The Effects of Adalimumab in Behçet Disease Patients on Clinical Manifestations and on Pro-Inflammatory Cytokines Milieu: Long-Term Follow-Up.

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

[ULTRASOUND FOR IMAGING OF ACUTE SHOULDER DISEASES].

INTRODUCTION: The shoulder is a complex multi-component structure of the musculoskeletal system with numerous elements within a limited space. These comprise of two joints, synovial sucks (bursa), tendons of rotator cuff, ligaments, multiple muscles, nerves, vessels, fat, bones and skin. Ultrasound (US) investigation of the shoulder enables us to obtain precise information of the anatomy at stasis and motion. Acquired experience and skills in the performance of the US study and knowledge of shoulder structure are a basis for diagnosis of shoulder problems. Analyzing six clinical cases with urgent shoulder diseases, we indicated the importance of US for diagnostic and therapeutic purposes.

[THE INPUT OF MEASURING INFLIXIMAB LEVELS AND LEVELS OF ANTIBODIES TO INFLIXIMAB IN THE MANAGEMENT OF PATIENTS WITH RHEUMATIC DISEASES].

BACKGROUND: High levels of infliximab (IFX) directed antibodies (IFX-Ab) may result in significant reduction in IFX concentration and loss of drug efficacy. OBJECTIVES: To assess the input of measuring serum IFX levels and levels of IFX-Ab in the management of rheumatic diseases. METHODS: Serum levels of IFX and anti-IFX-Ab were measured by ELISA (IFX-Abs were also identified by anti-human lambda chain Ab) and correlated to patients (responders and nonresponders) disease activity scores. RESULTS: A total of 144 tests for IFX were performed in 91 patients (mean age 50.2 years and disease duration 9.9 years). Among responders (57 patients) levels (mean, median) of IFX were significantly higher than in non-responders (34 patients) (4.2 mcg/ml (2.3) versus 1.1 mcg/ml (0.45)); levels of IFX-Ab in responders were significantly lower than in non-responders (4.59 mcg/ml (1.0) versus 13.1 (6.1)). High IFX-Ab levels predicted IFX discontinuation in 8.8% of responders and 55.9% among non-responders. In non-responders with low IFX levels and low IFX-Ab, the shortening of re-treatment intervals lead to significant improvement. In about 28% of patients, results of blood tests influenced treatment decisions. CONCLUSIONS: Assessment of immunogenicity of anti-TNF monoclonal antibodies proved useful information for guiding the therapy in rheumatic diseases with suboptimal clinical response. Patients with low IFX levels and low levels of IFXAb may benefit from increasing the drug dose or decreasing of re-treatment intervals. In patients with negligible serum levels of IFX and high levels of IFX-Ab, the therapy should be switched to another biological agent, probably with a different mechanism of action.

Ultrasound investigation of the glenohumeral joint by anterior access in patients with rheumatoid arthritis and healthy controls.

BACKGROUND: The aim of this study was to measure glenohumeral joint (GHJ) parameters via the anterior access through ultrasound and to compare to data from posterior and inferior accesses. MATERIAL AND METHODS: Twenty healthy controls (M: F=15: 5, aged 45.1±11.2 years) and 16 patients (M: F=5: 11, aged 54.6±14.7 years) with active rheumatoid arthritis (RA) (DAS 28 4.6±1.2) were investigated (SonoSite-Titan). To make the GHJ visible on the anterior access, we used the original GHJ opening maneuver. The GHJ width was measured for every transducer position at 2 points. The positions were: posterior transversal, inferior longitudinal, anterior longitudinal along the articular line, anterior transversal upper, middle and lower. The joint width included thickness of cartilage plus synovial fluid/pannus. Rotator interval (RI) width and height (upper biceps channel) were measured. RESULTS: Our normal GHJ values by posterior and inferior accesses were within previously estimated values (<2 mm and <3 mm, respectively). We acquired the first values of GHJ width from the anterior access. The last were within a range of 0.7-1.7 mm for healthy controls. Patients with RA showed significantly enlarged joint cavities. RI was not inflamed. Posterior and inferior data of GHJ width were significantly correlated (p=0.01). The data did not correlate with anterior values (p=+0.44, p=-0.56). Synovitis was much more prominent in posterior, upper anterior transversal, and anterior longitudinal accesses. CONCLUSIONS: The GHJ may be visualized by anterior access using a special maneuver. Synovitis in the anterior region of the GHJ may develop at an independent rate. Anterior GHJ sonography may be complementary to the classic access.

Long-term follow-up of patients with scleroderma interstitial lung disease treated with intravenous cyclophosphamide pulse therapy: a single-center experience.

BACKGROUND: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12-24 months in most reports. OBJECTIVES: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up. METHODS: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1,4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed. RESULTS: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0-4 and 4-7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G). CONCLUSIONS: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

Rituximab: rescue therapy in life-threatening complications or refractory autoimmune diseases: a single center experience.

Rituximab (RTX) is a chimeric anti-CD20 antibody, approved for rheumatoid arthritis (RA) patients who failed anti-Tumor Necrosis Factor therapy. It has been used occasionally for life-threatening autoimmune diseases (AID). We report our center experience in the use of RTX in life-threatening complications or refractory AID. Clinical charts of patients treated with RTX at our center were reviewed, cases treated for life-threatening complications or refractory AID were analyzed. Acute damage to vital organs such as lung, heart, kidney, nervous system with severe functional impairment were defined as life-threatening complications; treatment failure with high-dose corticosteroids, cyclophosphamide, IVIG, plasmapheresis was defined as refractory autoimmune disease. During the years 2003-2009, 117 patients were treated with RTX, most of them for RA. Nine patients (6 females, mean age 51.5 years, mean disease duration 6.3 years) answered the criteria. The indications were as follows: pulmonary hemorrhage (1 patient with cryoglobulinemic vasculitis, 1 with systemic sclerosis, 1 with ANCA-associated vasculitis), catastrophic anti-phospholipid syndrome (2 SLE patients), non-bacterial endocarditis and pulmonary hypertension (1 patient with mixed connective tissue disease), vasculitis and feet necrosis (1 patient with systemic lupus erythematosus), severe lupus demyelinative neuropathy and acute renal failure (1 patient), and severe rheumatoid lung disease with recurrent empyema and pneumothorax (1 patient). B cell depletion was achieved in all patients. The median time since starting of complications to RTX administration was 3 weeks (range 2-15 weeks). Complete remission (suppression of the hazardous situation and return to previous stable state) was seen in 7 out of 9 patients. Partial remission (significant improvement) was achieved in the remained. The median time to response was 3 weeks (range 1-8 weeks), mean follow-up 47.2 months (range 6-60 months). A rapid tapering off of steroids was achieved in all patients. Two patients relapsed and were successfully retreated with RTX: the patient with severe RA lung relapsed after 3 years, one of the patients with ANCA-associated pulmonary alveolar hemorrhage relapsed after 10 months. There were no side effects during RTX infusion. Two episodes of serious infections were registered: fatal Gram-negative sepsis 6 months after RTX treatment, and septic discitis 4 months after receiving RTX. RTX serves as a safe, efficient, and prompt rescue therapy in certain life-threatening conditions and resistant to aggressive immunosuppression AID. RTX when administrated at an earlier stage, prevented irreversible vital organ damage, and allowed rapid steroid tapering off in already severe immunodepressed patients.

Large leg ulcers due to autoimmune diseases.

BACKGROUND: Large leg ulcers (LLU) may complicate autoimmune diseases. They pose a therapeutic challenge and are often resistant to treatment. To report three cases of autoimmune diseases complicated with LLU. CASE REPORT: Case 1. A 55-year old woman presented with long-standing painful LLU due to mixed connective tissue disease (MCTD). Biopsy from the ulcer edge showed small vessel vasculitis. IV methylprednisolone (MethP) 1 G/day, prednisolone (PR) 1mg/kg, monthly IV cyclophosphamide (CYC), cyclosporine (CyA) 100mg/day, IVIG 125G, ciprofloxacin+IV Iloprost+enoxaparin+aspirin (AAVAA), hyperbaric oxygen therapy (HO), maggot debridement and autologous skin transplantation were performed and the LLU healed. Case 2. A 45-year old women with MCTD developed multiple LLU's with non-specific inflammation by biopsy. MethP, PR, hydroxychloroquine (HCQ), azathioprine (AZA), CYC, IVIG, AAVAA failed. Treatment for underlying the LLU tibial osteomyelitis and addition of CyA was followed by the LLU healing. Case 3. A 20-year-old man with history of polyarteritis nodosa (PAN) developed painful LLU's due to small vessel vasculitis (biopsy). MethP, PR 1 mg/kg, CYC, CyA 100 mg/d, AAVAA failed. MRSA sepsis and relapse of systemic PAN developed. IV vancomycin, followed by ciprofloxacin, monthly IVIG (150 g/for 5 days) and infliximab (5 mg/kg) were instituted and the LLU's healed. CONCLUSIONS: LLU are extremely resistant to therapy. Combined use of multiple medications and services are needed for healing of LLU due to autoimmune diseases.

Sacroiliitis and severe disability due to isotretinoin therapy.

We report a case of acute sacroiliitis with severe disability after only 3 weeks of isotretinoin therapy with graduate reduction of pain, limitation and muscle incompetence after discontinuation of the drug and ACTH-depo injection and Ethodolac therapy. Naranjo probability scale indicated a probable relationship between isotretinoin therapy and bilateral sacroiliitis. We discussed possible mechanisms of sacroiliitis and disability due to isotretinoin treatment.

Depletion of B lymphocytes in rheumatoid arthritis patients modifies IL-8-anti-IL-8 autoantibody network.

Cytokines and chemokines are key regulatory molecules involved in rheumatoid arthritis (RA). B-cell depletion therapy improves RA clinically but its mechanism is not completely understood. One possible mechanism for this therapy is the modification of the proinflammatory cytokine homeostasis of RA. We show here that the levels of the proinflammatory chemokine IL-8 in serum samples from RA patients unexpectedly increased by up to 100-fold 8 weeks after the administration of rituximab, despite clinical improvement. We also show that RA patients produced anti-IL-8 autoantibodies and that their levels dropped after RTX treatment. Moreover, we identified antibody-IL-8 immune complexes in the synovial fluid and serum of RA patients, and found that the amount of these complexes decreased after the administration of RTX. Our results indicate that B-cell depletion therapy modifies the cytokine-autoantibody network by reducing the levels of anti-cytokine autoantibodies and, consequentially, the formation of antibody-cytokine immune complexes.

Hereditary persistence of hemoglobin F is protective against red cell sickling. A case report and brief review.

Fetal hemoglobin (HbF) is a physiologic protein tetramer that is crucial for a developing fetus to survive in utero. Maternal hemoglobin has a relatively lower affinity for oxygen, and thus allows for an efficient transfer of oxygen from maternal to fetal blood. In addition to fulfilling a critical physiologic role, HbF is also known to alleviate symptoms of sickle-cell disease (SCD). The concentration of HbF depends on several factors. HbF is elevated in inherited conditions, such as hereditary persistence of HbF, hereditary spherocytosis, and thalassemia. The level of HbF is also increased in acquired states, such as pregnancy, aplastic anemia, thyrotoxicosis, hepatoma, myeloproliferative disorders, or hypoplastic myelodysplastic syndrome. It has been identified that some genetic loci have significant influence on HbF levels. The XmnI polymorphism, the HMIP locus, and the BCL11A gene are responsible for 45% of variations in HbF levels. Although SCD has been well described in the subpopulations of Africa, it is less common in the subpopulations of India. We describe a case of SCD, in which a patient with high HbF level presented at a very late age (27 years old). We presume the patient's inherently elevated HbF levels were able to compensate for the hypoxic episodes associated with SCD. The onset of symptoms was delayed as a result of elevated HbF levels.

Ultrasound imaging of fasciitis due to body-building supplement.

BACKGROUND: Fascia and soft tissues, rich in collagen, receptors of pain and capable of significant distention, may be targets of autoimmune inflammatory diseases. We observed fasciitis due to the protein supplement Pure Whey, which has not been reported previously. METHODS: Sonography (Sonosite-Titan, 5 to 10 MHz, L-38) was performed on a patient (age, 26 years; body mass index, 38 kg/m2) with protein fasciitis. He had developed compact swelling of his forearms, hands, and legs, with skin irregularity and severe disability (without peripheral eosinophilia, normal Ig and ESR 18/hr) after taking Pure Whey, containing L-tryptophan (1.4 g per 100 g of protein). A deep skin biopsy was performed. The thickness of the brachioradial fascia (BRF) was measured and compared with 10 healthy control subjects (men ages 36.7 +/- 8.3 years; body mass index, 26.4 +/- 6.5 kg/m2). RESULTS: The deep skin biopsy showed severe fat interlobular and fascial thickening with mononuclear (noneosinophilic) infiltrate and fibrosis associated with fasciitis. BRF of the 10 healthy men had a thickness of 0.75 +/- 0.19 mm, compared with the patient's 2.4 mm thickened and cleaved BRF. After 2.5 months of corticosteroid therapy (30 mg/d with tapering) and discontinuation of the protein supplement, the patient's BRF returned to a monolayer appearance. Its thickness reduced to normal (0.8 mm), with significant clinical improvement. CONCLUSIONS: This case of noneosinophilic fasciitis associated with ingestion of L-tryptophan-containing protein supplement responded favorably to corticosteroid therapy. Sonography proved to be an effective method to visualize and confirm the fasciitis and to follow the course and therapy.

Differentiating subscapular tendon and glenohumeral joint on anterior shoulder sonography.

BACKGROUND: Anterior sonography of the glenohumeral joint has been suggested as a useful method of assessing inflammatory joint disease. The proximity of the subscapular tendon (SSC) to the glenohumeral joint (GHJ) in the shoulder might require differentiating between these two structures. CASE REPORTS: Anterior shoulder sonographic evaluation (Sonosite-Titan) was carried out on four patients: active rheumatoid arthritis (1), osteoarthritis (1), healthy young man (1), silent crystal induced joint disease (1). The shoulder was in a position of supination and external rotation. SSC and GHJ were compared with the transducer located just medial to the biceps tendon (for SSC) and just lateral to the coracoid process (for GHJ). The structural and location differences between the subscapular tendon and the glenohumeral joint on anterior shoulder sonography were discerned. A transverse view of SSC with the transducer located just medial to the biceps tendon (BT) shows the following distinguishing features of the SSC: minor tuberositas, concave surface of the lower surgical neck, fibrillar structure of SSC, continuation of the lower bone margin without demonstration of the thickness of the labrum. A longitudinal view of GHJ with the transducer located just lateral to the coracoid process indicates a rate of GHJ synovial distension, convex, round humeral head with termination of its lower margin and labrum thickening, lack of fibrillar structure of GHJ, and convex round shape of the GHJ capsule. CONCLUSIONS: Differentiating SSC and GHJ on anterior shoulder sonography with above mentioned sonographic features misinterpretation of US data might be minimized.

Anti-tumor necrosis factor therapy: 6 year experience of a single center in northern Israel and possible impact of health policy on results.

BACKGROUND: Infliximab and etanercept have been included in the Israeli national list of health services since 2002 for rheumatoid arthritis and juvenile idiopathic arthritis, and since 2005 for psoriatic arthritis and ankylosing spondylitis. The regulator (Ministry of Health and health funds) mandates using fixed doses of infliximab as the first drug of choice and prohibits increased dosage. For other indications (e.g., vasculitis), anti-tumor necrosis factor therapy is given on a "compassionate" basis in severe refractory disease. OBJECTIVES: To describe our experience with anti-TNF therapy in a single tertiary referral center in northern Israel and to analyze the impact of the national health policy on the results. METHODS: We reviewed the medical records of patients who received anti-TNF therapy in our institution, and analyzed demographic data, diagnosis, clinical and laboratory features, previous and current therapies, and anti-TNF treatment duration and side effects. RESULTS: Between 2001 and 2006, 200 patients received anti-TNF therapy for rheumatoid arthritis (n = 108), juvenile idiopathic arthritis (n = 11), psoriatic arthritis (n = 37), ankylosing spondylitis (n = 29), adult Still's disease (n = 4), overlap disease (RA and scleroderma or polymyositis, n = 6), temporal arteritis (n = 1), polyarteritis nodosa (n = 1), dermatomyositis (n = 1), amyloidosis secondary to RA (n = 1) and Wegener's granulomatosis (n = 1). Forty percent of RA patients discontinued the first anti-TNF agent due to side effects or insufficient response. Higher sedimentation rate and lower or negative rheumatoid factor predicted better response to therapy among RA patients. AS and PS patients had a better safety and efficacy profile. Severe infections occurred in 2% of patients. All eight patients who presented lung involvement as part of their primary rheumatic disease remained stable or improved. A significant improvement was achieved in all six patients with overlap disease. CONCLUSION: Our daily practice data are generally in agreement with worldwide experience. The 'deviations' might be explained by the local health policy at that time. The impact of health policy and economic and administrative constraints should be taken into account when analyzing cohort daily practice data.

Alcohol poisoning and venous hyperoxia.

ABSTRACT Venous PCO(2) and PO(2) in the presence of normal arterial PCO(2) and PO(2) in patients with alcoholic intoxication have not been previously evaluated. The objective of this study was to compare arterial and venous blood gases in patients with alcoholic intoxication and healthy controls. Sixteen patients with alcoholic intoxication and 20 controls underwent simultaneous blood sampling from a radial artery and an antecubital vein for acid-base analysis. Osmolality and ethanol blood concentration was estimated. Elevated venous pO(2) were found in 56% of patients with alcoholic poisoning compared with 15% of controls. A formula was found describing possible arterio-venous shunt accounting for elevated venous pO(2) and enabling calculation of the relevant venous carbon dioxide content and CO(2) product. The values of the venous pO(2) and arterio-venous shunt were more significant in the alcohol group than in controls (p = 0.002, p = 0.001, respectively). Percentage of patients with a-v shunts was significantly higher in the alcohol group (81%) than in controls (25%) (p = 0.002, OR 2.6, 95% CI 0.13-6.52). The relevant venous CO(2) and CO(2) product had the non-significant trend to be higher in the alcohol group. In conclusion, this study reports ethanol-induced venous pO(2) and pCO(2) elevation. This may be associated with the effects of tissue perfusion stealing and high oxygen consumption. On the other hand, possible beneficial consequences may occur: acceleration of alcohol elimination and reduction of alcohol-induced tissue damage.

Advancing Understanding of the Aesthetics of Temporal Sequences by Combining Some Principles and Practices in Music and Cuisine With Psychology.

We consider how to optimize remembered aesthetic pleasure resulting from temporal sequences of events such as music and meals. We examine what psychology and music can learn from each other and how this knowledge might be applied to tasting menus and other temporal sequences. Common practices in longer musical works suggest the importance of (a) beginnings and endings, (b) variations in affective intensity over time, (c) repetitions, (d) variations on a theme, and (e) a return to prior material at the end of a piece. Results from psychology suggest that for affective memory, the final and peak experiences are most critical. For example, because a strong positive ending may be important for affective memory, and because return is a major feature of the ending of musical works, it may be an error to end meals with desserts, which are not the favorite courses for most people and typically bear no relation to prior courses (hence no return).

From molecular mimicry to cross-reactivity or pathogen expansion? A hypothesis.

Very recently, several studies have convincingly demonstrated the role of infection in the development of the antiphospholipid syndrome. Cross antibody-mediated reactivity due to molecular mimicry between endothelial glycoproteins and microbial products was considered as an important pathogenic mechanism. However, another consequence of the molecular mimicry may be proposed. Similar tissues have less likelihood of being rejected and have a greater chance of being accepted by the host. According to this principle, pathogens with common-to-host antigens may attach readily and not be eliminated. A direct expansion of such pathogens may involve new territories. The targets of the approach 1, "from molecular mimicry to cross-reactivity," are T-B cells system inhibition-modulation. The targets of approach 2, "from molecular mimicry to pathogen expansion," are pathogens, enforcement of barriers, elimination techniques, and preventive strategy.

Fever due to aortitis.

We report a case of vasculitis with predominant aortic involvement. Vasculitis of large vessels has a limited number of tools for diagnosis and follow-up. A 78-year-old woman was referred to the internal medicine department with a 2-month history of fever of unknown origin (FUO), night sweats, weight loss and markedly elevated ESR and CRP. The results of an extended routine investigation found no infection, malignancy, hypersensitivity or autoimmune disorder. The patient did not suffer from claudication; systolic blood pressure difference between arms was 20 mm Hg. Temporal artery biopsies were negative. 2-18F-Fluorine-2-deoxy-D -glucose positron emission tomography (FDG PET) scan imaging demonstrated intense FDG uptake along the aorta and in the brachio-cephalic and carotid arteries consistent with arteritis. A high dose of corticosteroid therapy (1 mg/kg) was instituted with further tapering. The therapy was followed by complete resolution of the symptoms and pathological FDG uptake on repeated FDG PET. Second-line therapy was not added because of positive conversion of Mantaux test followed by rifampicin prophylaxis. FDG PET should be a part of the work-up of FUO when routine investigation fails to determine its etiology. FDG PET is useful both for diagnosis and assessment of response to therapy for large-vessel vasculitis.

Antioxidant status after iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis.

Oxidative stress is involved in pathogenesis of Raynaud's phenomenon (RP), a hallmark of systemic sclerosis (SSc). Frequent episodes of ischemia-reperfusion may lead to release of free radicals and enhanced lipid peroxidation reflected by elevated levels of malondialdehyde (MDA). The failure of native antioxidants (Catalase [CAT], Superoxide dismutase [SOD], and Ceruloplasmin [CP]) might be crucial in endothelial cells damage in RP. Iloprost (IL) synthetic prostacyclin analogue is currently used in the treatment of SSc patients with RP. The objectives of this study were to compare the serum levels of MDA and CP, CAT and SOD activity in red blood cells hemolysate in SSc patients compared to healthy controls; and to study the effect of 5-days IL infusions on MDA and CP levels, and CAT and SOD activity in SSc patients with RP. Twelve SSc patients were treated with 50 mug IL for 5 days. Blood samples were taken before and after day 1st and after day 5th of IL infusions. Levels of CAT were measured according to the Aebi's method; SOD, according to the Misra and Fridovich method; MDA, according to Slater's method; and CP, according to Ravin's method. Activities of CAT (p < 0.001) and SOD (p < 0.04) were significantly reduced; levels of CP (p < 0.006) and MDA (p < 0.06) were raised in SSc compared to controls. IL infusions caused reduction in MDA (p < 0.0001) levels and enhanced production of SOD (p < 0.006) and CAT (p < 0.003). The levels of CP did not change (p = 0.48). Oxidant status in SSc patients with RP is impaired. Therapy with IL led to normalization of antioxidant activity. We suggest that CAT may be a sensitive and reliable laboratory marker of oxidative stress severity in RP. We found that IL, in addition to its vasoactive properties, has a potential to activate inner antioxidant system. Activation of inner antioxidant activity may explain long-term effect of IL instead of its very short half-life time.

Documenting and explaining the common AAB pattern in music and humor: establishing and breaking expectations.

The AAB pattern consists of two similar events followed by a third dissimilar event. The prevalence of this pattern in the aesthetic domain may be explained as violation of expectation: A minimum of two iterations is required to establish a repetitive pattern; once established, it is most efficient to promptly violate the expected continuance of the pattern to produce the maximal aesthetic effect. We demonstrate the prevalence of this pattern (in comparison to AB or AAAB) in a representative sample of a variety of musical genres and in a representative sample of repetitive genre of jokes. We also provide experimental evidence that the AAB pattern in jokes is maximally effective in producing a humor response in participants.