the pressor response to cocaine to a depressor response by prazosin was not seen after erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol (ICI 118,551) (3 mg/kg) treatment or adrenal demedullation. Treatment with ICI 118,551 alone enhanced the magnitude of the sustained phase of the pressor response to cocaine. These results indicate that inhibition of peripheral sympathetic neuronal amine uptake mechanism by cocaine is not critical for initiating its pressor, tachycardiac and plasma catecholamine increasing effects in conscious rats and that central stimulation of sympathoadrenal neural axis activity plays an important role in these effects.(ABSTRACT TRUNCATED AT 400 WORDS)