Results of Utilizing Cerclage Wires in the Management of Intraoperative Vancouver B1 Fractures in Primary Total Hip Arthroplasties: A Retrospective Cohort Investigation into Clinical and Radiographic Outcomes.

BACKGROUND: Due to an increase in total hip arthroplasties (THAs), the incidence of periprosthetic hip fractures (PPHFs) is forecast to rise considerably in the next decades, with Vancouver B1 fractures (VB1) accounting for one third of total cases. Femur fixation with cerclages (with or without screws) is considered the current treatment option for intraoperative VB1. METHODS: The study retrospectively includes data from patients who developed VB1 PPHFs during THAs from 3 December 2020 to 30 November 2022. The primary outcome of this study was to identify the reintervention-free survival rate. The secondary aim was to determine clinical and radiographic assessment at follow-up, based on Harris hip score (HHS) and limb length discrepancy (LLD). RESULTS: Thirty-seven patients with a mean age of 60.03 ± 15.49 (22 to 77) years old were included. Overall, the Kaplan-Meier analysis estimated a reoperation-free survival rate of 99% (CI 95%) at 6 months. The mean limb length discrepancy (LLD) improved from -3.69 ± 6.07 (range -27.9 to 2.08) mm to 0.10 ± 0.67 (range -1.07 to 1.20) mm. The mean HHS improved from 42.72 ± 14.37 (range 21.00-96.00) to 94.40 ± 10.32 (range 56.00-100.00). CONCLUSIONS: The employment of cerclage wires represents an effective strategy for handling intraoperative VB1 fractures. Level III retrospective cohort study.

Clinical and Radiographic Outcomes of Hip Revision Surgery and Cerclage Wires Fixation for Vancouver B2 and B3 Fractures: A Retrospective Cohort Study.

BACKGROUND: The number of patients presenting with periprosthetic hip fractures has increased in recent decades. METHODS: Patients who underwent hip revision arthroplasty procedures for Vancouver type B2 and B3 fractures between 2010 and 2021 were included. The primary intended outcome of this study was to determine the reintervention-free survival rate. The secondary intended outcome was to determine clinical and radiographic assessment outcomes at the time of follow-up, and the correlation between time to surgery and postoperative Harris hip score (HHS). RESULTS: A total of 49 patients with mean age of 71.2 ± 2.3 (37-88) years old were included. Overall, the Kaplan-Meier method estimated a survival rate of 95.8% (CI 84.2% to 98.9%) at one year, 91.1% (CI 77.9% to 96.6%) at two years, and 88.5% (CI 74.4% to 95.1%) at three, and up to 10, years. The mean limb length discrepancy (LLD) improved from -13.3 ± 10.5 (range -39 to +10) mm at the preoperative stage to -1.16 ± 6.7 (range -17 to +15) mm, p < 0.001 postoperative. The mean HHS improved from 31.1 ± 7.7 (range 10 to 43) preoperative to 85.5 ± 14.8 (range 60 to 100), p < 0.001 postoperative. Postoperative HHS was not affected by preoperative time to surgery. CONCLUSIONS: Revision arthroplasty is an effective treatment for Vancouver type B2 and B3 fractures.

Using Three-Dimensional Printing Technology to Solve Complex Primary Total Hip Arthroplasty Cases: Do We Really Need Custom-Made Guides and Templates? A Critical Systematic Review on the Available Evidence.

The burden of osteoarthritis (OA) is around 300 million people affected worldwide, with the hip representing a commonly affected joint. Total hip arthroplasty (THA) has been used with notable success as a definitive treatment to improve pain and function in hip OA patients. The recent advent of new technologies, such as 3D printing, has pushed the application of these new concepts toward applications for the well-known THA. Currently, the evidence on the use of 3D printing to aid complex primary THA cases is still scarce. METHODS: An extensive literature review was conducted to retrieve all articles centered on the use of 3D printing in the setting of primary THA. RESULTS: A total of seven studies were included in the present systematic review. Four studies investigated the use of 3D-printed surgical guides to be used during surgery. The remaining three studies investigated the benefit of the use of 3D-printed templates of the pelvis to simulate the surgery. CONCLUSIONS: The use of 3D printing could be a promising aid to solve difficult primary total hip arthroplasty cases. However, the general enthusiasm in the field is not supported by high-quality studies, hence preventing us from currently recommending its application in everyday practice.

Perioperative Complications after Hip and Knee Revision Arthroplasty in the over 80 Years Old Population: A Retrospective Observational Case-Control Study.

BACKGROUND: The number of joint revision arthroplasties has increased in the elderly population, which is burdened by several perioperative risks. METHODS: Patients who underwent hip and knee revision arthroplasty were retrospectively included, and they were divided into two groups by age: <80 years old (Group 1) and ≥80 years old (Group 2). The primary outcome was to compare perioperative complication rates. The secondary outcome was to compare the 30-day, 90-day, and 1-year readmission rates. RESULTS: In total, 74 patients in Group 1 and 75 patients in Group 2 were included. Postoperative anemia affected 13 patients in Group 1 (17.6%) and 25 in Group 2 (33.3%, p 0.027); blood units were transfused in 20 (26.7%) and 11 (14.9%, p 0.076) patients, respectively. In Group 1, two (2.7%) patients reported wound infection. In Group 2, eight (10.7%) patients presented hematomas, and two (2.7%) patients reported dislocations. No significant differences in the two groups were observed for 30-day (p 0.208), 90-day (p 0.273), or 1-year readmission rates (p 0.784). CONCLUSION: The revision arthroplasty procedure in patients over 80 years old is not associated with a higher risk of perioperative complications, or higher readmission rate compared with younger patients undergoing hip and knee revision surgery.

Tantalum Cones for Severe Bone Defects in Revision Knee Arthroplasty: A Minimum 10-Year Follow-Up.

BACKGROUND: Two-to 6-year results of reconstruction of severe bone defects in revision total knee arthroplasty (TKA) with highly porous tantalum cones have been encouraging, but 10-year follow-up is lacking. The purpose of this study was to determine the minimum 10-year results of tantalum cones in revision TKA. METHODS: From 2005 to 2010, 30 consecutive patients (30 knees) underwent revision TKA with the use of cones. All patients were followed clinically and radiographically for a minimum of 10 years. A total of 42 cones (25 tibial and 17 femoral) were used to reconstruct massive bone defects classified as Anderson Orthopaedic Research Institute Types 2A (10), 2B (12), and 3 (19). The mean age of the patients was 73 years (range, 55 to 84) at the time of revision. The indication for the revision included aseptic loosening (15 patients) and second-stage reimplantation for deep infection (15 patients). Six patients were lost to follow-up. RESULTS: In total, 6 cones had to be revised. Minimum 10-year cone survivorship for any reason was 81% (25 of 31 cones). With cone revision for aseptic loosening as the end point, survivorship was 96% (30 of 31). No evidence of loosening or migration of any implant was noted on the most recent radiographs. CONCLUSION: Metaphyseal fixation with tantalum cones in revision TKA demonstrated excellent survivorship and fixation at a minimum follow-up of 10 years. This type of metaphyseal reconstruction can be a durable option for revision TKA in patients who have massive bone defects.

Short-Term Survivorship of 3D-Printed Titanium Metaphyseal Cones in Revision Total Knee Arthroplasty: A Systematic Review.

Background: Several studies have evaluated the outcomes of tantalum cones in revision knee arthroplasty with moderate-to-severe metaphyseal bone defects. However, recent innovations have led to the development of 3-D printed titanium cones to better adapt to host bone, there remains no consensus on their overall performance. Objective: We therefore performed a systematic review of the literature to examine short-term survivorship and complication rates of their usage in revision TKAs. Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of PubMed, MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews was conducted for English articles using various combinations of keywords. Results: In all, 7 articles met the inclusion criteria. A total of 687 cones were implanted in 557 revision TKAs. The all-cause revision-free survivorship of the implants was 95.3% (26 revisions), and of the cones was 95.5% (31 cones revised) at mean 24 months follow-up. The cones revision-free survivorship from aseptic loosening was 99.7%. The overall complication rate was 19.7% with infection as the most common complications observed and the most frequent reason for revision with an incidence of 10.4% and 4.1%, respectively. Overall, functional outcomes improved as documented by postoperative knee scores. Conclusion: 3-D printed metal cones represent a reliable option in metaphyseal bone defects reconstruction that provides high fixation, good short-term survivorship, and complications rates in line with similar devices. In addition, they are associated with lower intraoperative complications, and higher survivorship from aseptic loosening.

Survivorship and clinical outcomes of proximal femoral replacement in non-neoplastic primary and revision total hip arthroplasty: a systematic review.

BACKGROUND: Several studies have evaluated the survivorship and clinical outcomes of proximal femoral replacement (PFR) in complex primary and revision total hip arthroplasty with severe proximal femoral bone loss; however, there remains no consensus on the overall performance of this implant. We therefore performed a systematic review of the literature in order to examine survivorship and complication rates of PFR usage. METHODS: A systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A comprehensive search of PubMed, MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews was conducted for English articles using various combinations of keywords. RESULTS: In all, 18 articles met the inclusion criteria. A total of 578 PFR were implanted. The all-cause reoperation-free survivorship was 76.6%. The overall complication rate was 27.2%. Dislocation was the most common complication observed and the most frequent reason for reoperation with an incidence of 12.8 and 7.6%, respectively. Infection after PFR had an incidence of 7.6% and a reoperation rate of 6.4%. The reoperation rate for aseptic loosening of the implant was 5.9%. Overall, patients had improved outcomes as documented by postoperative hip scores. CONCLUSION: PFR usage have a relatively high complication rate, however, it remains an efficacious treatment option in elderly patients with osteoporotic bone affected by severe proximal femoral bone loss. Modular designs have shown reduced dislocations rate and higher survivorship free from dislocation. However, PFR should only be used as salvage procedure when no other reconstruction options are available.

Mid-term survivorship and clinical outcomes of the medial stabilized systems in primary total knee arthroplasty: A systematic review.

INTRODUCTION: Medial Pivot Total Knee Arthroplasty was introduced in clinical practice in 1990s to reproduce the in vivo-natural knee kinematics. This design is characterized by an asymmetric constraint profile, with aa highly congruent medial compartment, and a less congruent lateral compartment. Short-term outcomes of the medial pivot systems in primary knee arthroplasty have been widely reported in the current literature, however, only few studies have described results beyond 5-year follow-up. OBJECTIVES: The primary objectives of this systematic review of the literature is to analyze the mid-term studies on medial pivot total knee arthroplasty focusing on the reoperation rate, survivorship and clinical outcome scores. METHODS: The US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews were queried for publications from January 1980 to December 2019 utilizing the following keywords: "medial pivot", "medial stabilized", "medial rotating", "medial congruent", medial ball and socket", "arthroplasty", "TKA", "TKR", and "knee surgery". RESULTS: 18 articles met the inclusion criteria for the present study. The average quality was 11.4 for non-comparative studies and 21.7 for comparative studies based on MINORS criteria. A total 2832 knee arthroplasties were included for the final analysis with an average age of 69 years, and an average follow-up of 8.1 years (minimum 5 years). The overall reoperation rate was 2.4%, with periprosthetic joint infection as the leading cause of revision in 0.9% of cases, followed by aseptic loosening in 0.4% of cases. The average Knee Society Score improved to a mean preoperative score of 40.1 to a mean postoperative score of 89.2. The functional knee society score improved from a mean preoperative score of 44.8 to an average postoperative score of 82.9. The global range of motion improved from 104.8° preoperatively to 115.6° postoperatively. CONCLUSION: We found that medial pivot system in primary total knee arthroplasty provide overall mid-term survivorship comparable to other standard implasnts. In addition, medial pivot system is associated with better high-end function compared to standard implants.

Reconstruction options and outcomes for acetabular bone loss in revision hip arthroplasty.

Revision total hip arthroplasty in the setting of acetabular bone loss is a challenging procedure and requires a solid understanding of current acetabular reconstruction options. Despite major developments in the field of revision hip surgery in recent decades, reconstruction of acetabular defects remains a major problem in order to achieve primary stability and durable fixation without sacrificing additional bone stock. Although there are several ways to classify acetabular bone defects, the Paprosky classification system is the most commonly used to describe the defects and guide treatment strategy. An understanding of the bone defects associated with detailed pre-operative assessment and planning are essential elements in order to achieve satisfactory outcomes. Multiple acetabular reconstructive options are currently available including impaction bone grafting with metal mesh, reinforcement rings and antiprotrusio cage, structural allografts, cementless hemispherical cups, extra-large "jumbo cups", oblong cups, modular porous metal augments, cup-cage constructs, custom- made triflange cups, and acetabular distraction. To date, debate continues as to which technique is most effective due to the lack of long-term studies of modern reconstruction systems. Further long-term studies are necessary to assess the longevity of the different implants. The purpose of this study was to review the current literature and provide a comprehensive understanding of the available reconstruction options with their clinical outcomes.

What are the benefits of robotic-assisted total knee arthroplasty over conventional manual total knee arthroplasty? A systematic review of comparative studies.

Total knee arthroplasty (TKA) is a highly successful operation that improves patients' quality of life and functionality. Yet, up to 20% of TKA patients remain unsatisfied with the functional outcomes. Robotic TKA has gained increased attention and popularity in order to improve patient satisfaction and implant survivorship by increasing accuracy and precision of component implantation. The current systematic review was run in order to compare implant survivorship, complication rates, clinical outcomes, and radiological outcomes between robotic-assisted TKA (RA) and conventional manual TKA (CM). Articles were referenced from the US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews. Nine comparative studies with 1199 operated knees in 1159 patients were included, 614 underwent active or semiactive robotic-assisted TKA compared to 585 CM-TKA. Improvements in the RA group were reported for early functional outcomes, radiographic outliers (RA 16% vs CM 76%) and radiolucent lines (RA 0% vs CM 35%). No significant differences between the two groups were reported in overall survivorship (RA 98.3% vs CM 97.3%), complication rate (RA 2.4% vs CM 1.4%) and operative time (RA 88 min vs CM 79 min). Despite higher costs, roboticassisted TKA offers better short-term clinical outcomes when compared to conventional manual technique with reduction in radiographic outliers and reduced risks of iatrogenic soft tissues injuries (reduced blood loss and postoperative drainage). Further high-quality long-term studies of modern robotic systems are required in order to evaluate how the increased accuracy and reduced outliers affect the long-term survivorship of the implants and the clinical outcomes.

Surgical implications of the hip-spine relationship in total hip arthroplasty.

Total hip arthroplasty (THA) is considered the most successful orthopedic surgical procedure of the last century with excellent survivorship up to 20-years. However, instability remains a major issue representing the most common reason for revision after THA. Hip-spine relationship has gained progressive interest between arthroplasty surgeons and its understanding is crucial in order to identify high-risk patients for postoperative dislocation. Spinal deformity and abnormal spinopelvic mobility have been associated with increased risk for instability, dislocation and revision THA. Preoperative workup begins with standing anteroposterior pelvis x-ray and lateral spinopelvic radiographs in the standing and sitting position. Hip-spine stiffness needs to be addressed before THA in consideration of adapting the preoperative planning to the patient's characteristics. Acetabular component should be implanted with different anteversion and inclination angles according to the pattern of hip-spine motion in order to reduce the risk of impingement and consequent dislocation. Different algorithmic approaches have been proposed in case of concomitant hip-spine disease and in case of altered sagittal balance and pelvic mobility. The aim of this review is to investigate and clarify the hip-spine relationships and evaluate the impact on modern total hip arthroplasty.

Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain.

The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.

Filosofia e liberdade: o desafio da psicanálise(AU) / Philosophy and liberty: the challenge of psychoanalysis

O texto analisa as relações e as implicações da questão da liberdade com a do inconsciente psicanalítico. Num primeiro momento, é registrado o evento de Bonneval (1960) quando o tema do inconsciente foi objeto de reflexão entre psiquiatras, psicanalistas e filósofos franceses. Em seguida, são apresentadas algumas perspectivas para se repensar os limites e a possibilidade da liberdade humana dentro da atual conjuntura cultural.(AU)

The text analyzes relations and implications of the question of freedom with the psychoanalytic unconscious. At first, is recorded the event in Bonneval (1960) when the issue of the unconscious was the object of discussion between psychiatrists, psychoanalysts and French philosophers. Then, some perspectives to rethink the limits and the possibility of human freedom within the current cultural context are presented.(AU)

Bioethanol production from steam-pretreated corn stover through an isomerase mediated process.

Agricultural by-products such as corn stover are considered strategic raw materials for the production of second-generation bioethanol from renewable and non-food sources. This paper describes the conversion of steam-pretreated corn stover to ethanol utilising a multi-step process including enzymatic hydrolysis, isomerisation, and fermentation of mixed hydrolysates with native Saccharomyces cerevisiae. An immobilised isomerase enzyme was used for the xylose isomerisation along with high concentrations of S. cerevisiae. The objective was to assess the extent of simultaneity of the various conversion steps, through a detailed analysis of process time courses, and to test this process scheme for the conversion of lignocellulosic hydrolysates containing several inhibitors of the isomerase enzyme (e.g. metal ions, xylitol and glycerol). The process was tested on two types of hydrolysate after acid-catalysed steam pretreatment: (a) the water soluble fraction (WSF) in which xylose was the largest carbon source and (b) the entire slurry, containing both cellulose and hemicellulose carbohydrates, in which glucose predominated. The results indicated that the ethanol concentration rose when the inoculum concentration was increased in the range 10-75 g/L. However, when xylose was the largest carbon source, the metabolic yields were higher than 0.51g(ethanol)/g(consumed) sugars probably due to the use of yeast internal cellular resources. This phenomenon was not observed in the fermentation of mixed hydrolysates obtained from the entire pretreated product and in which glucose was the largest carbon source. The ethanol yield from biomass suspensions with dry matter (DM) concentrations of 11-12% (w/v) was 70% based on total sugars (glucose, xylose, galactose). The results suggest that xylulose uptake was more effective in mixed hydrolysates containing glucose levels similar to, or higher than, xylose. Analysis of the factors that limit isomerase activity in lignocellulosic hydrolysates excluded any inhibition due to residual calcium ions after the detoxification of the hemicellulose hydrolysates with Ca(OH)2. By contrast, most of the enzyme activity ceased during the fermentation of the entire slurry after steam explosion, probably due to synergistic inhibition effects of various fermentation co-products.

5-HT2 receptors-mediated modulation of voltage-gated K+ channels and neurophysiopathological correlates.

The activity of voltage-gated K(+) channels (Kv) can be dynamically modulated by several events, including neurotransmitter stimulated biochemical cascades mediated by G protein-coupled receptors such as 5-HT2 receptors (5-HT2Rs). Activation of 5-HT2A/CR inhibits the Shaker-like K(+) channels Kv1.1 and Kv1.2, and this modulation involves the dual coordination of both RPTPα and distinct tyrosine kinases coupled to this receptor; 5-HT2Rs-mediated modulation of Kv channels controls glutamate release onto prefrontal cortex neurons that might play critical roles in neurophysiological, neurological, and psychiatric conditions. Noticeably, hallucinogens modulate Kv channel activity, acting at 5-HT2R. Hence, comprehensive knowledge of 5-HT2R signaling through modulation of distinct K(+) channels is a pivotal step in the direction that will enable scientists to discover novel 5-HT functions and dysfunctions in the brain and to identify original therapeutic targets.

Morphological and metabolic changes in the nigro-striatal pathway of synthetic proteasome inhibitor (PSI)-treated rats: a MRI and MRS study.

Systemic administration of a Synthetic Proteasome Inhibitor (PSI) in rats has been described as able to provide a model of Parkinson's disease (PD), characterized by behavioral and biochemical modifications, including loss of dopaminergic neurons in the substantia nigra (SN), as assessed by post-mortem studies. With the present study we aimed to assess in-vivo by Magnetic Resonance (MR) possible morphological and metabolic changes in the nigro-striatal pathway of PSI-treated rats. 10 animals were subcutaneously injected with PSI 6.0 mg/kg dissolved in DMSO 100%. Injections were made thrice weekly over the course of two weeks. 5 more animals injected with DMSO 100% with the same protocol served as controls. The animals underwent MR sessions before and at four weeks after the end of treatment with either PSI or vehicle. MR Imaging was performed to measure SN volume and Proton MR Spectroscopy ((1)H-MRS) was performed to measure metabolites changes at the striatum. Animals were also assessed for motor function at baseline and at 4 and 6 weeks after treatment. Dopamine and dopamine metabolite levels were measured in the striata at 6 weeks after treatment. PSI-treated animals showed volumetric reduction of the SN (p<0.02) at 4 weeks after treatment as compared to baseline. Immunofluorescence analysis confirmed MRI changes in SN showing a reduction of tyrosine hydroxylase expression as compared to neuron-specific enolase expression. A reduction of N-acetyl-aspartate/total creatine ratio (p = 0.05) and an increase of glutamate-glutamine-γ amminobutirrate/total creatine were found at spectroscopy (p = 0.03). At 6 weeks after treatment, PSI-treated rats also showed motor dysfunction compared to baseline (p = 0.02), accompanied by dopamine level reduction in the striatum (p = 0.02). Treatment with PSI produced morphological and metabolic modifications of the nigro-striatal pathway, accompanied by motor dysfunction. MR demonstrated to be a powerful mean to assess in-vivo the nigro-striatal pathway morphology and metabolism in the PSI-based PD animal model.

Nitric oxide modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders.

Several recent studies have emphasized a crucial role for the nitrergic system in movement control and the pathophysiology of the basal ganglia (BG). These observations are supported by anatomical evidence demonstrating the presence of nitric oxide synthase (NOS) in all the basal ganglia nuclei. In fact, nitrergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high expression of nitric oxide (NO)-producing neurons, with the striatum having the greatest number, together with important NO afferent input. In this paper, the distribution of NO in the BG nuclei will be described. Furthermore, evidence demonstrating the nitrergic control of BG activity will be reviewed. The new avenues that the increasing knowledge of NO in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. For example, inhibition of striatal NO/guanosine monophosphate signal pathway by phosphodiesterases seems to be effective in levodopa-induced dyskinesia. However, the results of experimental studies have to be interpreted with caution given the complexities of nitrergic signalling and the limitations of animal models. Nevertheless, the NO system represents a promising pharmacological intervention for treating Parkinson's disease and related disorders.

Role of serotonin in central dopamine dysfunction.

The interaction between serotonin (5-HT) and dopamine (DA)-containing neurons in the brain is a research topic that has raised the interest of many scientists working in the field of neuroscience since the first demonstration of the presence of monoamine-containing neurons in the mid 1960. The bulk of neuroanatomical data available clearly indicate that DA-containing neurons in the brain receive a prominent innervation from serotonin (5-hydroxytryptamine, 5-HT) originating in the raphe nuclei of the brainstem. Compelling electrophysiological and neurochemical data show that 5-HT can exert complex effects on the activity of midbrain DA neurons mediated by its various receptor subtypes. The main control seems to be inhibitory, this effect being more marked in the mesocorticolimbic DA system as compared to the DA nigrostriatal system. In spite of a direct effect of 5-HT by its receptors located on DA cells, 5-HT can modulate their activity indirectly, modifying gamma-aminobutyric (GABA)-ergic and glutamatergic input to the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Although 5-HT/DA interaction in the brain has been extensively studied, much work remains to be done to clarify this issue. The recent development of subtype-selective ligands for 5-HT receptors will not only allow a detailed understanding of this interaction but also will lead to the development of new treatment strategies, appropriate for those neuropsychiatric disorders in which an alteration of the 5-HT/DA balance is supposed.

Critical role of nitric oxide on nicotine-induced hyperactivation of dopaminergic nigrostriatal system: Electrophysiological and neurochemical evidence in rats.

Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose-dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N-omega-nitro-l-arginine methyl ester (l-NAME) and 7-nitroindazole (7-NI) were both capable of blocking the nicotine-induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l-NAME and 7-NI-pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions.

Involvement of nitric oxide in nigrostriatal dopaminergic system degeneration: a neurochemical study .

The present study was undertaken to explore the involvement of nitric oxide (NO) in the 6-hydroxydopamine (6-OHDA) experimental model of Parkinson's disease (PD) in rats. The effect of pharmacological manipulation of the NO system was evaluated on striatal dopamine (DA) level decrease produced by the toxin. 7-nitroindazole (7-NI, 50 mg/kg i.p.; n= 5) pretreatment significantly restored the striatal DA contents. Conversely, 40 mg/kg i.p. of molsidomine (MOL, n= 5), an NO donor, significantly worsened the neurodegeneration (n= 5) and completely counteracted the neuroprotective effect of 7-NI (n= 5). Thus, a crucial role for NO in 6-OHDA induced neurodegeneration is suggested together with a protective benefit for inhibitors of NOS in the treatment of PD.