Anti-tumor Necrosis Factor Alpha (Infliximab) Attenuates Apoptosis, Oxidative Stress, and Calcium Ion Entry Through Modulation of Cation Channels in Neutrophils of Patients with Ankylosing Spondylitis.

Ankylosing Spondylitis (AS) is known to be associated with increased neutrophil activation and oxidative stress, however, the mechanism of neutrophil activation is still unclear. We have hypothesized that the antioxidant and anti-tumor necrosis factor properties of infliximab may affect intracellular Ca(2+) concentration in the neutrophils of AS patients. The objective of this study was to investigate the effects of infliximab on calcium signaling, oxidative stress, and apoptosis in neutrophils of AS patients. Neutrophils collected from ten patients with AS and ten healthy controls were used in the study. In a cell viability test, the ideal non-toxic dose and incubation time of infliximab were found as 100 µM and 1 h, respectively. In some experiments, the neutrophils were incubated with the voltage-gated calcium channel (VGCC) blockers verapamil + diltiazem (V + D) and the TRPM2 channel blocker 2-aminoethyl diphenylborinate (2-APB). Intracellular Ca(2+) concentration, lipid peroxidation, apoptosis, caspase 3, and caspase 9 values were high in neutrophils of AS patients and were reduced with infliximab treatment. Reduced glutathione level and glutathione peroxidase activity were low in the patients and increased with infliximab treatment. The intracellular Ca(2+) concentrations were low in 2-APB and V + D groups. In conclusion, the current study suggests that infliximab is useful against apoptotic cell death and oxidative stress in neutrophils of patients with AS, which seem to be dependent on increased levels of intracellular Ca(2+) through activation of TRPM2 and VGCC.

Protective Effects of Caffeic Acid Phenethyl Ester on Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats.

We investigated the protective effect of caffeic acid phenethyl ester (CAPE) on cyclophosphamide-induced hemorrhagic cystitis in rats in comparison with 2-mercaptoethane sulfonate (MESNA). Forty male rats were randomized into four groups: group 1 (control), group 2 (cyclophosphamide), group 3 (cyclophosphamide + MESNA), group 4 (cyclophosphamide + CAPE). Cyclophosphamide injection increased malondialdehyde levels indicating oxidative stress, whereas CAPE and MESNA ameliorated malondialdehyde levels in the bladder (p < 0.05). Only catalase activities were decreased significantly in both groups (cyclophosphamide + MESNA and cyclophosphamide + CAPE, p < 0.05). Pretreatment with CAPE (p < 0.01) resulted in a significant decrease in nitric oxide levels when compared with the cyclophosphamide group. When we consider the studies that show the critical importance of increased nitric oxide levels in pathogenesis of cyclophosphamide-induced hemorrhagic cystitis, we suggest that it would be more beneficial to use MESNA with CAPE to prevent histological damage.

Hypericum perforatum modulates apoptosis and calcium mobilization through voltage-gated and TRPM2 calcium channels in neutrophil of patients with Behcet's disease.

Behcet's disease (BD) is a chronic, inflammatory, and multisystemic condition although its pathogenesis is uncertain. Main component of St. John's wort (Hypericum perforatum, HP) is hyperforin and induces antiinflammatory and antioxidant properties. We aimed to investigate effects of HP on oxidative stress, apoptosis, and cytosolic-free Ca²âº [Ca²âº](i) concentration in neutrophil of BD patients. Nine new-diagnosed active patients with BD and nine control subjects were included in the study. Disease activity was considered by clinical findings. Neutrophil samples were obtained from the patients and controls. The neutrophils from patients were divided into three subgroups and were incubated with HP, voltage-gated calcium channel (VGCC) blockers, (verapamil+dilitiazem) and non-specific TRPM2 channel blocker (2-aminoethyl diphenylborinate, 2-APB), respectively. The neutrophils were stimulated by fMLP as a Ca²âº-concentration agonist and oxidative stress former. Caspase-3, caspase-9, apoptosis, lipid peroxidation, and [Ca²âº](i) values were high in the patient groups, although cell viability, glutathione (GSH), and glutathione peroxidase (GSH-Px) values were low in patient group. However, the [Ca²âº](i), caspase-3, and caspase-9 values decreased markedly in patient+HP group although GSH and GSH-Px values increased in the group. The [Ca²âº](i) concentration was also decreased in the patient group by V+D, 2-APB, and HP incubations. In conclusion, we observed the importance of neutrophil Ca²âº entry, apoptosis, and oxidative stress through gating VGCC and TRPM2 channels in the neutrophils in the pathogenesis and activation of the patients with BD. HP induced protective effects on oxidative stress by modulating Ca²âº influx in BD patients.

Demographic and clinical features of gout patients in Turkey: a multicenter study.

Gout results from multifactor interactions between gender, age, genetic and environmental factors. Environmental factors underlying gout and precipitating factors triggering acute attacks might vary in different populations with different lifestyles. In this study, we aimed to collect data regarding the demographic and clinical features, comorbid factors, and precipitating factors associated with the initiation of acute attacks in gout patients in Turkey. A total of 312 patients were included in this study (mean age, 58.8 ± 13.8 years; female/male ratio, 55/257). The demographic features, alcohol intake, clinical and laboratory features, and comorbid conditions including obesity, diabetes mellitus, hyperlipidemia, hypertension, and coronary heart disease were noted in a standard questionnaire. Precipitating factors initiating acute attacks (if any) were also noted. The patients were divided into 4 groups according to the region of location as central Anatolian region, southeast Anatolian region, Aegean region, and Trakya region. Our results were compared according to the gender and the location of the patients. The mean age at the start of the symptoms was 10 years higher in women (60.4 ± 14.8 and 50.6 ± 13.5 years in women and men, respectively, p < 0.001).Obesity was present in 40.1 %, diabetes mellitus in 17.9 %, hyperlipidemia in 30.1 %, hypertension in 53.5 %, coronary artery disease in 17 %, and nephrolithiasis in 21.8 % of patients. Precipitating factors triggering gout flares were as follows: diet (high consumption of meat or fish) in 46.5 %, alcohol consumption in 15.7 %, diuretics in 8.3 %, diet or diuretics in 5.1 %, diet or alcohol in 4.5 %, diet or alcohol or diuretics in 1.6 %, others in 4.2 %, and none in 14.1 %. The presence of diabetes and diuretic use was more common among women. Use of diuretics is a more common trigger for gout flares among women. On the other hand, various comorbid conditions, such as obesity and hypertension, and triggers for gout flares may differ between patients living in different geographic regions. In summary, we reported the first data regarding clinical and demographic characteristics of gout in Turkey. The majority of our patients could describe at least one "trigger" that initiated gout flare. Both comorbid conditions and triggers of attack might differ between men and women, and in different geographic areas. Better knowledge of the modifiable risk factors can be useful for the management strategy to optimize long-term patient outcomes in local clinics.

Dentofacial characteristics of patients with rheumatoid arthritis.

OBJECTIVES: The aims of this study are to evaluate the dentofacial morphology of patients with rheumatoid arthritis (RA) and to compare the morphological data with those of healthy age- and sex-matched control subjects. METHODS: Twenty-seven RA patients (mean age, 45.77 ± 8.64 years) and 25 healthy subjects (mean age, 44.80 ± 8.24 years) participated in this prospective study. Clinical and functional evaluations of the RA patients were assessed. The erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor level, and anti-citrullinated peptide antibodies (ACPA) titers of RA patients were determined, and DAS28 scores were calculated. Linear and angular measurements were performed on cephalometric tracings and condylar erosion was evaluated on lateral panoramic radiographs. Statistical comparison of the two groups was performed with an independent samples t test. Pearson correlation analysis was used to assess the relationship between the clinical and laboratory parameters. RESULTS: Based on DAS28 scores, no patient with RA was in the remission period, 3 patients had low, 23 had medium, and 1 had high disease activity. Sixteen (59.26 %) patients with RA had positive ACPA titers. Lateral cephalometric radiographs revealed statistically significant difference between the two groups for the measurement of U1-NA (millimeter; p = 0.047), U1-NA (degrees; p = 0.031), L1-NB (degrees; p = 0.030), IMPA (L1-MP; p = 0.001), interincisal angle (U1-L1; degrees; p = 0.022) and midface length (Co-A; millimeter; p = 0.033). A significant positive linear correlation was found between disease duration time and DAS28 scores (r = 0.066, p = 0.040). CONCLUSIONS: Dentoalveolar effects of RA on dentofacial morphology are more significant than the skeletal effects. Future studies with larger sample sizes are required to evaluate the exact effects of RA on dentofacial morphology. CLINICAL RELEVANCE: Clinicians should consider the fact that RA-associated dentoalveolar changes can be observed and may affect the orthodontic treatment process.

Clinical and magnetic resonance imaging findings of the temporomandibular joint and masticatory muscles in patients with rheumatoid arthritis.

The aim of this study was to investigate the clinical, radiographic, and magnetic resonance imaging (MRI) findings of temporomandibular joint (TMJ) and masticatory muscles in rheumatoid arthritis (RA) patients. Twenty-eight RA patients and 29 healthy subjects were participated in the study. The patient underwent clinical and laboratory investigation. DAS28 scores were calculated. Lateral panoramic radiography was performed to evaluate condylar erosion and condylar movement. Craniofacial MRI was performed to evaluate TMJ and masseter, medial and lateral pterygoid muscles' thickness, and cross-sectional area. It was found that the mean maximal interincisal distance, range of lateral, retrusive (P < 0.05) and protrusive motion were all lesser in RA group. Lateral panoramic radiography revealed a distinct erosion in 10.7% (3/28) and restricted condylar movement in 53.6% (15/28) of RA patients. Two RA patients demonstrating marked condylar erosion in lateral panoramic radiographs were RF negative and had DAS28 scores 3.41 and 4.61. MRI findings revealed condylar erosion and effusion in one RA patient and atrophic changes of masticatory muscles in another patient. There was no statistical significance between RA and healthy groups for the thickness and cross-sectional areas of the masticatory muscles. RA group revealed a strong linear relationship for the right and left muscle thickness and cross-sectional areas in regression analysis. TMJ symptoms are frequent findings and thought to be affected from mean disease duration in RA. Laboratory findings should be considered for disease activity-related TMJ involvement. RA patients did not present muscular atrophy or hypertrophy.

A clinical threat in patients with granulomatosis polyangiitis in remission: Subglottic stenosis.

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing granulomatous disease that involves small- and medium-sized arteries and affects the main respiratory tracts and kidneys. Upper respiratory tract involvement usually occurs in 90% of patients, who most frequently present with symptoms of chronic sinusitis. Subglottic stenosis (SS) is a rare and severe complication that is usually observed in approximately 15% of patients. Here we present a case of SS in a patient with limited form of GPA during remission.

Catastrophic antiphospholipid syndrome treated with rituximab: A case report.

Catastrophic antiphospholipid syndrome (CAPS) is a rare and fatal condition that is characterized by diffuse venous and/or arterial thromboembolism within a short period of time and histopathological confirmation of small-vessel occlusion in at least one organ or tissue in the presence of positive antiphospholipid antibodies. Here we report the case of a 19-year-old woman with CAPS. During the first week of her hospitalization, she was diagnosed with CAPS on the basis of skin necrosis, pulmonary artery thrombosis, cerebral venous sinus thrombosis, and positive lupus anticoagulant. She was treated with corticosteroids, intravenous immunoglobulins, plasmapheresis, and anticoagulants. Forty days after the onset of CAPS, cutaneous lesions were recurred during skin surgery. She required a high dose of corticosteroids, intravenous immunoglobulins, and rituximab. No further thrombotic events occurred. Rituximab may be an effective treatment option for patients with CAPS.

Sacroiliitis and Polyarteritis Nodosa in a Patient with Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder with autosomal recessive inheritance, characterized by recurrent fever and episodes of serositis. The condition is known to be caused by mutations in the MEFV (Mediterranean FeVer) gene, located in the short arm of chromosome 16. While more than 310 sequence variants in the MEFV gene have been described to date, the diagnosis is still established clinically. FMF may be accompanied by sacroiliitis and various forms of vasculitis. The most common forms of associated vasculitis are Henoch-Schonlein purpura and polyarteritis nodosa (PAN). We have presented here a fairly rare case of FMF, accompanied by both sacroiliitis and PAN.

The significance of urinary beta-2 microglobulin level for differential diagnosis of familial Mediterranean fever and acute appendicitis.

The clinical and laboratory parameters widely used are not specific to discriminate the abdominal pain due to FMF attack from that of acute appendicitis. The present study aims to investigate the urinary beta-2 microglobulin (U-ß2M) level as a potential parameter to identify these two diseases mimicking each other. A total of 51 patients with established FMF diagnosis due to Tel Hashomer criteria on colchicine treatment (1-1.5 mg/day), 15 patients with acute appendicitis who had appropriate clinical picture and were also supported pathologically after the surgery, and 20 healthy controls were enrolled in the study. Of the 51 patients with FMF, 25 were at an attack period, while remaining 26 were not. For the diagnosis of acute attack, as well as physical examination, laboratory tests including white blood cell count, C-reactive protein, and erythrocyte sedimentation rate were performed. From urine specimens U-ß2M, microalbumin, and N-acetyl glucosaminidase (U-NAG) were measured. U-ß2M levels were significantly higher in acute appendicitis group compared to FMF attack, FMF non-attack, and control groups (p < 0.001, p < 0.001, and p < 0.001, respectively). U-NAG and microalbuminuria were significantly higher in acute appendicitis, FMF attack, and FMF non-attack groups compared to controls (U-NAG p < 0.001, p = 0.016, p = 0.004, microalbuminuria p < 0.001, p < 0.001, p < 0.001, respectively). Microalbuminuria was significantly higher in acute appendicitis group compared to the FMF attack group (p = 0.004). Determination of U-ß2M levels may be helpful for differential diagnosis of peritonitis attacks of FMF patients on colchicine treatment and acute appendicitis. However, this finding should be substantiated with other studies.

Arterial stiffness is associated with left ventricular dysfunction in patients with rheumatoid arthritis.

Arterial stiffness (AS) has a detrimental effect on cardiovascular system particularly on left ventricle (LV). The aim of the study was to evaluate the impact of AS on LV functions in patients with rheumatoid arthritis (RA). Forty patients with RA and 25 age-sex matched control subjects (mean age 48.5 ± 6.3 vs. 45.1 ± 6.9 years, respectively, p = 0.06) were enrolled in study. AS was assessed by carotid-femoral pulse wave velocity (CF-PWV) and heart rate corrected augmentation index (AIx@75) measured by applanation tonometry (SphygmoCor). LV function was evaluated using tissue Doppler-derived myocardial performance index (MPI) from lateral mitral annulus. CF-PWV (28.3 ± 10.3 vs. 21.8 ± 9.3 m/s, p = 0.03), AIx@75 (10.2 ± 2.3 vs. 9.2 ± 1, %, p = 0.01) and MPI (0.46 ± 0.12 vs. 0.36 ± 0.1, p < 0.001) were significantly higher in patients with RA than in controls. LV MPI was found to be significantly positive correlated with CF-PWV, AIx@75, and ESR (r = 0.360, p = 0.005; r = 0.334, p = 0.009; r = 0.293, p = 0.023, respectively). Arterial stiffness parameters including CF-PWV and AIx@75 are associated with subclinical left ventricular dysfunction in patients with RA.

Two new inflammatory markers associated with Disease Activity Score-28 in patients with rheumatoid arthritis: neutrophil-lymphocyte ratio and platelet-lymphocyte ratio.

AIM: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with unknown etiology and systemic involvement. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are two new inflammatory markers used in the assessment of systemic inflammation. The aim here is to study NLR and PLR in patients with RA to investigate their relation with Disease Activity Score of 28 joints (DAS-28). METHODS: The study included 104 patients with RA and a control group of 51 age- and gender-matched healthy subjects. We divided the patients into two groups according to the DAS-28 score. Group 1 included patients with a score of lower than 2.6 by the DAS-28 (patients in remission) and Group 2 included patients with a score of 2.6 and higher (patients with active disease). RESULTS: NLR was 2.12 ± 0.83 in the patient group and 1.58 ± 0.57 in the control group. PLR was 136.50 ± 53.52 in the patient group and 114.84 ± 29.41 in the control group. There was a statistically significant difference in NLR and PLR between the patient and control groups (P ≤ 0.0001 and P = 0.001, respectively). Patients in Group 1 had an NLR of 1.84 ± 0.61 and a PLR of 119.25 ± 41.77. Patients in Group 2 had an NLR of 2.29 ± 0.90 and a PLR of 147.28 ± 56.96. There was a statistically significant difference in NLR and PLR between the two groups (P = 0.003 and P = 0.005 respectively). A correlation was observed between NLR and PLR by DAS-28 (r = 0.345, P ≤ 0.0001 and r = 0.352, P ≤ 0.0001, respectively). CONCLUSIONS: The present study showed us that NLR and PLR were two new inflammatory markers which could be used to assess disease activity in patients with RA.

Anti TNF-α therapy might be responsible for an increased incidence of varicocele in patients with ankylosing spondylitis.

AIM: To evaluate the effects of anti-tumor necrosis factor-alpha (TNF-α) therapy on the frequency of varicocele in patients with ankylosing spondylitis (AS) using color Doppler ultrasound. MATERIALS AND METHODS: The patients were divided into 2 groups: patients with AS who were on anti-TNF-α treatment and patients with AS who were not regularly taking any antiinflammatory drugs. Thirty-one healthy volunteers were included as controls. RESULTS: Left-sided varicocele was determined in 14 patients of Group 1 (44%), 10 patients of Group 2 (33%), and 7 of the controls (23%). There was a statistically significant difference only between Group 1 and controls (P = 0.009). However, right-sided varicocele was determined in 12 patients of Group 1 (38%), 2 patients of Group 2 (6%), and 2 of the controls (6%) (P = 0.01 vs. Group 2, P = 0.005 vs. controls). CONCLUSION: The present study shows that patients with AS who were taking anti-TNF-a therapy had an increased prevalence of right- sided and bilateral varicocele compared to patients with AS who were not taking any disease-modifying antirheumatic drugs and the healthy control group.

Potential role of interleukin-18 in patients with rheumatoid arthritis-associated carotid intima-media thickness but not insulin resistance.

OBJECTIVE: Plasma interleukin-18 (IL-18) has been reported to be associated with homeostasis model assessment of insulin resistance (HOMA-IR). It also has been described as one of the factors that, in addition to insulin resistance, may also contribute to atherosclerosis. Parameters of systemic inflammation are also significantly associated with circulating IL-18. Our objective was to investigate whether IL-18 is associated with insulin resistance and atherosclerosis in patients with rheumatoid arthritis (RA) in which accelerated atherogenesis develops. MATERIAL AND METHODS: Fifty-one female RA patients and 30 female controls were enrolled in the study; 31 of them were without disease-modifying antirheumatic drug (DMARD) treatment and had a relatively short disease duration. Disease activity was assessed by Disease Activity Score (DAS) 28 index. HOMA-IR method was used to detect insulin resistance. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fasting plasma glucose (FPG), insulin, tumor necrosis factor alpha (TNF-α), and IL-18 levels were evaluated. Also, carotid intima-media thickness (cIMT) was measured. RESULTS: There were no differences between patients and the control group according to age, sex, and body mass index. ESR, CRP, insulin, FPG, HOMA-IR, TNF-α, IL-18 levels, and cIMT measurements were significantly high in the patient group. HOMA-IR and cIMT measurements were similar and high in both the DMARD and non-DMARD patient groups. HOMA-IR correlated with TNF-α (r=0.308, p=0.028), but no correlation was found between IL-18 and HOMA-IR. However, IL-18 was correlated positively with cIMT (r= 0.318, p=0.028) and negatively with BMI (r=-0.360, p=0.01). CONCLUSION: IL-18 is associated with atherosclerosis in RA patients. However, no significant relation was found with insulin resistance. IL-18 may be a marker for early evaluation of atherosclerosis in RA patients.

The efficacy and safety of etanercept in patients with rheumatoid arthritis and spondyloarthropathy on hemodialysis.

We aimed to evaluate the efficacy and safety of long-term use of etanercept therapy in patients with spondyloarthropathy (SpA) and rheumatoid arthritis (RA) on hemodialysis (HD). Selected RA or SpA patients treated with etanercept under HD were retrospectively evaluated. Etanercept-related adverse events were closely recorded for all patients. At the follow-up, erythrocyte sedimentation rate and C-reactive protein levels were monitored. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for SpA patients and Disease Activity Score (DAS28) for RA patients were measured at every 3 or 6 months. In total five end-stage renal disease (ESRD) patients were enrolled to the study. The causes of ESRD in the study subjects were amyloidosis (n = 2), analgesic nephropathy (n = 2), and nephrolithiasis (n = 1). Three were diagnosed as SpA and two were RA. All patients used etanercept. The median age was 39 years (range 22-72 years). The median disease duration was 12 years (range 2-20 years). The median follow-up after etanercept therapy was 18 months (range 5-33 months). DAS28 score decreased after the treatment and did not increase during follow-up in RA patients. BASDAI score decreased after the treatment during follow-up in three patients with SpA. At the follow-up, only one patient was diagnosed with septic arthritis. As a result of our study, etanercept treatment in RA and SpA patients on HD seems to be safe, well tolerated, and effective in most of the patients. Above all, due to impaired host defense in patients with ESRD, enhanced risk of infections should be kept in mind during follow-up period and larger trials are needed to prove the safety of etanercept in HD patients.

Effect of endemic fluorosis on hematological parameters.

Although so many studies exist on effect of fluoride on hematological parameters in experimental animals, a few studies have been conducted to investigate the effects of chronic fluorosis on hematological parameters in humans' subjects with endemic fluorosis. So we aimed to determine the hematological parameters in patients with endemic fluorosis. The study group consisted of 60 patients with endemic fluorosis (27 females, 33 males, and mean age 33.4 ± 9.6 years). An age-, gender-, and body mass index-matched control group was composed of 34 healthy volunteers (11 females, 23 males with a mean age 32.6 ± 5.6 years). Urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (0.42 ± 0.09 vs 1.92 ± 0.14 mg/l, respectively; P < 0.001). There were no statistically significant differences between the fluorosis group and control group with respect to hematological parameters (complete blood count and ferritin). We concluded that chronic fluorosis has no effect on hematological parameters in patients with endemic fluorosis.