Continuous theta burst stimulation over the supplementary motor area in refractory obsessive-compulsive disorder treatment: A randomized sham-controlled trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a complex disorder with 40 to 60 % of patients resistant to treatment. Theta burst transcranial magnetic stimulation (TBS) is a promising new technique that has been shown to induce potent and long lasting effects on cortical excitability. The present study evaluated for the first time therapeutic efficacy and tolerability of continuous TBS (cTBS) over the supplementary motor area (SMA) in treatment resistant OCD patients using a double blind, sham-controlled design. METHODS: Thirty treatment resistant OCD outpatients were randomized to receive either active cTBS or sham cTBS for 6 weeks (5 sessions per week). Each treatment session consisted of 600 stimuli at an intensity of 70% of resting motor threshold. Patients were evaluated at baseline, at the end of treatment (week 6), and follow-up (week 12). Response to treatment was defined as at least 25% decrease on the Yale-Brown Obsessive Compulsive Scale. RESULTS: There was no significant difference between active and sham cTBS groups in treatment efficacy. Responder rates were not different between the two groups at week 6 (cTBS 28% versus sham 36%; p = 0.686) and week 12 (cTBS 28% versus sham 36%; p = 0.686). Depressive and anxious symptoms improvements were similar in the two groups. CONCLUSION: This study is the first controlled trial using cTBS in treatment resistant OCD patients. The use of cTBS over the SMA is safe but not sufficient to improve OCD symptoms. Further studies are needed to identify the optimal parameters to be used in OCD patients.

Evaluation of Distensibility and Stiffness of Ascending Aortic Aneurysm using Magnetic Resonance Imaging.

INTRODUCTION: Magnetic resonance imaging emerging as a new tool for the diagnosis and evaluation of ascending aortic aneurysm. The aim of our study is to evaluate in vivo distensibility and pulse wave velocity of the aortic wall using functional magnetic resonance imaging technique. METHODS: We enrolled 25 patients undergoing surgery for ascending aortic aneurysm and or aortic valve replacement for a period of 8 months. Preoperatively, all the patients underwent functional MRI study of the aorta. Aortic wall distensibility and pulse wave velocity of ascending aorta was evaluated. RESULTS: Mean age of the patient was 66 years (66.68 ± 5.62 years) with 60% (15) male patients. More than fifty percentages of patients were smoker (52%), hypertensive (64%) and diabetic (56%). We have observed significant decrease of distensibilty in the patients with aortic diameter above 50 mm (p-0.0002). Furthermore, we have found a significant inverse correlation between aortic distensibility and pulse wave velocity (R= -0.650, R2= 0.42, p-0.0004). Similarly, we have found a significant inverse correlation between ascending aortic diameter and distensibility of the aorta (R= -0.785, R2= 0.61, p-0.00001). Statistically significant positive correlation was observed between aortic diameter and pulse wave velocity (R= 0.865, R2= 0.74, p-0.00001). CONCLUSIONS: MRI measurement of aortic diameters, distensibility, and flow wave velocity is an easy, reliable and reproducible technique. Distensibility and pulse wave velocity define the elasticity of the aorta. We have observed that elasticity of aortic wall is decreased in ascending aorta aneurysm patients.

Nipple sparing mastectomy with immediate silicone implant reconstruction for malignant phyllodes tumor in a 19-year-old girl.

OBJECTIVE: Due to the rarity of MPT, the clinical records in the literature, collected along decades, lack to address a modern approach to breast reconstruction after mastectomy. CASE PRESENTATION: We report a case of a teen-aged female diagnosed to have a malignant phyllodes in her right breast. DISCUSSION: The surgical treatment of choice, taking in account the relation between the volume of the mass and the breast dimension, was considered to be a mastectomy. As the disease didn't involve the skin envelope a nipple-areolar-sparing gland removal allowed an immediate prosthetic reconstruction with a contralateral augmentation for symmetrization, so obtaining a satisfactory aesthetic outcome. CONCLUSIONS: At our knowledge we present for the first time this surgical approach that, in selected patients, can reach the oncologic radicality and an adequate cosmetic result too.

Evaluation of the HB&L System for the Microbiological Screening of Storage Medium for Organ-Cultured Corneas.

Aims. To compare HB&L and BACTEC systems for detecting the microorganisms contaminating the corneal storage liquid preserved at 31°C. Methods. Human donor corneas were stored at 4°C followed by preservation at 31°C. Samples of the storage medium were inoculated in BACTEC Peds Plus/F (aerobic microorganisms), BACTEC Plus Anaerobic/F (anaerobic microorganisms), and HB&L bottles. The tests were performed (a) after six days of storage, (b) end of storage, and (c) after 24 hours of preservation in deturgescent liquid sequentially. 10,655 storage and deturgescent media samples were subjected to microbiological control using BACTEC (6-day incubation) and HB&L (24-hour incubation) systems simultaneously. BACTEC positive/negative refers to both/either aerobic and anaerobic positives/negatives, whereas HB&L can only detect the aerobic microbes, and therefore the positives/negatives depend on the presence/absence of aerobic microorganisms. Results. 147 (1.38%) samples were identified positive with at least one of the two methods. 127 samples (134 identified microorganisms) were positive with both HB&L and BACTEC. 14 HB&L+/BACTEC- and 6 BACTEC+/HB&L- were identified. Sensitivity (95.5%), specificity (99.8%), and positive (90.1%) and negative predictive values (99.9%) were high with HB&L considering a 3.5% annual contamination rate. Conclusion. HB&L is a rapid system for detecting microorganisms in corneal storage medium in addition to the existing methods.

Cannabidiol inhibits angiogenesis by multiple mechanisms.

BACKGROUND AND PURPOSE: Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH: Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS: CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. CONCLUSIONS AND IMPLICATIONS: This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.

Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats.

Preclinical data support the long-term adverse effects on cognition, emotionality, and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids. To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress, female and male rats were subjected to 24-h maternal deprivation at postnatal day (PND) 9 and treated with tetrahydrocannabinol (THC) during adolescence (PND 35-45) according to our previously reported protocol. At adulthood, rats were tested in the novel object recognition, social interaction, and forced swim tests, to evaluate possible alterations in recognition memory, social behavior, and coping strategy. Moreover, cannabinoid CB1 receptor density and functionality, as well as NMDA and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies. In female maternally deprived rats, THC failed to impair recognition memory, counteracted aggressiveness induced by maternal deprivation, whereas no interaction was observed in the passive coping behavior. In males, the association of the two events increased passive coping response without affecting other behaviors. This behavioral picture was accompanied by gender-dependent and region-specific alterations in NMDA, D1 and D2 receptors. In conclusion, this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls. The interaction between the two events is not univocal, and different combinations may arise depending on the sex of the animals and the behavior considered. Alterations in NMDA, D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC.

Cannabinoid facilitation of behavioral and biochemical hedonic taste responses.

Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation). This article is part of a Special Issue entitled 'Central Control of Food Intake'.

Brain regions associated with the reversal of cocaine conditioned place preference by environmental enrichment.

In addition to the known preventive effects of environmental enrichment (EE) on drug addiction, we have recently shown that EE can also have "curative" effects and eliminate addiction-related behaviors in mice and rats. In the present study, using Fos immunohistochemistry, we investigated brain regions involved in the elimination of cocaine conditioned place preference (CPP) produced by a 30-day exposure to EE. A first group of mice was conditioned to cocaine in the CPP apparatus, a second group that served as control received cocaine in a cage different from the CPP apparatus and a third control group received only saline injections. At the end of conditioning, we kept mice abstinent in the animal facility, housing them in standard environments (SE) or EE for 30 days and then we tested them for expression of CPP. SE, but not EE mice, conditioned to cocaine showed long-lasting preferences for the cocaine-paired compartment. Expression of CPP was paralleled by significant increases in the expression of Fos in the anterior cingulate cortex, the lateral caudate putamen, the shell of the nucleus accumbens, the dentate gyrus of the hippocampus, the basolateral and central nuclei of amygdala, the bed nucleus of the stria terminalis, and the ventral tegmental area. In contrast, EE mice showed levels of expression of FOS similar to control groups. These results demonstrate that EE can eliminate context-induced cocaine seeking and that this effect appears associated with a general reduction in the activation of several brain regions implicated in relapse.

The endocannabinoid system in brain reward processes.

Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis.

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.

New findings on X-linked Adrenoleukodystrophy: 5alpha-reductase isoform 2 relative gene expression is modified in affected fibroblasts.

X-linked Adrenoleukodystrophy (X-ALD) is a neurodegenerative disease with an endocrinological component since, in addition to the nervous system, the adrenal cortex and the testis are mainly affected, with corresponding clinical signs. 5Alpha-reductase, a key enzyme in steroid hormone metabolism, catalyzes the conversion of testosterone into the potent androgen dihydrotestosterone and other metabolic steps in steroidogenesis. It is present in two isoforms, 5alpha-reductase isoform 1 and 2, that are encoded by different genes. The isoforms are differently expressed in the tissues, where they have distinct physiological relevance. Our study shows that the expression of isoform 2, evaluated by Real-Time PCR, is significantly altered in fibroblasts from patients affected by X-ALD with respect to controls, whereas isoform 1 is not affected. This is the first demonstration of an alteration of 5alpha-reductase isoform 2 gene expression in X-ALD, that may be related to the steroidogenesis impairment and to the specific organ malfunction.

Beta-endorphin elevations in the ventral tegmental area regulate the discriminative effects of Delta-9-tetrahydrocannabinol.

beta-Endorphin is an endogenous opioid that produces behavioral effects similar to heroin and morphine and is released in the nucleus accumbens by cocaine, amphetamine and ethanol, suggesting a general involvement in the reinforcing effects of abused drugs. Here we show that, in rats, Delta-9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, produces large increases in extracellular levels of beta-endorphin in the ventral tegmental area and lesser increases in the shell of the nucleus accumbens. We then used a two-lever choice THC-discrimination procedure to investigate whether THC-induced changes in endogenous levels of beta-endorphin regulate the discriminative effects of THC. In rats that had learned to discriminate injections of THC from injections of vehicle, the opioid agonist morphine did not produce THC-like discriminative effects but markedly potentiated discrimination of THC. Conversely, the opioid antagonist naloxone reduced the discriminative effects of THC. Bilateral microinjections of beta-endorphin directly into the ventral tegmental area, but not into the shell of the nucleus accumbens, markedly potentiated the discriminative effects of ineffective threshold doses of THC but had no effect when given alone. This potentiation was blocked by naloxone. Together these results indicate that certain psychotropic effects of THC related to drug abuse liability are regulated by THC-induced elevations in extracellular beta-endorphin levels in brain areas involved in opiate reward and reinforcement processes.

Evaluating patients with vertigo: bedside examination.

Dizziness and vertigo are common complaints in patients referred for neurological evaluation. With a basic understanding of vestibular physiology and proper examination techniques, a correct diagnosis can generally be made at the bedside. This article reviews the most common peripheral and central vestibular syndromes as well as the key elements of the bedside vestibular system examination.

Exposure to delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin's reinforcing efficacy: a self-administration study in rats.

One concern about the widespread use of cannabis is that exposure to its active ingredient, delta-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 microg/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 microg/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves. Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FR1/100 microg/kg and FR1/50 microg/kg) but there were no differences in the reinforcing efficacy of heroin between THC- and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer.

The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats.

Activation or blockade of cannabinoid CB1 receptors markedly alters many effects of opioids. In the present study, we investigated whether the cannabinoid antagonist (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) could alter the reinforcing effects of heroin in rats. A Delta9-tetrahydrocannabinol (THC) drug-discrimination procedure was first used to determine effective CB1 antagonist doses of SR-141716A and optimal pretreatment times for self-administration studies. Subsequently, Sprague-Dawley rats learned to self-administer heroin under three different schedules of intravenous drug injection: a continuous reinforcement schedule [fixed ratio (FR)1], a five-response, fixed ratio schedule (FR5), and a progressive ratio schedule. Then, SR-141716A (1 mg/kg i.p.) was administered 60 min before the start of the session for three consecutive daily sessions. SR-141716A markedly decreased heroin self-administration under the progressive ratio schedule at heroin doses ranging from 12.5 to 100 micro g/kg/injection. In contrast, SR-141716A had no effect on heroin self-administration under the FR1 schedule at heroin doses of 50 or 100 micro g/kg/injection, but produced small decreases in self-administration at lower doses (25 and 12.5 micro g/kg/injection). Consistent with a behavioral economics evaluation, SR-141716A produced a small but significant decrease in self-administration of the higher 50 micro g/kg/injection dose of heroin when the fixed ratio requirement was raised to five (FR5). Thus, blockade of CB1 receptors differentially decreased the reinforcing efficacy of heroin depending on the number of responses required for each injection (price). These findings indicate a facilitatory modulation of opioid reward by endogenous cannabinoid activity and provide support for the use of cannabinoid CB1 antagonists as medications for heroin addiction.

The usefulness of 99mTc tetrofosmin scintigraphy in patients with breast cancer recurrences.

To verify the usefulness of 99mTc tetrofosmin scintigraphy in the follow-up of breast cancer patients, we studied 72 surgically treated breast cancer patients with suspected local recurrences (20 cases) or distant metastases (52 cases) at clinical examination and/or at conventional imaging procedures (CIPs). In all patients, a whole-body scan followed by planar and single photon emission tomography (SPET) images of selected sites were acquired 10 min after the intravenous injection of 740 MBq of 99mTc tetrofosmin, using a rectangular dual-head gamma camera equipped with high-resolution parallel-hole collimators. Loco-regional recurrences were diagnosed in 19 patients and distant metastases in 44 cases, while benign lesions were ascertained in nine cases. 99mTc tetrofosmin SPET showed higher sensitivity, specificity and accuracy per patient than did CIP (96.8% vs 85%, 77.7% vs 55.5% and 94.4% vs 81.1%, respectively) with statistical significance for accuracy (P <0.05). The combined use of SPET and CIP achieved 100% sensitivity and 98.6% accuracy. Planar imaging did not give additional information in respect of either SPET or CIP, showing significantly lower sensitivity and accuracy values (47.6% and 52.8%, respectively). Our data seem to suggest that 99mTc tetrofosmin SPET, but not planar, may be useful in the follow-up for the detection of loco-regional and distant recurrences in patients with breast cancer. The technique can play a complementary role to conventional diagnostic imaging procedures in selected patients.

Visual and auditory event-related potentials in sporadic amyotrophic lateral sclerosis.

OBJECTIVES: To investigate the relationship between amyotrophic lateral sclerosis (ALS) and cognitive function by means of oddball event-related potentials (ERPs) and to determine the usefulness of this methodology in the cognitive status assessment of physically disabled patients. METHODS: Visual and auditory oddball ERPs were recorded in 16 consecutive sporadic ALS patients. A comprehensive battery of neuropsychological (NP) tests assessed intelligence, executive functions, attention, memory, word fluency, visuo-motor and visual-constructive skills. RESULTS: All patients performed visual and auditory ERPs and 75% of cases showed abnormal N200 and/or P300 waves. Ten patients (62.5%) carried out the entire psychometric evaluation with significant impairment on tests of executive function and attention. A significant correlation between delayed visual (P<0.04) and auditory (P<0.04) P300 latency and impaired NP tests was found. CONCLUSIONS: In agreement with literature data, our findings confirm the hypothesis of cognitive impairment in ALS patients especially on attention and executive functions suggesting a more extensive degeneration beyond the motor areas. ALS causes severe physical disabilities and such a condition may interfere with NP testing. Thus, the P300 seems to be a useful tool for the assessment of cognition and attention when severe physical deficits are present.

(99)mTc-tetrofosmin SPET in the detection of both primary breast cancer and axillary lymph node metastasis.

The aim of this study was to evaluate the usefulness of (99m)Tc-tetrofosmin single-photon emission tomography (SPET) in the detection of both primary breast cancer and axillary lymph node metastasis. We studied 192 consecutive patients in whom primary breast cancer was suspected on the basis of mammography and/or physical examination. After intravenous injection of 740 MBq (99m)Tc-tetrofosmin, both planar and SPET scintimammography was performed in all patients using a rectangular dual-head gamma camera equipped with low-energy, high-resolution, parallel-hole collimators. In 175 patients with breast cancer at histology, the per-lesion overall sensitivity of SPET and planar imaging for the detection of breast cancer was 95.8% and 75.9% (P<0.0005), respectively. The sensitivity of SPET and planar imaging was, respectively, 96.5% and 79.5% in palpable (P<0.0005) and 90% and 45% in non-palpable lesions (P<0.01). With regard to lesion size, the sensitivity of SPET and planar imaging was, respectively, 90.5% and 45.2% in lesions < or =10 mm ( P<0.0005), 95.3% and 81.4% in lesions of 11-20 mm (P<0.005), 100% and 84.6% in lesions of 21-30 mm (P<0.05) and 100% and 95.8% in lesions >30 mm (P>0.05). In the remaining 17 patients with benign mammary lesions at histology, per-lesion overall specificity of SPET and planar imaging was 76.2% and 85.7% (P>0.05), respectively. Neither SPET nor planar imaging showed false-positive results in non-palpable lesions or in those < or =10 mm. In 173 breast cancer patients submitted to axillary lymph node dissection (ALND), per-axilla overall sensitivity of SPET and planar imaging in the detection of axillary lymph node metastasis was 93% and 52.3% ( P<0.0005), respectively. The sensitivity of SPET and planar imaging was, respectively, 100% and 82.6% in palpable nodes (P>0.05), 90.5% and 41.3% in non-palpable nodes (P<0.0005), 92.8% and 35.7% in the presence of < or =3 nodes ( P<0.0005) and 93.2% and 68.2% in the presence of >3 nodes (P<0.005). The specificity of SPET and planar imaging was 91% and 100% (P<0.05), respectively. (99m)Tc-tetrofosmin SPET appears to be a reliable method for the detection of both primary BC and axillary lymph node metastasis, and its diagnostic accuracy exceeds that of (99m)Tc-tetrofosmin planar scintimammography. The use of SPET is particularly important in the identification of small non-palpable primary carcinomas and metastatic axillae with < or =3 non-palpable lymph nodes. More extensive use of SPET appears warranted in the management of breast cancer patients.

Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine.

RATIONALE: Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids. OBJECTIVES: In this study we investigated if repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Delta(9)-THC and morphine. METHODS: Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Delta(9)-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Delta(9)-THC (75 and 150 microg/kg i.v.), with a synthetic cannabinoid agonist WIN55212-2 (75 and 150 microg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded. RESULTS: Rats previously administered with Delta(9)-THC showed a greater behavioural activation compared to controls in response to challenge with Delta(9)-THC (150 microg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Delta(9)-HC and WIN55212-2, 75 and 150 microg/kg i.v.). The effect of the challenge with Delta(9)-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand. CONCLUSIONS: The results of the present study demonstrate that repeated exposure to Delta(9)-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.

99mTc-Tetrofosmin pinhole-SPECT (P-SPECT) and radioguided sentinel node (SN) biopsy and in breast cancer axillary lymph node staging.

We compared 99mTc-Tetrofosmin P-SPECT with radioguided SN biopsy in 101 T1/T2 BC pts to predict axillary lymph node status. The day before surgery all pts underwent lymphoscintigraphy (LS) to mark the SN, following subdermal injection of 99mTc-colloidal sulphur surrounding the breast lesion. LS was combined with pre and intraoperative gamma probe. Previously, all pts had also undergone P-SPECT. ALND was performed in all cases. The SN(s) was detected in 97/101 cases (96%) by LS and gamma probe; in the 4 missed cases P-SPECT predicted lymph node status. In the 97 comparable cases, radioguided SN biopsy showed a slightly higher accuracy than P-SPECT (94.8% vs 93.8%), but a higher false-negative rate (14.3% vs 8.6%); P-SPECT had a higher NPV (95.2% vs 92.5%). The two procedures when combined achieved 100% accuracy. Radioguided SN biopsy alone had 100% accuracy only in pts with BC < 15 mm. P-SPECT had 3 false negative cases, 2 of which were micrometastatic SNs, and 3 false positives. P-SPECT identified 81.2% of cases with a single node, determined the exact number of nodes in 82.6% of cases with 1 to 3 node and correctly classified 93.7% of pts as having < or = 3 or > 3 metastatic nodes. Radioguided SN biopsy seems indicated in selected, early stage, small BC pts, while P-SPECT shows a high sensitivity independent of primary tumor size, giving additional important preoperative prognostic information. The two procedures combined provided a better axillary lymph node status prediction in T1/T2 carcinomas, and could thus improve ALND pt selection.