Aetiology, diagnosis, and treatment of brachymetatarsia: a narrative review.

Brachymetatarsia (BM), or hypoplastic metatarsal, is an abnormal shortening of one or more metatarsal bones with a female-to-male ratio of 10.53:1. Different causes are described in the literature, such as congenital, acquired, or iatrogenic, associated with different conditions and syndromes. Its presence may develop deformity and pain; however, often feet are pain free and the major worries of patients are cosmetics. Non-operative treatments aim to improve the comfort of metatarsal heads and the possible dorsal conflict through comfortable shoes or the use of specific orthotics. The surgical treatment is anything but straightforward, with "one-stage" or "two stage" techniques, the latter better called "by gradual distraction". One-stage procedures are more rapid techniques but have limited ability to restore the desired length due to neurovascular compromise caused by acute lengthening. Insufficient correction is also possible. On the contrary, by gradual distraction procedures allow gradual distraction lengthening of more than 1.5 cm, but require the use of an external fixator, with a higher risk of complications in more than about 50% of surgeries. The adjacent metatarsal shortening should be considered in combination with other techniques, to diminish the excessive lengthening. In each case, surgeries should be always decided on each patient's concerns, deformities, and clinical needs.

ALIF in the correction of spinal sagittal misalignment. A systematic review of literature.

PURPOSE: We aim at analysing the impact of anterior lumbar interbody fusion (ALIF) in restoring the main spinopelvic parameters, along with its potentials and limitations in correcting sagittal imbalance. MATERIALS AND METHODS: The 2009 PRISMA flow chart was used to systematically review the literature; 27 papers were eventually selected. The following spinopelvic parameters were observed: pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), segmental lumbar lordosis (LLseg) and sagittal vertical axis (SVA). Papers reporting on hyperlordotic cages (HLC) were analysed separately. The indirect decompression potential of ALIF was also assessed. The clinical outcome was obtained by collecting visual analogue scale (VAS) for back and leg pain and Oswestry Disability Index (ODI) scores. Global fusion rate and main complications were collected. RESULTS: PT, SS, LL, LLseg and SVA spinopelvic parameters all improved postoperatively by - 4.3 ± 5.2°, 3.9 ± 4.5°, 10.6 ± 12.5°, 6.7 ± 3.5° and 51.1 ± 44.8 mm, respectively. HLC were statistically more effective in restoring LL and LLseg (p < 0.05). Postoperative disc height, anterior disc height, posterior disc height and foraminal height, respectively, increased by 58.5%, 87.2%, 80.9% and 18.1%. Postoperative improvements were observed in VAS back and leg and ODI scores (p < 0.05). The global fusion rate was 94.5 ± 5.5%; the overall complication rate was 13%. CONCLUSION: When managing sagittal imbalance, ALIF can be considered as a valid technique to achieve the correct spinopelvic parameters based on preoperative planning. This technique permits to obtain an optimal LL distribution and a solid anterior column support, with lower complications and higher fusion rates when compared to posterior osteotomies.

Fusion rate and influence of surgery-related factors in lumbar interbody arthrodesis for degenerative spine diseases: a meta-analysis and systematic review.

The aim of this meta-analysis and systematic review is to summarize and critically analyze the influence of surgery-related factors in lumbar interbody fusion for degenerative spine diseases. A systematic review of the literature was carried out with a primary search being performed on Medline through PubMed. The 2009 PRISMA flowchart and checklist were taken into account. Sixty-seven articles were included in the analysis: 48 studies were level IV of evidence, whereas 19 were level III. All interbody fusion techniques analyzed have proved to reach a good fusion rate. An overall mean fusion rate of 93% (95% CI 92-95%, p < 0.001) was estimated pooling the selected studies. The influence of sagittal parameters and cages features in fusion rate was not clear. Autograft is considered the gold standard material. The use of synthetic bone substitutes and biological factors alone or combined with bone graft have shown conflicting results. Low level of evidence studies and high heterogeneity (χ2 = 271.4, df = 72, p < 0.001; I2 = 73.5%, τ2 = 0.05) in data analysis could result in the risk of bias. Further high-quality studies would better clarify these results in the future.

Incidence, diagnosis and management of sacroiliitis after spinal surgery: a systematic review of the literature.

The sacroiliac joint (SIJ) is a possible source of persistent or new onset pain after lumbar or lumbosacral fusion. The aim of this paper is to systematically review and analyze the available literature related to the incidence, diagnosis and management of sacroiliitis after spinal arthrodesis. The authors independently screened the titles and abstracts of all articles identified concerning sacroiliac joint pain after lumbar or lumbosacral fusion, to assess their suitability to the research focus. The average incidence of sacroiliitis after lumbar or lumbosacral arthrodesis was found to be 37 ± 28.48 (range 6-75), increasing directly to the number of fused segments involved, especially when the sacrum is included. The most accurate evaluation is the image-guided injection of anesthetic solutions in the joint. Surgery treatment may be considered when conservative therapy fails, with open surgery or with minimally invasive SIJ fusion. Although the risk of developing SIJ degeneration is unclear, the results indicate that pain and degeneration of SIJ develop more often in patients undergoing lumbosacral fusion regardless of the number of melting segments. The treatment of sacroiliitis appears to be independent of his etiology, with or without previous instrumentation on several levels.

Metaphyseal cones and sleeves in revision total knee arthroplasty: Two sides of the same coin? Complications, clinical and radiological results-a systematic review of the literature.

Revision total knee arthroplasty (rTKA) is increasing of relevance in orthopaedic surgeon daily practice and this trend is likely to continue in the years ahead. The aim of this systematic review of English literature is to summarize and compare indications, complications, clinical and radiological results of metaphyseal cones and sleeves in management of bone loss in rTKA. Retrospective or prospective studies with at least 1 year of follow-up (FU) were included. The PRISMA 2009 flowchart and checklist were considered to edit the review. Clinical and radiological results, rates of intraoperative fractures, aseptic loosening, periprosthetic joint infection, septic failure, reoperations and re-revisions were extrapolated by the papers. Thirty-seven articles were included in the systematic review. Results of 927 cones (mean FU of 3.6 ± 1.4 years) and 1801 sleeves (mean FU of 4.5 ± 1.6 years) were analysed. The studies showed good clinical and functional outcomes. Cones and sleeves allowed a stable metaphyseal fixation. The aseptic survivorship of the implants was 97.3% in cones group and 97.8% in sleeves group. Metaphyseal cones and sleeves represent a viable option in management of type IIb and III AORI bone defects in aseptic and septic TKAr with overlapping survival rate. Further high-quality long-term studies would better clarify complications, clinical and radiological results of these promising techniques in revision total knee arthroplasty.

Management of ramp lesions of the knee: a systematic review of the literature.

PURPOSE: The purpose of this systematic review is to evaluate the current literature and to assess the clinical outcomes following meniscal ramp lesion treatment and anterior cruciate ligament (ACL) reconstruction. A consensus of the treatment of this pattern of tears is still lacking. METHODS: A systematic review of the literature was performed with a comprehensive search on Medline through PubMed, CINAHL, Cochrane, Embase and Google Scholar databases. The PRISMA 2009 flowchart and checklist were considered to edit the review. The included studies were evaluated based on indications, management, surgical technique and clinical results. RESULTS: Seven studies (two level II and five level IV evidence) were identified that met inclusion criteria, including a total of 509 patients. The overall main follow-up was 23.6 months. Treatment failure occurred in 8.3% of patients receiving ACL repair and ramp lesion treatment. The repair of ramp lesion is the most used approach in the literature. CONCLUSION: There is a lack of literature focused on the management of ramp lesion and ACL injuries. The repair resulted in the most used approach with good clinical results and low failure rate. However, further high-quality studies evaluating the long-term outcomes of different surgical strategies are needed.

Goldthwait technique for patellar instability: surgery of the past or here to stay procedure? A systematic review of the literature.

Patellar instability is the pathologic condition where the patella is prone to recurrent lateral dislocation. The clinical results on large series of patients and long-term outcome of Goldthwait techniques have not been described in the literature. The aim of this systematic review is: (1) to analyze and summarize the available literature focused on Goldthwait procedure in the treatment of recurrent patellar dislocation and (2) to evaluate the clinical and functional outcomes of patients treated with this surgical procedure. A systematic review of the literature was performed to investigate the results of Goldthwait procedure according to the PRISMA 2009 guidelines. A total of 7 articles published were systematically reviewed. A total of 197 knees (182 patients: 86 males and 96 females) have been treated with Goldthwait procedure. The mean reported follow-up was 6.8 years. The mean age at surgery was 18 years old. The Goldthwait procedure was associated with open lateral retinacular release in 127 (64.5%) knees to arthroscopic lateral retinacular release in 20 (10.1%) knees, and with retinacular plasty and a vastus medialis advancement in 33 (16.7%) knees. Only in 17 (8.6%) knees the Goldthwait procedure was performed as an isolated procedure. Poor standardization of methodological assessment has been observed. Despite the limitations of the available literature, the Goldthwait technique provides satisfying results for the treatment of patellar instability even in pediatric population. More high-quality studies are necessary to evaluate the long-term complications and the real incidence of long-term PF osteoarthritis.

Unilateral external fixator in the treatment of humeral shaft fractures: results of a single center retrospective study.

BACKGROUND: The aim of our work is to evaluate and critically analyze long-term clinical and radiological data of a new unilateral external fixator (MIKAI KIT FEP©-Mikai S.p.A, Genoa, Italy), in the treatment of humeral shaft fractures. MATERIALS AND METHODS: We reviewed 47 patients affected by humeral fractures that underwent surgery from July 2010 to March 2016 with unilateral external fixator. Demographic characteristics of the patients were recorded, which included age, sex and baseline comorbidities and mechanism of injury. Surgical data such as time of surgery and time of fixation according to AO-type of fracture, clinical objective and subjective outcomes were collected. RESULTS: The mean follow-up was 50.4 months (range 12-74). The patients' average age was 41.8 years (range 14-92). Mean surgical time was 66.8 (±37.7 min); and mean time of fixation was 4.5 (±1.7 months). We observed five delayed union (10.6%); one refracture (2.1%); and one case of non-union (2.1%) who underwent a revision surgery with nailing. No malunion was detected. Average quick-DASH was 11.7 (±14.8). The mean Constant Score at final follow-up was 81.5 (±14). 95.8% of patients were satisfied of our treatment. According to SF-12 scores, we observed 44 (93.6%) good results and 3 (6.4%) poor results. CONCLUSION: We suggest the use of MIKAI KIT FEP© as a feasible option in the treatment of humeral shaft fractures. We reported optimal clinical and radiological outcomes at long-term follow-up. We advocate more powerful evidence to validate this new possible approach.

What is the clinical evidence on regenerative medicine in intervertebral disc degeneration?

PURPOSE: This review aims to explore and summarize the current clinical evidence about the use of regenerative medicine such as mesenchymal stem cells or platelet-rich plasma in intervertebral disc regeneration, in order to clarify the state of art of these novel approaches. MATERIALS AND METHODS: We performed a research of the available literature about regenerative medicine strategies aiming to prevent intervertebral disc degeneration. All preclinical trials and in vitro studies were excluded. Only clinical trials were critically analysed. RESULTS: The manuscript selection produced a total of 7 articles concerning the use of regenerative therapies in intervertebral disc degeneration, covering the period between 2010 and 2016. Articles selected were 4 about the injection of mesenchymal stem cells-related results and 3 using platelet-rich plasma. The total population of patients treated with regenerative medicine strategies were 104 patients. CONCLUSIONS: Regenerative medicine, such as the use of mesenchymal stem cells or platelet-rich plasma, in intradiscal disc degeneration has shown preclinical and clinical positive results. Randomized clinical trials studying the potential of MSCs intradiscal injection have not been conducted, and PRP effect has been studied only preliminarily. Additional more powered high-quality studies are needed to really appreciate the long-term safety and efficacy of regenerative medicine approaches in IDD.

Surgical management of complex proximal humeral fractures: pinning, locked plate and arthroplasty : Clinical results and functional outcome on retrospective series of patients.

PURPOSE: The aim of the study was to compare the clinical results and related complications of four different surgical treatments of complex proximal humeral fractures according to their classification and features of patients. METHODS: Between 2007 and 2011, 92 consecutive patients with diagnosis of three-four-part displaced fractures, fractures with head dislocation and head-splitting fractures were evaluated postoperatively with Constant-Murley score, disability of arm, shoulder and hand score and simple shoulder test. RESULTS: All the treatment modalities showed from optimal to good mean functional results. The statistical analysis comparing each treatment group showed better outcomes scores (p < 0.05) for: locked plating versus HA, locked plating versus RSA and RSA versus HA. No differences between postoperative range of motion, complication rate and overall revision rate of the treatment groups were found at the end of follow-up (p > 0.05). Overall complication rate of surgical treatment of complex PHF was 31.5% (29 patients) with overall revision rate of 14.1%. Among patients with complications 77.8% of HA (7 of 9) required revision surgery (p < 0.05). CONCLUSIONS: The treatment of complex PHF is nowadays a challenge even for skilled shoulder surgeons. The several viable operative options give good results whenever used for the correct indication. The range of reported complications from 18.2 to 37.5% remains concerning, but most of them did not affect clinical outcome in this series. Accurate preoperative characterization of the fracture pattern is necessary, and high surgical skills of the different operative techniques, including arthroplasty, are recommended to meet the increased functional expectations of patients. LEVEL OF EVIDENCE: Therapeutic series, Level IV.

Comparison of clinical, MRI and arthroscopic assessments of chronic ACL injuries, meniscal tears and cartilage defects.

PURPOSE: The aim of this study was to compare the accuracy of clinical examination to that of MRI evaluated by two independent radiologists for the diagnosis of meniscal tears and chronic anterior cruciate ligament injuries and to assess the MRI accuracy in the diagnosis of cartilage defects. METHODS: Seventy-six consecutive patients with suspected intra-articular knee pathology were prospectively evaluated by objective examination, 1.5 T MRI, re-examined by trained radiologist and arthroscopy. Accuracy, sensitivity, specificity, positive predictive value and negative predictive value were calculated. Agreement analysis with kappa (К) coefficient values was performed for meniscal and ACL tears. RESULTS: No differences were found between diagnostic accuracy of clinical examination, the first and second MRI reports in diagnosis of medial meniscus (84 vs 96 vs 97 %) and anterior cruciate ligament injuries (93 vs 78 vs 89 %). For the lateral meniscal tears, the accuracy of the second radiologist was significantly higher than those of the first (96 vs 75 %; p < 0.01) and clinical examination (96 vs 86 %; p = 0.02). High diagnostic values were obtained for the diagnosis of full-thickness chondral defects with sensitivity of 100 %, specificity of 95 % and accuracy of 95 %. CONCLUSION: Clinical and MRI evaluations have no differences in the diagnosis of medial meniscus and anterior cruciate ligament injuries. A trained radiologist obtained better sensitivity, specificity and accuracy in the diagnosis of lateral meniscus. 1.5 T MRI does not represent the technique of choice in the evaluation of chondral defect but demonstrated high diagnostic accuracy for detection of full-thickness chondral defects. LEVEL OF EVIDENCE: Diagnostic prospective study, Level II.

The Endo-Model(®) rotating hinge for rheumatoid knees : Functional results in primary and revision surgery.

BACKGROUND: Major joints of the lower limbs are commonly affected by rheumatoid arthritis (RA), with consequent pain, loss of function, and progressive disability. Knee replacement represents a useful solution, but a highly constrained implant design is often needed in order to face the severe anatomical deformities and the gross instability that the surgeon may encounter in the rheumatoid knee. OBJECTIVES: The aim of this work was to evaluate the Endo-Model(®) rotating hinge knee prosthesis implanted in patients affected by RA and severely damaged knees. PATIENTS AND METHODS: We retrospectively evaluated a series of 38 patients with RA implanted with the Endo-Model(®) rotating hinge knee prosthesis for primary or revision surgery (mean follow-up 6.1 years; mean age at surgery 71.5 years). At the time of surgery, the mean duration of RA was 13.2 years. Patients were evaluated clinically and radiographically and the Knee Society Score (KSS) was used. RESULTS: Implant survival at most recent follow-up was 91.7 %. Mean final knee flexion was 102.7 °. The mean KSS was 93.5 (excellent) and 67.1 (good) for clinical and functional score, respectively. Mild pain was present in 10 patients. No sign of malalignment or residual instability was found. No evidence of loosening or implant failure was observed in x-rays. CONCLUSION: The Endo-Model(®) rotating hinge knee prosthesis provides excellent pain relief, functional recovery, and intrinsic knee stability both in complex primary and in revision knee arthroplasty in the majority of patients with severely affected rheumatoid knees.

Reverse shoulder arthroplasty in older patients: is it worth it? A subjective functional outcome and quality of life survey.

BACKGROUND: Reverse shoulder arthroplasty (RSA) use has largely spread in the last decade. Doubts still exist, however, about its use in the elder population, because of high risk of complications and possibly limited cost-efficiency of the procedure. AIMS: Our work was aimed at defining the subjective outcome, complication and satisfaction rate, and perceived recovery of individual autonomy and quality of life after RSA, in a cohort of patients 79 or more years old at the time of surgery. METHODS: Between 2007 and 2012, 52 patients 79 years old or older received a RSA. In the setting of this study, 27 patients (31 shoulders) were available for clinical evaluation. The ASES score was used for subjective outcome evaluation, while the health-related quality of life was studied with the SF-12 form. An ad hoc questionnaire was used in order to evaluate the satisfaction rate and the recovery in individual autonomy. RESULTS: At 59,3 months mean follow-up, only one patient required revision due to periprosthetic fracture. ASES score attested at 78.2, and SF-12 scores showed values similar to the general age-matched population. Sensible improvement in perceived quality of life was described by 24 patients. When present, comorbidities were associated with lower results. DISCUSSION: RSA outcomes in the elderly are good in terms of function, satisfaction and quality of life recovery. Complications appear primarily linked to age-related conditions and comorbidities show critical association with lower results. CONCLUSIONS: Our study confirms that RSA represents a useful solution for end-stage shoulder disease also in the advanced age population.

Structural comparison of the interaction of tubulin with various ligands affecting microtubule dynamics.

Microtubules (MTs), which are highly dynamic assemblies of the protein tubulin, play important and diverse roles in eukaryotic cells. MT dynamics are regulated during the cell cycle by interacting with a large number of endogenous cellular regulators. In addition, many anti-tumour drugs and natural ligands that interact directly with tubulin are able to either stabilise or destabilise MTs and to disrupt the normal dynamics. Herein, we compare the structures of tubulin when complexed with different ligands in order to analyse: (i) various binding-sites of the protein and different positions of ligands within the microtubule (ii) the diverse effect on the microtubule dynamics. The structures and data given are essential for understanding tubulin-ligand interactions and their influence on the regulation of the microtubule system.

[CTLA4-Ig interferes and downregulates the proinflammatory activities of rheumatoid synovial macrophages in monoculture]. / CTLA4-Ig influenza e inibisce le attività proinfiammatorie di macrofagi sinoviali reumatoidi in monocoltura.

OBJECTIVE: CTLA4-Ig, a biologic agent employed in rheumatoid arthritis (RA) treatment, downregulates the immune response and exerts anti-inflammatory effects acting on different cells including dendritic/T cells interaction and directly on osteoclasts. We investigated the anti-inflammatory effects of CTLA4-Ig in primary monocultures of RA synovial macrophages (SM). METHODS: SM were obtained, from 8 RA patients (7 F, 1 M; DAS28>5.2) who underwent therapeutic arthroscopic synoviectomy and were cultured in the absence and in the presence of CTLA4-Ig at the concentration of [500 microg/ml], the most reliable dose related to the previous pharmacological clinical and experimental experiences. Inflammatory cytokine (IL-6, TNFalpha, IL-1beta) expression was evaluated by immunocytochemistry (ICC with relative image analysis), western blot (WB), and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: ICC analysis revealed that CTLA4-Ig treatment significantly downregulated cytokine expression (p<0.001 for IL-6, TNFalpha and IL-1beta) when compared to untreated RA SM. WB and qRT-PCR confirmed partially the data. CONCLUSIONS: CTLA4-Ig was found to exert a direct and significant anti-inflammatory effect on primary monocultures of RA SM, suggesting a therapeutic power in different phases of the disease activity.

Role of the non-receptor tyrosine kinase fes in cancer.

Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signaling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions.

Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine.

Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T(3)) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25x10(-9) M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10(-11) M and above), and increased basal igf2 (10(-8) M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10(-8) M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10(-7) M and above), whereas T(3) suppressed basal and Gh-stimulated igf2 at the single concentration tested (10(-7) M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.

Metabolic hormones regulate insulin-like growth factor binding protein-1 mRNA levels in primary cultured salmon hepatocytes; lack of inhibition by insulin.

IGF-binding proteins (IGFBPs) modulate the effects of the IGFs, major stimulators of vertebrate growth and development. In mammals, IGFBP-1 inhibits the actions of IGF-I. Rapid increases in circulating IGFBP-1 occur during catabolic states. Insulin and glucocorticoids are the primary regulators of circulating IGFBP-1 in mammals. Insulin inhibits and glucocorticoids stimulate hepatocyte IGFBP-1 gene expression and production. A 22 kDa IGFBP in salmon blood also increases during catabolic states and has recently been identified as an IGFBP-1 homolog. We examined the hormonal regulation of salmon IGFBP-1 mRNA levels and protein secretion in primary cultured salmon hepatocytes. The glucocorticoid agonist dexamethasone progressively increased hepatocyte IGFBP-1 mRNA levels (eightfold) and medium IGFBP-1 immunoreactivity over concentrations comparable with stressed circulating cortisol levels (10(-9) -10(-6) M). GH progressively reduced IGFBP-1 mRNA levels (0.3-fold) and medium IGFBP-1 immunoreactivity over physiological concentrations (5 x 10(-11)-5 x 10(-9) M). Unexpectedly, insulin slightly increased hepatocyte IGFBP-1 mRNA (1.4-fold) and did not change medium IGFBP-1 immunoreactivity over physiological concentrations and above (10(-9) -10(-6) M). Triiodothyronine had no effect on hepatocyte IGFBP-1 mRNA, whereas glucagon increased IGFBP-1 mRNA (2.2-fold) at supraphysiological concentrations (10(-6) M). This study suggests that the major inhibitory role of insulin in the regulation of liver IGFBP-1 production in mammals is not found in salmon. However, regulation of salmon liver IGFBP-1 production by other metabolic hormones is similar to what is found in mammals.

Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating myeloid monocytic cells (THP-1) but not on synovial macrophages from patients with rheumatoid arthritis.

OBJECTIVE: We investigated the antiproliferative and antiinflammatory effects of methotrexate (MTX) on differentiating/differentiated cells, namely cultured human monocytic myeloid cells (THP-1), and primary cultures of synovial macrophages from patients with rheumatoid arthritis (RA). METHODS: We evaluated early and late apoptosis as well as natural cytokine inhibitor production, such as the interleukin 1 (IL-1) receptor antagonist (IL-1ra) and the soluble tumor necrosis factor receptor (sTNFr). RESULTS: Within THP-1 cells we observed a significant (p < 0.001) dose-dependent inhibition of proliferation (at 24-48 and 72-96 h) and a significant presence of apoptosis (at 24-48 h) with MTX concentrations of 500, 100, and 75 microg/ml compared with untreated controls. No significant changes were observed with 5 microg/ml or 500 to 50, and 5 ng/ml. A significant increase of IL-1ra (p < 0.001) was observed with MTX concentrations of 5 microg (51.43 +/- 2.53 vs 16.22 +/- 5.19 pg/ml control) and 500 ng (36.43 +/- 3.3 vs 16.22 +/- 5.19 pg/ml control) at all the tested times. No significant changes were observed for the sTNFr p75. Evaluating the RA synovial macrophages, we obtained no significant effects on cell proliferation and apoptosis with MTX treatment at 24 h and at the concentration of 50 microg/ml (achievable in the serum with low dose MTX treatment in RA). No significant changes were observed for the IL-1ra and no detectable levels for the sTNFr p75 were detected after treatment with MTX. CONCLUSION: This study shows that the antiproliferative and antiinflammatory effects of MTX on human cultured monocytes are dose-dependent. The antiproliferative activity seems to be mediated by cell apoptosis and the antiinflammatory activity seems to be related to cytokine inhibitor release.