Pre-operative MRI staging of endometrial cancer in a multicentre cancer network: can we match single centre study results?

OBJECTIVES: To evaluate the staging accuracy of magnetic resonance imaging (MRI) for endometrial cancer in daily practice over a 3-year period at a tertiary referral centre receiving scans from a large number of hospitals with varying protocols. To compare these daily practice results to published data from single-centre studies. METHODS: After ethical approval, MRI staging records for 270 studies from nine network and three centre hospitals were retrospectively collected and compared with final operative histopathology. The International Federation of Gynaecology and Obstetrics (FIGO) stage, depth of invasion assessment and cervical stromal invasion were analysed and reasons for discrepancies reviewed. RESULTS: MRI-based complete FIGO stage was fully concordant with histopathology in 65.6%. MRI accuracy for depth of myometrial invasion and cervical stromal invasion was 73.3% and 89.3% respectively. Our results did not match the high accuracy previously reported in studies based on single centres. CONCLUSIONS: Published MRI staging accuracy from small single-centre studies were not replicated in a tertiary referral centre receiving scans with heterogeneous protocols over a 3-year period. These results highlight the challenges faced in daily practice and may reflect achievable and realistic MRI staging accuracies in large rapid throughput referral networks. Adherence to standardised high-quality protocols may help to improve future results. KEY POINTS: • Three-year MRI-staging accuracy for endometrial cancer in a multicentre cancer network • Daily practice MRI-staging accuracy did not meet results of single-centre studies • Large scale cancer network MRI-staging accuracies should be further evaluated • Treatment recommendations should be based on achievable MRI-staging accuracies.

Masseteric cooptation and crossfacial nerve grafting: Is it still applicable 22 months after the onset of facial palsy?

BACKGROUND: Eighteen months is usually considered the cutoff time within which recovery of the mimic muscle remains possible using facial nerve cooptation. Few reports on the use of cooptation after this interval have appeared. Purpose of this study is to investigate the feasibility of this procedure also after 22 months. METHODS: Six patients treated via crossfacial nerve grafting between healthy and paralyzed middle and middle-upper facial nerve branches and masseteric cooptation of the main trunk of the paralyzed facial nerve between 20 and 24 months after the onset of palsy were analyzed. Population consisted of two males and four females ages 8-42 years (mean 24 years). Facial palsy developed after acoustic neuroma resection in three patients, after the removal of a cerebellopontine angle astrocytoma in one, and as a consequence of Bell's palsy or cerebral hemorrhage in the other two (one each). House-Brackman and Sunnybrook clinical evaluation systems and FDI questionnaire were used to assess results. RESULTS: House-Brackman scores changed from VI before the operation for all patients to II for two patients and III for four patients. Sunnybrook scores were 0-10 before the operation, but 62-84 at the last visit. Mean FDI scores moved from 24 to 38.5 meaning a statistical high significant improvement (P < .01). CONCLUSIONS: Masseteric/crossfacial nerve grafting is feasible for patients with palsies 20-24 months in duration, affording satisfactory functional and esthetic results and a dramatic improvement in quality of life.

Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers.

The transcription factor Sox2 is essential for neural stem cells (NSC) maintenance in the hippocampus and in vitro. The transcription factor Emx2 is also critical for hippocampal development and NSC self-renewal. Searching for 'modifier' genes affecting the Sox2 deficiency phenotype in mouse, we observed that loss of one Emx2 allele substantially increased the telencephalic ß-geo (LacZ) expression of a transgene driven by the 5' or 3' Sox2 enhancer. Reciprocally, Emx2 overexpression in NSC cultures inhibited the activity of the same transgene. In vivo, loss of one Emx2 allele increased Sox2 levels in the medial telencephalic wall, including the hippocampal primordium. In hypomorphic Sox2 mutants, retaining a single 'weak' Sox2 allele, Emx2 deficiency substantially rescued hippocampal radial glia stem cells and neurogenesis, indicating that Emx2 functionally interacts with Sox2 at the stem cell level. Electrophoresis mobility shift assays and transfection indicated that Emx2 represses the activities of both Sox2 enhancers. Emx2 bound to overlapping Emx2/POU-binding sites, preventing binding of the POU transcriptional activator Brn2. Additionally, Emx2 directly interacted with Brn2 without binding to DNA. These data imply that Emx2 may perform part of its functions by negatively modulating Sox2 in specific brain areas, thus controlling important aspects of NSC function in development.

Perioperative pain management after scapular tip free flap harvesting for head and neck reconstruction using mini-catheters to inject the local anesthetic.

PURPOSE: Although functional and esthetic results after the use of a scapular tip free flap (STFF) in head and neck reconstruction, and the related donor-site morbidity, have been extensively described, data regarding acute postoperative donor-site pain management are lacking. Purpose of this study is to explore the use of mini-catheters to administer local anesthetics for donor-site pain management after reconstruction using STFF. METHODS: Patients who underwent head and neck reconstruction using a STFF were prospectively enrolled and, through a perineural catheter placed in the donor site during the surgical procedure, a bolus of chirochaine was injected before the patient regained consciousness and at 8, 16, and 24 h postoperatively. Before and 40 min after each dose administration, donor-site pain on a numerical rating scale (NRS; 0-10) was evaluated. RESULTS: Study population consisted of 20 patients (40-88 years). At 8 h, the pain scores before and after the injection were 0-10 (mean 3.35) and 0-5 (mean 1.25), respectively. At 16 h, the pain scores before and after the injection were 0-8 (mean 2.55) and 0-4 (mean 0.55), respectively. At 24 h, the pain scores before and after the injection were 0-8 (mean 1.30) and 0-4 (mean 0.30), respectively. CONCLUSION: Statistical analysis confirmed a significant difference between the pain scores before and after administration at 8, 16, and 24 h (p < 0.001, p < 0.001, and p = 0.003, respectively). Mini-catheters for local anesthetic administration represent an effective strategy for pain control after STFF harvesting for head and neck reconstruction.

IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo.

During embryonic development, and in certain neurodegenerative diseases, neurons die by apoptosis. A new family of anti-apoptotic proteins, termed inhibitors of apoptosis (IAP), suppresses apoptosis through the direct inhibition of caspases. The anti-apoptotic activity of IAPs is inhibited by second mitochondria-derived activator of caspase (Smac)/DIABLO and XAF1 (ref. 8). IAPs, as well as neurotrophic factors, can protect degenerating neurons both in vivo and in vitro. However, the downstream targets of neurotrophic factors have not yet been identified. Here, we demonstrate that XIAP and NAIP, but not HIAP2, are directly involved in the intracellular response to glial cell-derived neurotrophic factor (GDNF). In newborn rats, GDNF regulates endogenous levels of XIAP and NAIP in motor neurons after sciatic nerve axotomy. The inhibition of XIAP or NAIP activity prevents GDNF-mediated neuroprotective effects. These results suggest that XIAP and NAIP are essential for intracellular signalling of GDNF in motor neuron survival.

3D planning of ear prosthesis and navigated flapless surgery for craniofacial implants: A pilot study.

New 3D digital technologies can be applied to implant-supported ear prostheses to restore anatomical structures damaged by cancer, dysplasia, or trauma. However, several factors influence the accuracy of implant positioning using a cranial template. This pilot study describes an innovative navigated flapless surgery for craniofacial implants, prosthetically guided by 3D planning of the ear prosthesis. Laser surface scanning of the face allowed for mapping of the healthy ear onto the defect site, and projection of the volume and position of the final prosthesis. The projected ear volume was superimposed on the skull bone image obtained by cone-beam computed tomography (CBCT), performed with the navigation system marker plate positioned in the patient's mouth. The craniofacial implants were fitted optimally to the ear prosthesis. After system calibration, real-time navigated implant placement based on the virtual planning was performed with minimally invasive flapless surgery under local anesthesia. After 3 months of healing, digital impressions of the implants were made, and the digital manufacturing workflow was completed to manufacture the ear prosthesis anchored to the craniofacial implants. The proposed digital method facilitated implant positioning during flapless surgery, improving the ear prosthesis manufacturing process and reducing operation time, patient morbidity, and related costs. This protocol avoids the need for a reference tool fixed in the cranial bone, as is usually required for maxillofacial surgery, and confirmed that surgical navigation is useful for guiding the insertion of craniofacial implants during flapless surgery.

The cardiovascular burden of end-stage renal disease patients.

Patients with end-stage renal disease are 10 to 20 times more at risk of cardiovascular death than the general population. Traditional cardiovascular risk factors are not able to explain the increase in the onset of cardiovascular diseases in dialysis patients. Some of the most important non traditional risk factors in uremic patients are: the inflammatory state of the patients, cytokines and growth factors, hyperhomocysteinemia, the presence of alterations of the calcium phosphorous product which can already be in progress when the glomerular filtration rate decreases to less than 60 mL/min. Clinically, these alterations cause vascular calcifications, calcifications of the heart valves and calcific uremic arteriolopathy or calciphylaxis. The pathogenesis of vascular calcification is complex and cannot be assigned to a simple, passive process: in fact, it includes factors which promote or inhibit calcification. In turn, these pathologic conditions have been found to be highly predictive of general and cardiovascular death. Given the serious clinical consequences that vascular calcifications can cause, it is necessary to carry out an early mapping of the traditional and non traditional risk factors of uremic patients as it seems that therapeutic interventions aimed at reducing or inverting the calcification process can improve the outcome of patients, above all when they are started quickly.

The peopling of Madeira Archipelago (Portugal) according to HLA genes.

The Madeira-Porto Santo Archipelago was officially colonized in 1420 by Portuguese settlers. Its importance in Columbus' information for the American discovery and for slave traffic across the Atlantic is unquestionable. Thus, a complex peopling may have given rise to a present-day high admixture of ethnicities according to HLA genes. A sample of 173 healthy unrelated Madeirans was analysed and compared with 6986 HLA chromosomes from other worldwide populations. Genetic distances, neighbour-joining dendrograms and correspondence analyses were used for comparisons. Southern European, North African (including Canary Islands), Jewish and Mediterranean typical HLA alleles were found and genetic distances from Madeirans to these populations were the closest ones. In addition A*24-B*65-DRB1*0102-DQB1*0501 and A*68-B*08-DRB1*0301-DQB1*0201 haplotypes were newly found in Madeira and not found in any other population. Jewish-Armenian-Middle East haplotype (A*33-B*65-DRB1*0102-DQB1*0501) is one of the most common haplotypes; this haplotype is also present in Spaniards and North Africans. Quantitatively, Portuguese, North Africans (Algerians), Spaniards and Canary Islanders (in this order) are the most important parental populations to Madeirans. Results are discussed on the basis of the recorded historical peopling which does not show a noticeable African gene input in present-day Madeiran population according to our data; one of the closest related populations found is the Canary Islanders, suggesting that Guanche (Canary Islands first inhabitants) slaves gene flow is still noticed at present, both in Madeira and in Canary Islands populations.

Malignant tumors of intraoral minor salivary glands.

Between 1995 and 2004, 43 patients with intraoral minor salivary gland carcinomas were diagnosed and treated at the Department of Maxillofacial Surgery, University of Parma, Italy. The palate was the most common site of involvement and comprised 53.5% of the cases. Adenoid cystic carcinoma was the most common histological type (60.6%), followed by mucoepidermoid carcinoma (27.9%). All patients were treated with surgery as the primary modality. Neck dissection was performed in 20.9% of patients, and more than half (72.1%) were treated with adjuvant radiation therapy. The range of the follow-up was 24-132 months (mean: 66 months). Of the 43 patients examined in this study, 12 died due to the tumor. Treatment failure was documented in 18 of the 43 patients (41.9%). Disease-free intervals ranged from 1 month to 9 years and 13.9% of the patients had local failure, whereas 25,6% had distant metastases. The survival rates at 2, 5, and 10 years were 90.7%, 71.8%, and 68%, respectively. The local control rates were 93.1% at 2 years and 83.1% at 5 and 10 years. The 2-, 5-, and 10-year rates for freedom from distant relapse were 95.2%, 83.4%, and 57.5%, respectively. The T stage, cervical lymph node metastasis, surgical margin status and perineural invasion were statistically significant to the outcome.

Free and locoregional flap associations in the reconstruction of extensive head and neck defects.

Head and neck surgical defects after oncological resection of advanced carcinoma involving the oral cavity are often composite and involve bone, mucosa, soft tissues and skin. For the most extensive defects, the simultaneous association of two free flaps is the best choice to improve the function of the preserved structures. This procedure is difficult and involves prolonged surgery, therefore it is only possible in selected patients. In some composite head and neck defects the association of free and locoregional flaps seems to be indicated. This study, discusses the use of free and locoregional flap association, focusing on its aesthetic advantages and functional results. From January 1995 to December 2006, 30 patients received simultaneous locoregional and free flap transfer for closure of post-ablative oral cavity defects. Microvascular tissue transfer included the radial forearm, anterolateral thigh, rectus abdominis, and fibula and iliac crest free flaps. Locoregional flaps included the cervicofacial, cervicopectoral, deltopectoral, pectoralis major, latissimus dorsi and posterior scalp flaps. Based on the good functional and aesthetic outcome and low rate of complications, the association of free and locoregional flaps represents a good reconstructive option for patients with extensive post-oncological composite head and neck defects.

[Chronic allograft dysfunction: role of immunosuppressive treatment]. / Disfunzione cronica del trapianto renale (CAD): ruolo della terapia immunosoppressiva.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. In recent years a major improvement has been observed in short-term graft survival, but there has been no corresponding improvement in long-term survival. Chronic allograft dysfunction (CAD) is an anatomical and clinical alteration that can lead to the loss of the transplanted organ without any specific cause. The pathogenesis of CAD, which still remains to be fully clarified, involves both immunological factors (acute rejection, subclincial rejection, HLA mismatches between donor and recipient, noncompliance, etc) and non-immunological factors (marginal donor ischemia/reperfusion injury, infection, cardiovascular risk factors, nephrotoxicity, etc). Immunosuppressive therapy represents one of the strategies for the prevention of CAD. The introduction into clinical practice of novel immunosuppressive agents with no or lower nephrotoxicity, like mycophenolate mofetile, rapamycin and everolimus, will make therapeutic strategies aimed at decreasing the incidence of CAD feasible.

Melatonin decreases the oxidative stress produced by 2,4-dichlorophenoxyacetic acid in rat cerebellar granule cells.

2,4-Dichlorophenoxyacetic acid (2,4-D) is one of the most widely used herbicides due to its relatively moderate toxicity and to its biodegradability in the soil. In toxic concentrations, 2,4-D displays strong neurotoxicity, partly due to generation of free radicals. Since melatonin has remarkable antioxidant properties, the objective of this study was to assess to what extent it was effective in preventing the 2,4-D effect on redox balance of rat cerebellar granule cells (CGC) in vitro. Cellular viability, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), reduced glutathione (GSH) levels, and the activities of the antioxidant enzymes Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, selenium-glutathione peroxidase (Se-GPx) and catalase (CAT) were measured in CGC exposed to 2,4-D and/or melatonin for 48 h. In CGC cultures exposed to 2,4-D, cell viability, GSH levels and CAT activity decreased significantly whereas ROS generation and Se-GPx activities were augmented. Except for Se-GPx activity, all these changes were counteracted by the concomitant addition of 0.1 or 0.5 mM melatonin. In addition, incubation of CGC with melatonin alone resulted in augmentation of cell viability, GSH levels and Se-GPx activity. RNS generation and SOD activity remained unaffected by either treatment. Since melatonin was able to counteract most of redox changes produced by 2,4-D in CGC in culture, the experimental evidence reported further support the efficacy of melatonin to act as a neuroprotector.

HLA Genes in Mayos Population from Northeast Mexico.

HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations' profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies.

The submental island flap in head and neck reconstruction.

The authors describe their experience with the submental island flap for the primary correction of head and neck deformities following oncologic surgery, over the past 5 years. The use of this flap is reported in 12 patients, with a mean age of 67 years, requiring facial or intraoral reconstruction. A brief review of the key points and some refinements in the operative technique are discussed. The reconstruction of defects with a submental island flap was successful in every patient. Complications encountered were one case of temporary palsy of the marginal mandibular branch of the facial nerve and one case of orocutaneous fistula. All the donor site defects were closed primarily. The submental island flap is an excellent choice for the reconstruction of head and neck defects because of its reliability, versatility, colour and texture match, and relative ease of application.

Masseteric nerve for gracilis muscle re-innervation in unilateral facial palsy: Impact on quality of life.

BACKGROUND: Unilateral established or congenital facial palsies are usually treated with neuromuscular transplantation to reanimate the impaired side of the face. One of the most debated points is the motor nerve to choose for the reinnervation of the transplant. Contra-lateral healthy facial nerve is usually preferred, but in selected cases motor nerve to masseter is considered a valuable option. However only a few clinical studies focused on quality of life in this subset of patients are available in literature. METHODS: Twenty patients treated for established or congenital unilateral facial palsy reanimated with gracilis muscle transplant reinnervated with masseteric nerve were retrospectively analyzed. The FDI questionnaire on quality of life was administered before and after surgery and statistical analysis of results was conducted to score changes. RESULTS: Overall results of the questionnaire resulted in a statistically significant improvement after surgery, with a p value of 0.05. CONCLUSION: Facial animation with gracilis muscle transplant re-innervated with masseteric nerve is a safe and reliable procedure in selected unilateral facial palsy patients. Results reported here confirm that surgery mainly improves the functional aspects of a patient's daily life quality, while the impact on social interactions and self-perception is less significant. The comparison of these results with those obtained in patients treated with gracilis muscle transplant re-innervated via contralateral facial nerve suggests that spontaneity is probably highly relevant to improve social aspects of QOL in this subset of patients.

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis.

AIMS: To evaluate the diagnostic significance of anti-filamentous actin antibodies (A-FAA) assessed with a commercial ELISA in comparison with immunofluorescence reactivity and patterns of anti-smooth muscle antibodies (SMA); and to correlate A-FAA positivity with clinical, immunogenetic, laboratory, and histological features in patients with autoimmune hepatitis type 1 (AIH-1). METHODS: We studied 78 consecutive untreated AIH-1 patients and 160 controls: 22 with autoimmune hepatitis type 2 (AIH-2), 51 with hepatitis C, 17 with coeliac disease (CD), 20 with primary biliary cirrhosis (PBC) and 50 blood donors. SMA was evaluated by indirect immunofluorescence (IIF) on frozen sections of rat tissues, and A-FAA with a modified commercial ELISA. RESULTS: SMA was detected by IIF in 61 (78%) of 78 AIH-1 patients, of whom 47 (60%) had the SMA-T/G and 14 (18%) the SMA-V pattern. Of the pathological controls, 32 (20%) had the SMA-V pattern (25 with hepatitis C, 2 with AIH-2, 2 with PBC, 3 with CD). A-FAA were present in 55 AIH-1 patients (70.5%; 46 with SMA-T/G, 7 with SMA-V, and 2 SMA-negative), and in 10 controls (6%), of whom five had hepatitis C, two AIH-2, two PBC and one CD. The association between A-FAA and the SMA-T/G pattern was statistically significant (p<0.0001). A-FAA levels were higher in SMA-T/G positive than SMA-V positive AIH-1 patients and controls (p<0.0001). A-FAA positivity was significantly associated with higher gamma-globulin and IgG levels, but did not correlate with other considered parameters. CONCLUSION: The modified A-FAA ELISA strictly correlates with the SMA-T/G pattern and is a reliable and operator independent assay for AIH-1. Detection of A-FAA, even if devoid of prognostic relevance, may be useful when interpretative doubts of standard IIF arise.

Detection of 2,4-dichlorophenoxyacetic acid in rat milk of dams exposed during lactation and milk analysis of their major components.

2,4-Dichlorophenoxyacetic acid (2,4-D) and its derivatives are herbicides widely used to control the growth of broadleaf and woody plant. Human and animal exposure to 2,4-D through agriculture use, food products, or use in lawn and garden care has been well documented, but little information is available on the transfer from serum to milk in exposed dams. In this study, we measured the content of 2,4-D in rat milk from mother exposed to 15, 25, 50 or 7 0mg 2,4-D/kg bw through the diet (4 treated groups, 8 dam each; 1 control group with 8 dams) over a period of 16 days starting on the post-natal day 1 (PND 1). The effect of 2,4-D on milk components was also evaluated. All doses tested caused a decrease in the body weight gain of the pups (4 groups, 64 pups each). It also produce a 30% in the content of total lipids and a changed the content of minor proteins in milk of the treated groups. 2,4-D produces an important decrease in some fatty acids content, being the polyunsaturated fatty acids the most affected. Further analysis showed that 2,4-D concentrations chromatographically detected both serum of dams and pups and milk were dose-dependent.

Phencyclidine-induced disruption of oscillatory activity in prefrontal cortex: Effects of antipsychotic drugs and receptor ligands.

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP) markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO, <4Hz) that temporarily group neuronal discharge. These actions are mainly driven by PCP interaction with NMDA-R in GABAergic neurons of the thalamic reticular nucleus and likely underlie PCP psychotomimetic activity. Here we report that classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripripazole) antipsychotic drugs--but not the antidepressant citalopram--countered PCP-evoked fall of LFO in the medial prefrontal cortex (mPFC) of anesthetized rats. PCP reduces LFO by breaking the physiological balance between excitatory and inhibitory transmission. Next, we examined the role of different neurotransmitter receptors to reverse PCP actions. D2-R and D1-R blockade may account for classical antipsychotic action since raclopride and SCH-23390 partially reversed PCP effects. Atypical antipsychotic reversal may additionally involve 5-HT1A-R activation (but not 5-HT2A-R blockade) since 8-OH-DPAT and BAYx3702 (but not M100907) fully countered PCP effects. Blockade of histamine H1-R (pyrilamine) and α1-adrenoceptors (prazosin) was without effect. However, the enhancement of GABAA-R-mediated neurotransmission (using muscimol, diazepam or valproate) and the reduction of excitatory neurotransmission (using the mGluR2/3 agonist LY379268 and the preferential kainite/AMPA antagonist CNQX--but not the preferential AMPA/kainate antagonist NBQX) partially or totally countered PCP effects. Overall, these results shed new light on the neurobiological mechanisms used by antipsychotic drugs to reverse NMDA-R antagonist actions and suggest that agents restoring the physiological excitatory/inhibitory balance altered by PCP may be new targets in antipsychotic drug development.