Does Reinfusion of Stem Cell Products on Multiple Days Affect Engraftment?

Objective: High-doses of melphalan treatment with autologous stem cell transplantation in multiple myeloma (MM) remains a major treatment modality in suitable patients. A minimal dose of 2x106/kg CD34+ cells is preferred to achieve engraftment. Some patients need multiple leukapheresis procedures to achieve the necessary number of CD34+ cells, but this can cause a high volume of stem cell product that cannot be given in a single day. Whether or not the number of infusion days affects engraftment has not been studied before. We aimed to evaluate the impact of reinfusion of stem cells on multiple days on engraftment results. Materials and Methods: Demographic features, CD34+ cell doses, neutrophil and platelet engraftment days, hospitalization days, and number of infusion days of 149 autologous transplantations of 143 MM patients were evaluated retrospectively. Results: The data of 143 MM patients who were transplanted were analyzed retrospectively. Median age was 55±8.5 (range: 26-70) years with a male/female ratio of 91/58. Hospitalization days for all patients were 24±6 (range: 14-50) days. Mean CD34+ cell number was (7.5±5.3)x106/kg (range: 1.5-31x106/kg). CD34+ cells were reinfused in 1 day in 80.5% (n=120) of the patients, 2 days in 18.2% of the patients (n=27), and 3 days in 1.3% of the patients (n=2). For 29 patients, reinfusion was applied in more than 1 day because of the high volume of stem cell product. We did not see any dimethyl sulfoxide toxicity, cardiac arrhythmia, or volume overload complications. Hypertensive attacks during infusion were easily controlled by furosemide treatment. In the group with multiple infusions, the infused CD34+ cell numbers had a mean of (4.8±2.8)x106/kg, and in the single infusion group the mean was (8.1±5.5)x106/kg. There were no statistical differences between the two groups regarding platelet and neutrophil engraftment days (p=0.850, r=0.820 and p=0.500, r=0.440). There was no statistical difference between the two groups for hospitalization days (p=0.060, r=0.050). Conclusion: In cases with a high volume of stem cell product to acquire adequate stem cells, reinfusion can be safely applied across multiple days without any delay in engraftment.

Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma.

Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases.

B-cell-activating factor, a proliferation inducing ligand and co-stimulatory molecules in the pathogenesis of immune thrombocytopenia in childhood.

The aim of this study was to measure the levels of B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and co-stimulatory molecules in immune thrombocytopenia (ITP) of childhood to investigate the interaction between T and B lymphocytes and the impact of proliferation of B lymphocytes in the pathogenesis. Twenty newly diagnosed ITPs, 20 chronic ITPs, and 20 healthy controls between 2 and 18 years were enrolled in this study. Hemogram, BAFF, APRIL, interleukin-4, and interferon (IFN)-γ levels in sera and expressions of CD19, CD 3, CD21, CD40, and CD 154 on leukocytes were measured by ELISA and flow cytometry. Mean BAFF level in newly diagnosed ITP group was higher than the mean BAFF level in other groups. BAFF levels were significantly decreased after the treatment in newly diagnosed ITP group. APRIL, interleukin-4, and IFN-γ in newly diagnosed ITP group and BAFF, APRIL, interleukin-4, and IFN-γ in chronic ITP group were similar before and after treatment. There was no statistical difference for expressions of CD 19 and CD3 on lymphocytes, CD40 on leukocytes, CD154 on T cells, and for percentages of CD21/CD40, CD21/CD40, CD21/CD40 B cells, and CD19/CD3 lymphocytes for pretreatment and posttreatment levels in both ITP groups. In conclusion, our study strongly demonstrated that BAFF has an important role in the pathogenesis of newly diagnosed childhood ITP. It may be important in the follow-up and in novel therapy modalities of these patients.

Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion.

BACKGROUND: There have been concerns about the possible prothrombotic effects of nilotinib, especially in patients having cardiovascular risk factors. The potential mechanism behind the increased risk of thromboembolic events is still not clear. OBJECTIVES: In this study, we aimed to evaluate possible harmful effects of nilotinib on endothelial cells. To this aim, we examined proliferative capacity and secretory functions of healthy human carotid artery endothelial cells (HCtAECs) in response to nilotinib. METHODS: 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation method was used to determine antiproliferative effects of nilotinib on HCtAECs. The HCtAECs were incubated with 5, 10, and 100 nmol/L doses of nilotinib for 72 hours. Then, in order to assess the endothelial function, levels of nitric oxide (NO), von Willebrand factor (vWF), tissue plasminogen activator, plasminogen activator inhibitor 1 (PAI-1), and endothelin 1 (ET-1) were evaluated using enzyme-linked immunosorbent assay from tissue culture supernatants. RESULTS: There were slight but statistically significant decreases in cell proliferation in response to nilotinib. Nilotinib increased the secretion of t-PA, PAI-1, and vWF in a dose-dependent manner when compared with the untreated control group. The ET-1 secretion was lower in 5 nmol/L and higher in 10 and 100 nmol/L nilotinib-treated cells as compared to untreated cells. Regarding NO secretion, lower levels were observed in 5 and 10 nmol/L, and higher levels were detected in 100 nmol/L nilotinib-treated cells as compared to untreated control group cells. CONCLUSION: Considering the results obtained in our study, nilotinib does not affect the functions of endothelial cells either in a prothrombotic or an antithrombotic fashion, despite a dose-dependent decline in cell viability.

Hyperglycemia is associated with lower levels of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in wound fluid.

AIMS: Wounds in patients with hyperglycemia show impaired healing. Plasminogen activation is crucial in several overlapping phases of wound healing process. In this study, we aimed i) to compare acute wound fluid in patients with hyperglycemia and normoglycemia, ii) to focus on the elements of plasminogen activation in the wound fluid, and iii) to determine if the acute wound fluid characteristics are associated with surgical site infections. METHODS: In a cohort of 54 patients, a closed suction drain was placed in the wound above the anterior abdominal wall fascia under the skin in order to collect postoperative acute wound fluid samples for 3 following days after colorectal surgery. Patients were classified as normoglycemic (n=25) or hyperglycemic (n=29; 17 with type 2 diabetes and 12 with stress induced hyperglycemia). Surgical site infection was defined according to the Centers for Disease Control criteria. The levels of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAr), plasminogen activator inhibitor-1 (PAI-1), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and fibroblast growth factor-1 (FGF-1) were measured in the wound fluid. RESULTS: Compared to normoglycemic subjects, patients with hyperglycemia had significantly lower levels of uPA and uPAr in the wound fluid despite similar or even higher circulating levels. There was no significant difference in IL-1ß, TNF-α, PAI-1 and FGF-1 levels. In the whole study population, the wound fluid levels of uPA and uPAr were negatively correlated with circulating glucose levels. No difference was detected in the wound fluid characteristics of patients with and without surgical site infection. CONCLUSION: Patients with hyperglycemia exhibit decreased levels of uPA and uPAr in the wound fluid, suggesting a local failure in plasminogen activation at the wound site.

The investigation of relationship between joint findings and serum angiogenic and inflammatory factor levels in severe hemophilia A patients.

Despite the use of primary prophylactic Factor VIII replacement in severe hemophilia A patients, bleeding into joints cannot be prevented completely and early diagnosis and treatment of the joint bleedings are important for prevention of permanent joint damage. Recent studies have shown that neoangiogenesis plays important role in development of synovitis after recurrent joint bleedings. This study aimed to investigate the relationship between joint findings and levels of serum angiogenic and inflammatory factors in severe hemophilia A patients.The patient groups consisted of 10 severe hemophilia A patients with acute joint bleeding and 25 severe hemophilia A patients without acute joint bleeding. They were all inhibitor negative. The control group consisted of 22 healthy male children. Complete blood cell count analysis, C-reactive protein (CRP), serum ferritin, lactic acid, and ELISA-based detection of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1, thrombomodulin, macrophage migration inhibitory factor (MIF), and endostatin were performed from peripheral blood of patient and the control groups. CRP and MIF levels were detected significantly higher in hemophilia patients with acute joint bleeding than patients without acute joint bleeding. There was a positive correlation between serum thrombomodulin, VEGF, and MIF levels. In this study, we demonstrated that serum CRP and MIF levels increases in acute bleeding period regardless of the presence of previous joint damage in children with severe hemophilia. CRP elevation may be a useful and rapid marker for acute bleeding in these patients.

Markers of endothelial damage and repair in Takayasu arteritis: are they associated with disease activity?

The current clinical and laboratory parameters of Takayasu arteritis (TA) are insufficient for proper assessment of disease activity. The aims of this study were to investigate the markers of endothelial injury and repair, including circulating endothelial cell (CEC), circulating endothelial progenitor cell (CEPC) and vascular endothelial growth factor (VEGF), and evaluate their associations with disease activity in patients with TA. Thirty-two patients with TA and 30 healthy age- and sex-matched controls were included in this study. Disease activity was assessed in TA patients using various tools, including Kerr's criteria, the Indian Takayasu's Arteritis Scoring (ITAS2010) and physician's global assessment (PGA). CECs and CEPCs were measured by flow cytometry, and VEGF was measured using an enzyme-linked immunosorbent assay. The CEC level was found to be higher in TA patients than in the healthy controls (HC) (p < 0.001). There was no significant difference in CEC level between the active and inactive patients, but its level was slightly correlated with C-reactive protein (CRP) level. CEPC and VEGF levels in TA patients with active disease were higher than those in the inactive patients and HC. CEPC and VEGF levels were positively correlated with ITAS-CRP and PGA scores. This study shows increased level of CEC in patients with TA. It also suggests that the CEPC and VEGF levels may be correlated with disease activity.

Circulating apelin levels are associated with cardiometabolic risk factors in women with previous gestational diabetes.

PURPOSE: Women with previous gestational diabetes mellitus (pGDM) are at high risk for type 2 diabetes and cardiovascular disorders. In this study, we aimed to compare plasma apelin levels between women with and without pGDM, and to investigate the possible association of apelin with cardiometabolic risk factors. METHODS: Among 252 consecutive Caucasian women with GDM being included in a prospective postpartum follow-up protocol, 141 women eligible for the study protocol were enrolled. Control group consisted of 49 age- and body mass index-matched healthy women without pGDM. Circulating apelin, IL-6 and plasminogen activator inhibitor levels, and carotid intima media thickness (IMT) were measured. To evaluate carbohydrate intolerance, 75-g oral glucose tolerance test was performed. Fasting insulin and lipids were measured, and homeostasis model assessment index was calculated. RESULTS: Plasma apelin levels were reduced in women with pGDM (p < 0.001). In multiple regression analysis, apelin was negatively associated with fasting (r (2) 0.090, ß -0.273, p = 0.001) and post-load glucose (r (2) 0.061, ß -0.187, p = 0.022), serum IL-6 (r (2) 0.082, ß -0.234, p = 0.002), and carotid IMT (r (2) 0.057, ß -0.168, p = 0.033). CONCLUSIONS: Our results suggested that suppressed apelin levels were associated with increased cardiovascular risk in women with pGDM.

The evaluation of protein Z levels of children with acute lymphoblastic leukaemia during induction therapy.

The objective of this study was to evaluate the protein Z levels of children with acute lymphoblastic leukaemia (ALL) during induction therapy. Although several studies investigated the association between steroid and L-asparaginase (L-ASP) administration and levels of coagulation proteins such as protein C, protein S and antithrombin in children with ALL, protein Z levels have not been examined in any study yet. Peripheral blood was drawn from the study group before chemotherapy (PZ0) at diagnosis, at 12th day (PZ1), 15th day (PZ2), 18th day (PZ3) and 21st day (PZ4) of treatment wherein L-ASP treatment is given along with steroid administration according to ALL BFM-1995 chemotherapy protocol. Plasma protein Z levels were measured by enzyme immunoassay method. Mean protein Z level at PZ0 was 1.628 ±â€Š0.485 µg/ml in the study group and 1.672 ±â€Š0.662 µg/ml in the control group. No statistical difference was observed. In the study group, there was a slight increase in protein Z levels between the PZ0 and PZ1 periods in which only steroid therapy was administered. Statistically significant decrease was observed between protein Z levels in PZ0-PZ4, PZ1-PZ2, PZ1-PZ3, PZ1-PZ4 and PZ3-PZ4 periods. During the induction treatment, symptomatic haemorrhage or thrombosis was not followed up in any patients. We demonstrated that children with ALL have similar protein Z values to those of the control group at diagnosis. A significant decrease occurs at the end of the induction treatment with steroid and L-ASP administration. However, this deficiency does not result in development of symptomatic thrombosis or bleeding in these patients.

Traditional and novel cardiovascular risk factors in non-functioning adrenal adenomas.

BACKGROUND: The majority of the incidentally discovered adrenal masses are non-functioning adrenal adenomas; however data regarding traditional and novel cardiovascular risk predictors in these subjects is lacking. The objective of our study was to investigate the levels of PAI-1, IL-6 and Apelin along with several traditional cardiovascular risk markers in subjects with non-functioning adrenal adenomas. METHODS: 38 subjects with non-functioning adrenal adenomas and 30, age, gender and BMI matched healthy controls were enrolled. Participants underwent hormonal evaluation including morning cortisol, adrenocorticotrophic hormone (ACTH), post dexamethasone suppression test (DST) cortisol, dehydroepiandrosterone sulfate (DHEAS) and urinary cortisol. Anthropometric and metabolic parameters, body composition, PAI-1, IL-6 and Apelin were measured. RESULTS: Subjects with non-functioning adrenal adenomas had significant elevations in systolic blood pressure, mean arterial pressure, waist circumference, uric acid, and post DST cortisol and had significantly reduced levels of DHEAS when compared to BMI matched controls. No significant difference was observed in terms of PAI-1, IL-6 and Apelin between groups. PAI-1 and IL-6 were significantly correlated with mean arterial pressure, BMI, uric acid, total and LDL-cholesterol. Linear regression analysis showed that morning cortisol and Apelin levels independently predicted HOMA levels in subjects with adrenal adenomas. CONCLUSION: Subjects with non-functioning adrenal adenomas feature several cardiovascular risk factors even when compared to BMI matched individuals. Subtle cortisol autonomy in adrenal adenomas may be associated with those findings.

Plasma thrombin-activatable fibrinolysis inhibitor levels are not associated with glucose intolerance and subclinical atherosclerosis in women with previous gestational diabetes.

We aimed to determine plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels in women with previous gestational diabetes mellitus (GDM) and to evaluate the possible association of plasma TAFI with glucose intolerance and markers of subclinical atherosclerosis. This cross-sectional study was performed in 111 women with previous GDM and 60 controls. Glucose intolerance was evaluated. Homeostasis model assessment score was calculated. Circulating lipids, interleukin-6, matrix metalloproteinase-1, fibrinogen, plasminogen activator inhibitor-1, and TAFI antigen levels were assayed. Carotid intima media thickness (IMT) was measured. Women with previous GDM had increased levels of atherosclerosis markers and carotid IMT. On the other hand, plasma TAFI antigen levels were similar (P = .395). Thrombin-activatable fibrinolysis inhibitor was not associated with the indices of insulin resistance, glucose intolerance, markers of atherosclerosis, and carotid IMT. Our data demonstrated that plasma TAFI was not altered in women with previous GDM. TAFI was not associated with glucose intolerance and subclinical atherosclerosis.

Increased osteoprotegerin levels in women with previous gestational diabetes developing metabolic syndrome.

Osteoprotegerin (OPG), a novel soluble member of tumour necrosis factor receptor superfamily, has been shown to link cardiovascular disorders. The aim of this study is to investigate the potential relationship between serum OPG levels, cardiovascular risk factors and metabolic syndrome in a relatively large group of women with previous GDM. In this cross-sectional case-control study, 128 women with previous GDM and 67 age-matched controls were enrolled. Subjects were evaluated for the diagnosis of metabolic syndrome according to the criteria of the American Heart Association (AHA). Fasting glucose, insulin, serum lipids, CRP and OPG were assayed. HOMA score was calculated. Carotid intima media thickness (IMT) was measured. There was no significant increase in OPG levels in women with previous GDM when compared to controls. On the other hand, women with previous GDM developing metabolic syndrome had higher OPG levels than those without metabolic syndrome and healthy controls. Serum OPG levels were associated with obesity, insulin resistance, serum CRP and carotid IMT. Serum OPG is related to cardiovascular risk factors and metabolic syndrome, and might be involved in the development of cardiovascular disorders in women with previous GDM.

Effect of levothyroxine suppression therapy on plasma thrombin activatable fibrinolysis inhibitor antigen levels in benign thyroid nodules.

OBJECTIVE: The aim of this prospective study was to investigate the effect of LT4 suppression therapy on plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen and plasminogen activator inhibitor-1 (PAI-1) levels in benign thyroid nodules. We also compared hyperthyroid patients and healthy controls. SUBJECTS AND METHODS: Twenty premenopausal women with benign thyroid nodules were given LT4 suppression therapy for 1 year. Plasma TAFI and PAI-1 antigen levels were measured at baseline and after LT4 suppression treatment. The endogenous hyperthyroid group was composed of 19 premenopausal females with newly diagnosed endogenous hyperthyroidism. Eighteen age-matched euthyroid healthy premenopausal women were enrolled as the control group. RESULTS: TAFI antigen levels decreased after LT4 suppression treatment; however, the difference was not statistically significant (p = 0.057). LT4 treatment resulted in a nonsignificant increase in PAI-1 levels. Patients with endogenous hyperthyroidism had decreased levels of TAFI antigen and increased levels of PAI-1 antigen (p < 0.05). There was a negative correlation between the FT(4) and TAFI antigen levels. Serum TSH was positively correlated with the plasma levels of TAFI antigen. CONCLUSION: LT4 suppression therapy for benign thyroid nodules did not result in a significant decrease in TAFI antigen levels in premenopausal women, but endogenous hyperthyroidism was associated with significantly decreased levels of TAFI antigen.

The effect of the acute submaximal exercise on thrombin activatable fibrinolysis inhibitor levels in young sedentary males.

Depending on type, duration, and intensity of the exercise, changes occur in hemostasis. In this study, we evaluated the changes in the parameters of coagulation and fibrinolytic systems that happened after the submaximal aerobic exercises by bicycle ergomater. Twelve healthy male participants whose ages were between 21 and 28 have been included. The venous samples have been drawn before the exercise as well as at the 0 th, 15th, and 60th minutes after the submaximal exercise. The values of prothrombin time (PT), active partial thromboplastin time (aPTT), D-dimer, fibrinogen, plasminogen activator inhibitor 1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) have been measured. Plasminogen activator inhibitor 1 values have shown an insignificant increase after exercise (P = .328), whereas, it has decreased significantly during the resting period (P = .033) Postexercise 15th and 60th minutes TAFI values have decreased significantly comparing to basal and postexercise (0 th minute) values (P = .001). Fibrinolytic system activation is observed after acute submaximal aerobic exercise of sedentary healthy participants.

Comparison of vitreous and plasma levels of vascular endothelial growth factor, interleukin-6 and hepatocyte growth factor in diabetic and non-diabetic retinal detachment cases.

We compared the vitreous and plasma levels of proinflammatory cytokines in diabetic patients who underwent pars plana vitrectomy. Levels of proinflammatory cytokines in the vitreous were higher in the diabetic patients than the non-diabetics while the levels of plasma cytokines were similar. It is thought that this increase in the vitreous is effective in the progression of angiogenesis and the development of proliferative diabetic retinopathy.

The levels of soluble CD40 ligand and C-reactive protein in normal weight, overweight and obese people.

OBJECTIVE: Obesity has been suggested as an independent risk factor for cardiovascular disease. Increasing evidence shows that engagement of soluble CD40 ligand (sCD40L) with its receptor plays a crucial role in the pathogenesis of atherosclerosis. The aim of the present study was to test whether obesity is associated with low-grade systemic inflammation as measured by serum high-sensitive C-reactive protein (hsCRP) and sCD40L concentration. METHODS: Serum hsCRP and sCD40L concentrations were measured in 148 nondiabetic people. The participants were divided into three groups depending upon their body mass index (BMI) levels: Group 1 (normal weight), BMI<25 kg/m(2); Group 2 (overweight), BMI 25 kg/m(2) to 29.9 kg/m(2); and Group 3 (obese), BMI>or=30 kg/m(2). RESULTS: Obese people had more elevated hsCRP levels than both their normal weight and overweight counterparts (P=0.000 and P=0.000, respectively). Similarly, serum concentrations of sCD40L were significantly higher, statistically, in obese subjects compared with normal weight subjects (P=0.003). In addition, obese subjects had higher values of sCD40L than overweight subjects, but the difference did not reach statistical significance (P=0.063). The levels of high-density lipoprotein cholesterol were significantly lower in obese subjects compared to normal weight subjects (P=0.048). The analysis of platelet count disclosed a statistically significant difference between obese subjects and normal weight subjects (P=0.028). The levels of BMI were positively correlated with the serum levels of hsCRP and sCD40L in all subjects (r=0.514, P=0.000 and r=0.283, P=0.000, respectively). Levels of hsCRP were positively correlated with waist circumference, fasting glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, leukocytes, platelets, systolic and diastolic blood pressure. Similarly, soluble CD40L levels were positively correlated with waist circumference, fasting glucose and leukocytes. CONCLUSION: Obese patients showed a significant increase of hsCRP and sCD40L levels compared with normal weight subjects, which might contribute to the known proinflammatory milieu found in these patients.

Enhanced levels of soluble CD40 ligand and C-reactive protein in a total of 312 patients with metabolic syndrome.

The metabolic syndrome (MS) is associated with a systemic inflammatory response that plays an important pathogenetic role in atherothrombotic disease. Increasing evidence indicates that CD40-CD40 ligand interactions constitute an important mediator for vascular inflammation. The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L) levels were increased in patients with MS. During the study period from January 2004 to August 2004, 312 patients with MS and 98 control subjects were included. Anthropometric measurements, blood pressure assessment, electrocardiography, and blood measurements including fasting blood glucose, postprandial blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glycated hemoglobin, white blood cell (WBC), platelets, hs-CRP, and sCD40L were performed. Patients with MS were divided into 3 groups based upon their glucose tolerance (group 1, normal glucose tolerance; group 2, prediabetic group; and group 3, diabetes mellitus). Patients with MS showed a significant increase of WBC, hs-CRP, and sCD40L levels compared with control subjects. The levels of both hs-CRP and sCD40L were positively correlated with body mass index (BMI). High-sensitivity CRP levels were also positively correlated with waist circumferences, fasting blood glucose, postprandial blood glucose, and glycated hemoglobin, and negatively correlated with high-density lipoprotein cholesterol. In patients with MS, both hs-CRP and sCD40L levels were positively correlated with WBC count. We found a positive correlation between sCD40L and platelets. Among the subgroups of patients with MS, the mean levels of WBC, hs-CRP, and sCD40L did not show any significant differences. In conclusion, elevated levels of WBC, hs-CRP, and sCD40L in MS patients provide further insight into the relationship between MS and inflammation. In our study, positive correlations between BMI and both hs-CRP and sCD40L levels suggest that BMI is an important determinant of a chronic inflammatory state in patients with MS. Moreover, this study reports significantly increased levels of WBC, hs-CRP, and sCD40L not only in diabetic subjects with MS but also in prediabetic subjects and nondiabetic subjects with MS compared with control subjects. Our data suggest that MS patients have proinflammatory state independent of their glucose tolerance status. In our study, the positive correlation between the levels of sCD40L and platelets in patients with MS supports previous reports indicating that sCD40L are derived predominantly from platelets.

Soluble CD40 ligand, plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor-1-antigen in normotensive type 2 diabetic subjects without diabetic complications. Effects of metformin and rosiglitazone.

OBJECTIVE: To evaluate subclinical inflammation and fibrinolysis in low-risk type 2 diabetic subjects and to assess the efficacy of metformin and rosiglitazone in this group. SUBJECTS AND METHODS: Sixty-one normotensive, normoalbuminuric type 2 diabetic subjects without diabetes-related complications were included in a 4-week standardization period with glimepiride. After the standardization period, 21 subjects were excluded and the remaining 40 were randomly divided into two groups matched for age, gender, body mass index and disease duration. The first group (n = 20) received metformin (1,700 mg/day), the second group (n = 20) rosiglitazone (4 mg/day) for 12 weeks. Patients with low-density lipoprotein-cholesterol higher than 130 mg/dl at the beginning of the randomization period were treated with simvastatin (maximum dose 20 mg/day). Twenty-three healthy controls were also recruited. Cytokine measurements were performed with ELISA kits. RESULTS: Baseline plasma plasminogen activator inhibitor-1 (PAI-1) level of type 2 diabetic subjects was significantly elevated (p = 0.038), but baseline levels of soluble CD40 ligand (sCD40L) and thrombin-activatable fibrinolysis inhibitor-1 (TAFI) antigen did not differ from healthy controls. Twelve weeks of metformin or rosiglitazone therapy did not cause significant changes in sCD40L, PAI-1 and TAFI antigen levels. In simvastatin-treated subjects (n = 9) significant reductions of PAI-1 were achieved (p = 0.028), while sCD40L and TAFI-Ag did not differ from baseline values. CONCLUSION: Our results showed that nonobese diabetic patients at low cardiovascular risk had similar levels of subclinical markers of inflammation and fibrinolysis as matched healthy controls. Neither metformin nor rosiglitazone caused marked changes in sCD40L, PAI-1 and TAFI antigen levels. A subset of patients who received simvastatin showed a modest decrease in PAI-1 level and could contribute to beneficial vasculoprotective effect of the drug in type 2 diabetics.

Levothyroxine (LT4) suppression treatment for benign thyroid nodules alters coagulation.

OBJECTIVE: Endogenous hyperthyroidism is associated with altered coagulation. The aim of the present study is to investigate the effect of levothyroxine (LT(4)) suppression treatment for benign thyroid nodules on coagulation system. DESIGN: Prospective case-control study. Patients Thirty consecutive euthyroid pre-menopausal women with nodular goitre disease and 28 healthy controls were included in the study. MEASUREMENTS: Plasma fibrinogen, d-dimer, von Willebrand factor (vWF), tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were measured at baseline and after LT(4) suppression therapy. RESULTS: Plasma levels of fibrinogen, d-dimer, vWF, TF and PAI-1 increased significantly after treatment with LT(4) for 1 year. Serum FT(4) was a significant predictor of increased fibrinogen, vWF and PAI-1 levels, when the data was controlled for age and BMI. CONCLUSIONS: Our results suggest that LT(4) suppression therapy for benign thyroid nodules is associated with enhanced coagulation.

Serum osteoprotegerin is associated with carotid intima media thickness in women with previous gestational diabetes.

Circulating levels of osteoprotegerin (OPG) have been shown to be increased in patients with cardiovascular disorders and diabetes. The aim of this study was to determine serum OPG levels in women with previous gestational diabetes (GDM), and to investigate the relationship between OPG and carotid intima media thickness (IMT) and circulating cardiovascular risk factors. Serum OPG was measured in 46 women with previous GDM and 30 age-matched healthy controls. Carotid IMT was evaluated. Serum lipid, insulin and hsCRP levels, plasma fibrinogen, vWF and PAI-1 levels were measured. Serum OPG levels tended to be increased in women with previous GDM (p=0.058). Carotid IMT was increased in the study group. Women with previous GDM had elevated levels of hsCRP and PAI-1. OPG levels were positively correlated with age, fasting and post-load glucose levels, hsCRP, and carotid IMT. Multiple regression analysis showed that serum OPG was a statistically significant predictor for elevated carotid IMT. Our results revealed that OPG levels tended to be elevated in women with previous GDM. Significant association of OPG with carotid IMT suggested that OPG might play a role in the pathogenesis of endothelial dysfunction in women with previous GDM.