Ali Sengul

Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy.

The specific associations between antidepressant treatment and alterations in the levels of cytokines remain to be elucidated. In this study, we aimed to explore the role of IL-2, IL-4, IL-12, TNF-α, TGF-β1, and MCP-1 in major depression and to investigate the effects of sertraline therapy. Cytokine and chemokine levels were measured at the time of admission and 8 weeks after sertraline treatment. Our results suggest that the proinflammatory cytokines (IL-2, IL-12, and TNF-α) and MCP-1 were significantly higher, whereas anti-inflammatory cytokines IL-4 and TGF-β1 were significantly lower in patients with major depression than those of healthy controls. It seems likely that the sertraline therapy might have exerted immunomodulatory effects through a decrease in the proinflammatory cytokine IL-12 and an increase in the anti-inflammatory cytokines IL-4 and TGF-β1. In conclusion, our results indicate that Th1-, Th2-, and Th3-type cytokines are altered in the depressed patients and some of them might have been corrected by sertraline treatment.

The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide.

Bisphosphonates have recently been introduced in the therapeutic armamentarium for long-term treatment of patients with multiple myeloma. These pyrophosphate analogs not only reduce the occurrence of skeletal events but also provide clinical benefit to patients and improve the survival of some of them. The existence of these capabilities raises the possibility that these compounds may have a direct antiproliferative effect on tumor cells. To investigate whether these drugs exert a direct antitumor effect, we exposed human myeloma cell lines ARH-77 and RPMI-8226 to increasing concentrations of zoledronic acid (ZOL) in vitro. A concentration- but not time-dependent cytotoxic effect was detected with drug treatment of ARH-77 and RPMI-8226 cell lines (30% and 60% at 48 hours and 38% and 62% at 72 hours, respectively, for 50µM of ZOL). Cytotoxicity was not due to ZOL-induced chelation of extracellular calcium as shown by control experiments with the calcium chelator ethylene glycol-bis(β-aminoethylether)-N,N,N’,N’-tetraacetic acid. Addition of the competitive inhibitor of the nitric oxide synthase Nω-nitro-L-arginine methyl ester did not modulate ZOL-induced cytotoxicity. However, a decrease in the number of apoptotic cells was detected when protein kinase C was inhibited by addition of staurosporine to ZOL-containing cultures. Cytotoxicity also was increased by addition of dexamethasone (Dex) and thalidomide (Thal) to ARH-77 and RPMI-8226 cultures. We demonstrated that exposing myeloma cell lines ARH-77 and RPMI-8226 to ZOL inhibits cell growth in a dose-dependent but not a time-dependent manner and that combination of Dex and Thal with ZOL induces apoptotic cell death, providing a rationale for potential applications in vivo.

Serum interleukin-18 levels in patients with Behçet’s disease. Is its expression associated with disease activity or clinical presentations?

Interleukin (IL)-18 is a proinflammatory cytokine which plays a crucial role in T helper (Th)1 type immune response. The aim of this study is to investigate the relationship of serum levels of IL-18 with disease activity and clinical presentations in patients with Behcet’s disease (BD). Sixty patients with BD and 20 healthy controls were included in the study. Patients were grouped as having active or inactive disease according to the Leeds activity score. They were also separated as a systemic involvement or mucocutaneous symptoms only. Patients with systemic involvement were further grouped according to the presence of ocular, articular and vascular involvement. IL-18 levels were significantly higher in all patient subgroups as compared to healthy controls and found to be correlated with the activity score in patients having active disease. In conclusion, this cytokine participates in the pathogenesis of BD and its levels are correlated with the disease activity. Detection of increased levels of IL-18 in patients with inactive disease implies that Th1 activation and subclinical inflammation persist during the inactive period of the disease.

Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behçet’s disease. Does interleukin-1β play a major role in Behçet’s synovitis?

The objective of this study has been the well established fact that proinflammatory cytokines and metalloproteinases play a crucial role in the pathogenesis of chronic arthritis as well as the development of pannus, with the eventual erosive changes. Among the proinflammatory cytokines, interleukin-18 (IL-18) has been shown to contribute to the pathogenesis of chronic synovitis by increasing the secretion of interleukin-1beta (IL-1β) and the tumor necrosis factor-alpha (TNF-α) and also stimulating angiogenesis. The aim of this study is to investigate the synovial IL-18, IL-1β, TNF-α and matrix metalloproteinase-3 (MMP-3) levels in patients with Behçet’s disease (BD), and compare them with the levels of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). 30 patients with BD, 20 with RA, and 20 with OA were included in the study. The synovial levels of IL-18, IL-1β, TNF-α and MMP-3 were detected using the two-step sandwich ELISA method. The synovial IL-18, TNF-α and MMP-3 levels were significantly higher in RA patients than patients with BD (P=0.004, 0.019, 0.025, respectively) and with OA (P=0.004, 0.045, 0.032, respectively). There were no differences, with respect to the cytokine levels, when patients with BD were compared with those with OA. Patients with RA and BD had higher IL-1β levels than patients with OA (P=0.017, 0.013, respectively). However, no such difference was found for IL-1β between BD and RA patients. Among patients with RA, positive correlations were found between TNF-α and MMP-3 (r=0.683, P=0.001). Our results showed that MMP-3 and proinflammatory cytokines, except IL-1β, were expressed in relatively small quantities in Behçet’s synovitis. Detection of the lower levels of these cytokines and metalloproteinases might explain the non-erosive character of Behçet’s arthritis. We suggest that IL-1β may be involved in the pathogenesis of Behçet’s synovitis.

Diagnostic Utility of Anti-Cyclic Citrullinated Peptide and Anti-Modified Citrullinated Vimentin Antibodies in Rheumatoid Arthritis

Several autoantibodies found in RA are directed to epitopes in citrullinated proteins. One of them is anti modified citrullinated vimentin (Anti-MCV). We tested the value a newly developed ELISA for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with an anti-CCP based ELISA system for the diagnosis of RA. Thirty-five patients with RA (mean age; 42.6 +/- 10.87 years, mean disease duration; 9.37 +/- 3.98 years) were enrolled in this study. Twenty -five ankylosing spondylitis (mean age; 35.88 +/- 6.64 years, mean disease duration; 10.25 +/- 4.61 years), and 19 healthy subjects (mean age; 40.26 +/- 5.11 years) served as controls. Anti-CCP antibodies and Anti-MCV antibodies were measured using ELISA. In all RA patients, mean anti- CCP level was 69.07 +/- 90.43 U/ml and anti-MCV level was 665.77 +/- 1040.19 U/ml. In patients with AS, the mean anti-CCP level was 10.7 +/- 5.22 U/ml and anti-MCV level was 40.54 +/- 20.15 U/ml. In healthy controls, the mean anti-CCP level was 11.11 +/- 7.65 U/ml, anti-MCV level was 23.12 +/- 12.04 U/ml. In patients with active RA, the mean serum anti-CCP level was 100.54 +/- 98.07 U/ml and anti-MCV level was 998.74 +/- 1154.93 U/ml. In patients with inactive RA, the mean serum anti-CCP level was 8.77 +/- 1.55 U/ml and anti-MCV level was 27.59 +/- 23.10 U/ml. According to these results; In patients with RA, the mean serum anti-MCV and anti-CCP levels were significantly high compared to patients with AS and healthy controls (p=0.002, p=0.001, p=0.002, p=0.001 respectively). The mean serum anti-MCV and anti- CCP levels were significantly higher in active patients with RA than in inactive patients with RA patients (p=0.001 and p=0.001 respectively). In inactive patients with RA, the mean serum anti-MCV and anti-CCP levels were similar in patients with AS and patients (p=0.484, p=0.308, p=0.09 and p=0.222 respectively). The mean serum anti-MCV levels were correlated with DAS 28 (r=0.531, p=0.001), VAS score (r=0.332, p=0.01), ESR (r=0.458, p=0.001), serum CRP levels (r=0.568, p=0.01), serum RF levels (r=0.529, p=0.001), swollen joints number (r=0.525, p=0.001) and tender joints number (r=0.638, p=0.001). As a result; measurement of serum anti-MCV levels is useful for diagnosis of RA and combined use of anti-MCV and RF may be more useful prognostic factor than either method alone, RF and anti-CCP.

Tissue levels of adiponectin, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1 and heart-type fatty acid-binding protein in human coronary atherosclerotic plaques

Background  There is little information available about any link between the levels of adiponectin, intercellular adhesion molecule‐1 (ICAM‐1), tumour necrosis factor‐α (TNF‐α) and heart‐type fatty acid‐binding protein (H‐FABP) in coronary atherosclerotic plaque specimens.

Ceftriaxone-related hemolysis and acute renal failure

A 5-year-old girl with no underlying immune deficiency or hematologic disease was treated with a combination of ceftriaxone and ampicilline-sulbactam for pneumonia. On the ninth day of the therapy, she developed oliguria, paleness, malaise, immune hemolytic anemia (IHA) and acute renal failure (ARF). Laboratory studies showed the presence of antibodies against ceftriaxone. Acute interstitial nephritis (AIN) was diagnosed by renal biopsy. The patient’s renal insufficiency was successfully treated with peritoneal dialysis without any complications. The patient recovered without any treatment using steroids or other immunosuppressive agents.

Immunosuppressive effects of multipotent mesenchymal stromal cells on graft-versus-host disease in rats following allogeneic bone marrow transplantation.

Objective: Graft-versus-host disease (GVHD) is a major obstacle to successful allogeneic bone marrow transplantation (allo-BMT). While multipotent mesenchymal stromal cells (MSCs) demonstrate alloresponse in vitro and in vivo, they also have clinical applications toward prevention or treatment of GVHD. The aim of this study was to investigate the ability of MSCs to prevent or treat GVHD in a rat BMT model. Materials and Methods: The GVHD model was established by transplantation of Sprague Dawley rats’ bone marrow and spleen cells into lethally irradiated (950 cGy) SDxWistar rat recipients. A total of 49 rats were randomly assigned to 4 study and 3 control groups administered different GVHD prophylactic regimens including MSCs. After transplantation, clinical GVHD scores and survival status were monitored. Results: All irradiated and untreated control mice with GVHD died. MSCs inhibited lethal GVHD as efficiently as the standard GVHD prophylactic regimen. The gross and histopathological findings of GVHD and the ratio of CD4/CD8 expression decreased. The subgroup given MSCs displayed higher in vivo proportions of CD25+ T cells and plasma interleukin-2 levels as compared to conventional GVHD treatment after allo-BMT. Conclusion: Our results suggest that clinical use of MSCs in both prophylaxis against and treatment of established GVHD is effective. This study supports the use of MSCs in the prophylaxis and treatment of GVHD after allo-BMT; however, large scale studies are needed. Conflict of interest:None declared.

Increasing the target number of nucleated cells and administration of r-metHuG-CSF expedite neutrophil engraftment in allogeneic bone marrow transplantation.

SINCE 1960, allogeneic bone marrow transplantation (AlloBMT) has been instituted to treat various malignant or nonmalignant disorders. However, AlloBMT has being increasingly replaced by allogeneic peripheral blood stem cell transplantation (AlloPBSCT) over the past 10 years. As Gratwohl and colleagues reported, AlloPBSCT accounted for 30% of whole allogeneic hematopoietic stem cell transplantations (AlloHSCT) performed in European countries in 1997, whereas all AlloHSCT were bone marrow derived in 1991. Faster neutrophil and platelet engraftment and no risk of general anesthesia for donors seems to be the major reasons for this trend. To obtain faster neutrophil engraftment, and reduce morbidity from infections in the allogeneic bone marrow setting, and because of the relatively prolonged neutropenia compared to AlloPBSCT, G-CSF or GM-CSF have been successfully employed. However, the hematologic recovery provided by AlloBMT has always remained slower than that provided by AlloPBSCT. Lower infectious complications, rapid immunologic recovery, shorter hospitalization stay, and lower cost appear as other advantages of AlloPBSCT. Despite these advantages, AlloPBSCT has certain drawbacks. One of the most serious complication is the concern that AlloPBSCT is associated with an increased incidence and severity of chronic graft-versus-host disease (GVHD) as compared to AlloBMT. Furthermore, whether chronic GVHD decreases relapse rate due to graft-versus-leukemia (GVL) effect in patients undergoing AlloPBSCT remains to be determined. Standards for AlloBMT or AlloPBSCT have not yet been optimized. Therefore, some centers have sought to combine both modalities by giving bone marrow and peripheral blood stem cells. In this report, the results of patients undergoing AlloBMT in which the targeted nucleated cell count was 3 10/kg and in which r-metHuG-CSF was administered after the transplantation are presented. Of interest, our patients had fast neutrophil engraftment, low infectious complications, and an acceptable relapse rate, which are comparable to those in AlloPBSCT as reported in the literature. Chronic GVHD rate seems to be less than that in AlloPBSCT.