Enhanced recovery after surgery (ERAS) in hip and knee replacement surgery: description of a multidisciplinary program to improve management of the patients undergoing major orthopedic surgery.

PURPOSE: Enhanced recovery after surgery (ERAS) protocols aim to develop peri-operative multidisciplinary programs to shorten length of hospital stay (LOS) and reduce complications, readmissions and costs for patients undergoing major surgery. The aim of this study is to evaluate the effects of an ERAS pathway for total hip (THR) and knee (TKR) replacement surgery in terms of length of stay, incidence of complications and patient satisfaction. METHODS: Patients scheduled for hip and knee replacement were included in the study. The main aspects of this program were preoperative education/physical therapy, rational choice of the anesthetic technique, optimization of multimodal analgesia, reduction of incidence of urinary retention and catheterization, active management of risk for blood loss and deep vein thrombosis, and early mobilization of the patients. All patients had 6 months predicted and planned follow-up appointments. Primary outcomes of the study were the mean LOS, readmission and complication rates. Secondary Outcomes were percentage of Knee Injury & Osteoarthritis Outcome Score (KOOS) and Hip disability and Osteoarthritis Outcome Score (HOOS) increase and patient's satisfaction. RESULTS: We consecutively enrolled 207 patients who underwent total joint arthroplasty, 78 hip and 129 knee joint replacements. The mean length of stay (LOS) for patients of the two groups was 4.3 days for ASA 3-4 patients subjected to TKR and THR, in ASA 1-2 patients 3.6 days for TKR and 3.9 days for THR respectively. Postoperative satisfaction level was higher than 7 (very satisfied) in 94.4% of the cases. All patients were discharged home: 61.8% continued physical therapy in complete autonomy, 23.7% supported by a home-physiotherapist and only 14.5% needed the attendance to a physiotherapy center on a daily basis. The overall incidence of major complications was 3.4%. CONCLUSIONS: The implementation of an ERAS program for hip and knee replacement surgery allows early patient's discharge and a quick return to independency in the daily activities. LEVEL OF EVIDENCE: IV.

Quadriceps muscles activity during gait: comparison between PFPS subjects and healthy control.

PURPOSE: The purpose of the study was to evaluate if during a common activity as walking, altered quadriceps muscular activity may be present in patellofemoral pain syndrome (PFPS) patients. METHODS: Forty subjects with clinically diagnosed PFPS and forty healthy males matching in age, weight, height and level of sport activity were enrolled in the study. Subjects were asked to walk on an instrumented walking path at their self-selected speed. Force platform and motion tracking system were used for the analysis of the gait. Wireless surface EMG probes were used to evaluate quadriceps muscles activity. Rectus femoris, vastus medialis and lateralis activity percentage, onset and offset time, walking speed, cadence, step length, stride length, knee ROM during gait were measured and reported. Tegner activity questionnaire was reported. RESULTS: Patient group showed a significant increasing in all quadriceps muscles activity when compared to the control (p < 0.05). In particular, for VM and VL muscle onset time was anticipated and offset time was postponed in PFPS group when compared with healthy group (p < 0.05). Knee range of motion during walking was significantly decreased in the patient group. CONCLUSIONS: Young athletes with PFPS showed increased length of quadriceps muscles activity and reduced functional knee Rom while walking, comparing with healthy subjects, in particular muscular onset was anticipated in respect of the loading response event of the gait. Nonetheless, walking parameters were not affected by these alterations.

Serologic and radiographic outcome of total hip arthroplasty with CoCr modular neck at mid-term follow-up.

PURPOSE: The aim of this study is a radiographic evaluation and to determine serologic values of chromium and cobalt in the blood and urine of patients who have been implanted with a Stryker® ABG II Modular Neck and see if there is correlation with the features of prosthesis and patients. METHODS: The study involves the collection of data from patients operated on for total hip model with the ABG II Modular Neck with a minimum follow-up of 1 year. RESULTS: We evaluated 22 patients who underwent implantation of a hip prosthesis with modular neck in CoCr. Of these, the average Cr in the blood was 0.63 µgL-1 (range 0.1-2.15 µgL-1), the average of Co in the blood was 3.50 µgL-1 (range 0.62-7.78 µgL-1), the average Cr in the urine was 1.24 µgL-1 (range 0.48-2.21 µgL-1), and the average Co in urine was 14.22 µgL-1 (range 3.3-31.2 µgL-1). None of these patients had undergone revision surgery. CONCLUSIONS: Our study seems to indicate that the restoration of offset and age are correlated with the release of metal ions, although the correlation is weak and needs better methodological studies and a greater number of patients to confirm this hypothesis. STUDY TYPE: Case series Level of Evidence 4.

Reconstruction of medial patello-femoral ligament: Comparison of two surgical techniques.

The medial patello-femoral ligament is considered the most important passive patellar stabilizer and its proper functionality is essential for the patello-femoral joint stability. In this work, 18 human knees were randomly divided into two groups and reconstructed through two different surgical techniques: the "Through tunnel tendon" and the "Double converging tunnel" reconstructions. Subsequently, the samples were mechanically tested to evaluate the structural properties of reconstructed femur-MPFL-Patella complex (rFMPC). Particular attention was given to maintain the anatomical orientation between the patella and the graft. Both procedures showed lower stiffness and higher ultimate strain and absorbed energy compared to the native MPFL, but the advantages of the double converging tunnel technique are related to the restoration of the native MPFL sail-shape, to a better stress distribution on the patella, to the use of a single interference screw as fixation device and to the simplicity, rapidity and cost-effectivity of the surgical procedure. The evaluation of the structural properties of rMPFL is fundamental to evaluate the adequacy of the different techniques to restore the physiological structural properties of the native MPFL.

Biomechanical evaluation of medial patello-femoral ligament reconstruction: comparison between a double-bundle converging tunnels technique versus a single-bundle technique.

BACKGROUND: Several MPFL reconstructions are commonly performed for recurrent patellar dislocation, but misleading data are currently available in the literature on the ability of the different techniques to re-create a functioning ligament. MATERIALS AND METHODS: In this study, we showed the biomechanical properties of two different procedures for MPFL reconstruction using a natural orientation during uniaxial tensile testing. Eighteen fresh-frozen human knees were randomly assigned to two groups of nine each. In the group A, the reconstruction was performed using a double converging tunnels technique and in the group B was used a single-tunnel technique with semitendinosus autograft. The specimens were loaded in natural orientation using an Instron tensile test machine, and the stiffness and ultimate load were determined. RESULTS: The ultimate load was 213 ± 90 and 171 ± 51 N using our double-bundle technique (group A) and the single-bundle technique (group B), respectively. One (11 %) specimen failed at the patellar side due to patellar fracture in the group B. There was no statistical significant difference (p > 0.05) between the two groups in terms of stiffness and ultimate load. CONCLUSION: This study is the first biomechanical evaluation of the MPFL reconstructions in natural orientation. Both the procedures achieved safe fixation of the graft at the femoral attachment; however, the single-bundle technique reported 11 % of failure at the patellar side due to patellar fracture. In addition, the double-bundle technique can better restore the anatomy of the native ligament.

Diagnostic value of the clinical investigation in acute meniscal tears combined with anterior cruciate ligament injury using arthroscopic findings as golden standard.

INTRODUCTION: The main purpose of our study was to evaluate the accuracy of clinical investigation for meniscal tears associated with ACL injuries. We hypothesized that combined ACL injury can decrease the accuracy of clinical examination in acute onset. MATERIALS AND METHODS: One hundred and thirty-seven patients with a mean age of 28.5 years (from 12 to 55) were prospectively examined for acute combined ACL and meniscal injuries, between March and November 2012 at our department. For meniscal tears, clinical examination was performed using McMurray test, Apley test and medial and lateral joint line tenderness. The diagnoses of ACL tear were made using Lachman test, jerk test and pivot-shift test, anterior drawer test and KT-2000 side-to-side difference. Each patient was examined using X-ray and MRI. All the patients underwent arthroscopic surgery performed by the same surgeon within 6 weeks after the injury. Finally, using the arthroscopic findings as gold standard, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of clinical investigation and MRI were evaluated. RESULTS: The specificity of clinical investigation was 63.5 and 46.0 % and the sensitivity was 74.4 and 77.3 % for the medial meniscus and the lateral meniscus, respectively. Overall, the accuracy of the clinical investigation was 70.3 % for the MM and 65.5 % for the lateral meniscus. The accuracy of MRI investigation was 76.4 and 69.5 % for medial and lateral meniscus, respectively. DISCUSSION: In combined acute ACL injury and meniscal tears, we have found a decreased accuracy of the clinical investigation. The remnants of the torn ACL and the synovitis increased the rate of false positives, and it could simulate meniscal tears. However, clinical investigation can provide sufficient information for the treatment decision and MRI can be avoided as a routine diagnostic tool. LEVEL OF EVIDENCE: Level II, prospective study.

Kyphoplasty vs conservative treatment: a case-control study in 110 post-menopausal women population. Is kyphoplasty better than conservative treatment?

OBJECTIVE: Osteoporosis is a highly prevalent disease worldwide. Consequences of vertebral osteoporotic fractures include pain and progressive vertebral collapse resulting in spinal kyphosis, decreased quality of life, disability and mortality. Minimally invasive procedures represent an advance to the treatment of osteoporotic VCFs. Despite encouraging results reported by many authors, surgical intervention in an osteoporotic spine is fraught with difficulties. Advanced patients age and comorbidities are of great concern. PATIENTS AND METHODS: We designed a retrospective case-control study on 110 post-menopausal women consecutively visited at our institution. Study population was split in a surgical and a conservative cohort, according to the provided treatment. RESULTS: Kyphoplasty treated patients had lower back pain VAS scores at 1 month as compared with conservatively treated patients (p < 0.05). EQ5D validated questionnaire also showed a better quality of life at 1 month for surgically treated patients (p < 0.05). SF-12 scores showed greater improvements at 1 month and 3 months with statistically significant difference between the two groups just at 3 months (p < 0.05). At 12 months, scores from all scales were not statistically different between the two cohorts, although surgically treated patients showed better trends than conservatively treated patients in pain and quality of life. Kyphoplasty was able to restore more than 54.55% of the original segmental kyphosis, whereas patients in conservative cohort lost 6.67% of the original segmental kyphosis on average. CONCLUSIONS: Kyphoplasty is a modern minimal invasive surgery, allowing faster recovery than bracing treatment. It can avoid the deformity in kyphosis due to VCF. In fact, the risk to develop a new vertebral fracture after the first one is very high.

Chondropenia: current concept review.

The term "chondropenia" indicates the early stage of degenerative cartilage disease, and it has been identified by carefully monitoring early-stage osteoarthritis (OA). Not only is it the loss of articular cartilage volume, but it is also a rearrangement of biomechanical, ultrastructural, biochemical and molecular properties typical of healthy cartilage tissue. Diagnosing OA at an early stage or an advanced stage is valuable in terms of clinical and therapeutic outcome. In fact degenerative phenomena are supported by a complex biochemical cascade which unbalances the extracellular matrix homeostasis, closely regulated by chondrocytes. In the first stage an intense inflammatory reaction is triggered: pro-catabolic cytokines such as IL-1ß and TNF-α triggering matrix metalloproteases and aggrecanase (ADAMT-4 and 5), responsible for the early loss of ultrastructural components, such as type II collagen and aggrecan. In addition nitric oxide and reactive oxygen species modulate the physiopathology of the condral matrix inducing apoptosis of chondrocytes through a mitochondria-dependent pathway. In addition, "Lonely Death": chondrocytes, are confined within a dense, avascular extracellular matrix capsule, and can trigger a genetically induced apoptosis and necrosis. The degenerative process starts from a central point and then spreads in a centrifugal manner in depth and in adjacent areas, eventually covering the whole joint; chondropenia represents a journey from the first clinically detectable time-point until it can be characterized as frank osteoarthritis. Currently, there are no instruments sensitive enough which allow a timely diagnosis of chondropenia. Innovative magnetic resonance imaging techniques, such as T2 mapping, can be effective and a sensitive diagnostic instrument for quantifying cartilage volume and proteoglycan content. However, avant-garde biophysical techniques, such as mechanical indenters, ultrasound and biochemical markers (uCTX-II), are rational and scientific tools applicable to the clinical and therapeutic management of early degenerative cartilage disease. The objective of this review on chondropenia is to present a state of the art and innovative concepts.

Degenerative facet joint changes in lumbar percutaneous pedicle screw fixation without fusion.

BACKGROUND: Aim of the study was to evaluate degenerative lumbar facet-joints changes after percutaneous pedicle screw fixation (PPSF) in the treatment of lumbar fractures. MATERIALS AND METHODS: Thirty patients underwent short PPSF without fusion. CT-scan was performed in the pre- and post-operative time at four, eight and 12 months. The six zygapophyseal joints adjacent the fracture's level were evaluated. RESULTS: At four months patients showed no differences between pre- and post-operative joint radiographic aspect. At eight and 12 months, CT-scan demonstrated a progressive degeneration only in the middle joints respectively in 21.42% and in 76.92% of the cases. All 10 disrupted facet joints showed progressive degenerative changes at eight and 12 months. CONCLUSION: Lumbar percutaneous fixation without fusion induces little degenerations essentially collocated in the middle joints close to fracture level at eight and 12 months. In the proximal and distal joints adjacent the screws degenerative changes can be seen only when associated to pedicle-screw encroachment.

Anatomy of the Medial Patello-Femoral Ligament: a systematic review of the last 20 years literature.

BACKGROUND: Although many studies have investigated the anatomy of the Medial Patello-Femoral Ligament (MPFL), some studies have even questioned its existence. In the last 20 years, there is a renewed interest on the role of the MPFL in patello-femoral instability. As a result, several studies have been published that describe the anatomy, function and possible surgical reconstruction of the MPFL. Despite the large amount of literature produced, there is still a lack of consensus on what is its real anatomy as there are currently no systematic reviews on this topic. PURPOSES: Thus, the aim of this review is to systematically report the results in literature regarding in anatomical papers, the existence, size, insertion sites and relationships of this ligament with the other medial structures of the knee. METHODS: We have systematically analyzed anatomical studies currently available in literature between 1980 and December 2012. The search was carried out on Medline, Embase, Cochrane Library and Google Scholar. We checked reference lists of articles, reviews and textbooks identified by the search strategy for other possible relevant studies. RESULTS: The outcomes examined are the presence of the ligament, its size (length, width, thickness), and its patellar and femoral insertions. A total of 312 cadaveric knees were included in the 17 studies; the MPFL was identified in 99% of cases (309). CONCLUSIONS: The consensus is that the MPFL is almost always present in the dissected knees. The size and insertions of the ligament demonstrate great variation between cadavers. LEVEL OF EVIDENCE: Systematic review of anatomical study, Level 1.

Relationship between serotonin and mast cells: inhibitory effect of anti-serotonin.

Serotonin (5-HT) is an important neurotransmitter that acts in both central and peripheral nervous system, and has an impact on cell proliferation, migration and apoptosis. 5HT exerts its effects via several receptors. Treatment with anti-5-HT receptors diminish the severity of contact allergy in experimental animals, an effect mediated by mast cells; while an agonist reduces the stress level and relieves pruritus in patients with atopic dermatitis. Mast cells are important for both innate and adaptive immunity and they are activated by cross-linking of FceRI molecules, which are involved in the binding of multivalent antigens to the attached IgE molecules, resulting in a variety of responses including the immediate release of potent inflammatory mediators. Serotonin is present in murine mucosal mast cells and some authors reported that human mast cells may also contain serotonin, especially in subjects with mastocytosis. Here we report the interrelationship between mast cells, serotonin and its receptor inhibitor.

Shape and size of the medial patellofemoral ligament for the best surgical reconstruction: a human cadaveric study.

PURPOSE: The aim of this study was to investigate the shape and the attachments of the medial patellofemoral ligament (MPFL) in cadaver specimens to determine an anatomical basis for the best MPFL reconstruction. METHODS: Twenty fresh-frozen knees were used. Dissection protocol implied performing dissections from within the knee joint. We investigated the shape and the attachments between the MPFL and the quadriceps tendon, the patellar and femur insertions, and all the other relationships with the medial soft tissues of the knee. RESULTS: The distal fibers of MPFL were interdigitated with the deep layer of the medial retinaculum. All isolated ligament had a sail-like shape with the patellar side bigger than the femoral side. The femoral insertion, distinct both from medial epicondyle and adductor tubercle, was located at 9.5 mm (range 4-22) distal and anterior respect to adductor tubercle and proximal and posterior to epicondyle. The medial third of the thickness of patella was involved in the insertion. The proximal third of the patella is always involved in the MPFL attachment; in 45% of the cases, it was extended to the medial third and in one case, an extension at the distal third was found. Additionally in 35% (7 cases), it extended to the quadriceps tendon and it were inconstantly attached at the vastus medialis obliques (VMO) tendon and at the vastus intermedius (VI) tendon in an aponeurotic structure. CONCLUSIONS: The MPFL is a distinct structure that goes from patella to femur with a sail-like shape; its patellar insertion, that mostly occur via an aponeurosis tissue with VMO and VI, is at the proximal third of the patella but it may extend in some cases to the medial third patella or to the quadriceps tendon, or very rarely to the distal third of the patella. In the femoral side, the MPFL is inserted in its own site, in most cases distinct both from epicondyle and adductor tubercle, located on average at a 9.5 mm distance distally and anteriorly in respect to the adductor tubercle. Its lower margin was difficult to define. Given the importance of this structure, it must be reconstructed as anatomically as possible in its insertion and in its shape. Many attempts have been made to make functional reconstructions with less than excellent results.

Interrelationship between IL-3 and mast cells.

It is well established that mast cells, which are found in the tissues in the proximity of small blood vessels and post-capillary venules, play a key role in the early phase of IgE-mediated allergic reactions. A greatly expanded understanding of the biology of IL-3 has emerged since the early 1980s. IL-3 is a specific factor that stimulates the growth of hematopoietic stem and progenitor cells of a variety of lineages and can promote the proliferation of certain classes of lymphocytes distinct from those that are dependent on IL-2. IL-3 has been identified among the most important cytokines for regulation of mast cell growth and differentiation, migration and effector function activities of many hematopoietic cells. IL-3 termed multi colony-stimulating-factor (multi-CSF) or mast cell growth factor (MCGF) is a haematopoietic growth factor which stimulates the formation of colonies for erythroid, megakaryocytic, granulocytic and monocytic lineages. It is predominantly produced by activated T cells, natural killer (NK) cells and mast cells and supports the growth-promoting effects of SCF on mast cell precursors. IL-3 causes severe hypersensivity reactions and plays a pivotal role in exacerbating the inflammatory response in vivo. Here we report the interrelationship between IL-3 and mast cells.

Impact of mast cells on the skin.

When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNgamma, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.

Luteolin inhibits mast cell-mediated allergic inflammation.

Mast cells are ubiquitous in the body and multifunctional immune cells; they are known to be primary responders in allergic reactions, orchestrating strong responses to minute amounts of allergens. Mature mast cells perform important beneficial roles in host defense, both in IgE-dependent immune responses to certain parasites and in natural immunity to bacterial infection. In IgE-associated biological responses, the crosslinking of FcεRI-bound IgE with multivalent antigens initiate the activation of mast cells by promoting aggregation of FceRI. This cross-linking receptor-bound IgE by multivalent Ag initiates a cascade of intracellular reactions leading to mediator release such as proinflammatory mediators, chemokines and cytokines. Luteolin belongs to a flavone group of compounds called flavonoids, it has anti-oxidant properties, inhibits some cancer cell proliferation and exerts a regulatory effect on mast cell-mediated inflammatory diseases and allergy. Here we report the impact of luteolin on mast cell activation.

Micropatterned hydrogenated amorphous carbon guides mesenchymal stem cells towards neuronal differentiation.

This study investigated how the design of surface topography may stimulate stem cell differentiation towards a neural lineage. To this end, hydrogenated amorphous carbon (a-C:H) groove topographies with width/spacing ridges ranging from 80/40µm, 40/30µm and 30/20µm and depth of 24 nm were used as a single mechanotransducer stimulus to generate neural cells from human bone marrow mesenchymal stem cells (hBM-MSCs) in vitro. As comparative experiments, soluble brain-derived neurotrophic factor (BDNF) was used as additional biochemical inducer agent. Despite simultaneous presence of a-C:H micropatterned nanoridges and soluble BDNF resulted in the highest percentage of neuronal-like differentiated cells our findings demonstrate that the surface topography with micropatterned nanoridge width/spacing of 40/30µm (single stimulus) induced hBM-MSCs to acquire neuronal characteristics in the absence of differentiating agents. On the other hand, the alternative a-C:H ridge dimensions tested failed to induce stem cell differentiation towards neuronal properties, thereby suggesting the occurrence of a mechanotransducer effect exerted by optimal nano/microstructure dimensions on the hBM-MSCs responses.

Impact of RANTES, MCP-1 and IL-8 in mast cells.

Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. RANTES, MCP-1 and related molecules, constitute the C-C class of chemokine supergene family and a group of cytokines produced by hematopoietic cells, while IL-8 constitute the C-X-C class. The roles of most of these chemokines are not well known, although members of the chemokine family are inflammatory agents. The C-C chemokine plays a role in regulating Th-cell cytokine production and leukocyte trafficking. In this study we clearly show that RANTES and MCP-1 are mediators of acute inflammatory responses. Our report describes additional biological activities for RANTES, MCP-1, and IL-8, suggesting that these chemokines play a fundamental role in histamine and serotonin generation and cell function in mast cells.

Infections and mast cells.

Mast cells play a role in various physiological functions: innate and acquired immunity, epithelium remodelling and proliferation, angiogenesis, cancer, inflammation and infections. Mast cells are activated by cross-linking of FcERI molecules, which are involved in the binding of multivalent antigens to the attached IgE molecules, resulting in a variety of responses including the immediate release of potent inflammatory mediators. In addition, mast cell biology consists in the capability to secrete preformed mediators which include biogenic amines and newly synthetized mediators, which include lipid-derived mediators and cytokines. It has been reported that parasite infections induce a systemic immunomodulatory network, including regulatory T cells, pro-inflammatory and anti-inflammatory cytokines, which might play a key role in the allergic phenotype. Here, in this article, we revisited the relationship between mast cells and infections.

IL-32: a newly-discovered proinflammatory cytokine.

IL-32, a newly-discovered proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, is an important player in innate and adaptive immune response. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and Crohn?s disease and in human stomach cancer, human lung cancer and breast cancer tissues. Moreover, it has been reported that IL-32 has pro-inflammatory effects on myeloid cells and causes the differentiation of osteoclast precursors into multinucleated cells expressing specific osteoclast markers. We recently found that human IL-32 has the capacity to provoke histamine release in human-derived cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat peritoneal mast cells (RPMC), showing that IL-32 may be specie specific and act more in mature human mast cells (HDCBMC) than in transformed mast cells (LAD 2 cells). Certainly, IL-32 is another potent proinflammatory cytokine, however, the specific role of this newly-discovered protein in the network of cytokine biology remains to be determined.

Substance P upregulates LTB4 in rat adherent macrophages from granuloma induced by KMnO4.

Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as cytokines have the capacity to activate and stimulate macrophages to produce arachidonic acid oxygenation and lipoxygenation products. Leukotriene B4 (LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions. LTB4 stimulates chemotaxis, lysosomal enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent granuloma macrophages (RAGMs). The chronic granuloma in rat was induced by dorsal injections of a potassium permanganate (KMnO4) saturated crystal solution (200 microl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of LTB4 in RAGMs and increases lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 microM), resulted in statistically significant increases of LTB4 Preincubation of RAGMs with NDGA (nordihydroguaiaretic acid (10 microM), completely abolished the production of LTB(4) in the supernatants and lipoxygenase expression on RAGMs challenged with SP, or the cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with dexamethasone (10 microM). Our results suggest that SP is able to stimulate the release of LTB4 and lipoxygenase expression in macrophages from chronic inflammatory granuloma and provide further evidence for a neuroinflammatory pathway.