Antibodies to N-homocysteinylated albumin and haemoglobin in patients with rheumatoid arthritis: a potential new marker of disease severity.

OBJECTIVES: To investigate whether anti-Nε-homocysteinylated albumin (anti-N-Hcy-Alb) and haemoglobin (anti-N-Hcy-Hb) antibodies occur in rheumatoid arthritis (RA) and whether they are associated with RA activity and/or severity. METHOD: Plasma total homocysteine (tHcy) and serum anti-N-Hcy-Alb and -Hb antibodies levels were determined in 76 RA patients (12 men and 64 women, median age 56 years) and 80 age- and sex-matched controls. RESULTS: RA patients compared to healthy controls demonstrated elevated tHcy [median (IQR), 13.20 (3.80) vs. 9.45 (3.25) µmol/L; p < 0.000001] and anti-N-Hcy-Alb and -Hb antibodies [absorbance at 490 nm, median (IQR), 0.546 (0.085) vs. 0.452 (0.056) and 0.649 (0.106) vs. 0.532 (0.057), respectively; all p < 0.000001]. In RA patients, RA radiological class was a strong independent predictor of tHcy [ß (SE), 0.59 (0.11); p = 0.000001] and anti-N-Hcy-Alb [0.36 (0.12); p = 0.003] and -Hb [0.49 (0.11); p = 0.00007] antibodies. The number of swollen joints, but not C-reactive protein (CRP), interleukin 6 (IL-6), positive rheumatoid factor (RF), or anti-cyclic citrullinated peptide (anti-CCP) antibodies, showed independent effects on anti-N-Hcy-Alb [ß (SE), 0.36 (0.11); p = 0.001] and -Hb [0.25 (0.11); p = 0.02] antibodies. Anti-N-Hcy-Hb antibodies, but not those against N-Hcy-Alb, were positively correlated with RA functional class and RA duration. No effect of any medications on tHcy or anti-N-Hcy-protein antibodies was observed. CONCLUSIONS: This study is the first to show that RA is characterized by enhanced autoimmune response to Nε-homocysteinylated proteins detectable in circulating blood, which is related to some clinical measures of RA severity.

Clinical characteristics of Polish patients with ANCA-associated vasculitides-retrospective analysis of POLVAS registry.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare small to medium-size vessel systemic diseases. As their clinical picture, organ involvement, and factors influencing outcome may differ between countries and geographical areas, we decided to describe a large cohort of Polish AAV patients coming from several referral centers-members of the Scientific Consortium of the Polish Vasculitis Registry (POLVAS). METHODS: We conducted a systematic multicenter retrospective study of adult patients diagnosed with AAV between Jan 1990 and Dec 2016 to analyze their clinical picture, organ involvement, and factors influencing outcome. Patients were enrolled to the study by nine centers (14 clinical wards) from seven Voivodeships populated by 22.3 mln inhabitants (58.2% of the Polish population). RESULTS: Participating centers included 625 AAV patients into the registry. Their distribution was as follows: 417 patients (66.7%) with GPA, 106 (17.0%) with MPA, and 102 (16.3%) with EGPA. Male-to-female ratios were almost 1:1 for GPA (210/207) and MPA (54/52), but EGPA was twice more frequent among women (34/68). Clinical manifestations and organ involvement were analyzed by clinical phenotype. Their clinical manifestations seem very similar to other European countries, but interestingly, men with GPA appeared to follow a more severe course than the women. Fifty five patients died. In GPA, two variables were significantly associated with death: permanent renal replacement therapy (PRRT) and respiratory involvement (univariate analysis). In multivariate analysis, PRRT (OR = 5.3; 95% confidence interval (CI) = 2.3-12.2), respiratory involvement (OR = 3.2; 95% CI = 1.06-9.7), and, in addition, age > 65 (OR = 2.6; 95% CI = 1.05-6.6) were independently associated with death. In MPA, also three variables were observed to be independent predictors of death: PRRT (OR = 5.7; 95% CI = 1.3-25.5), skin involvement (OR = 4.4; 95% CI = 1.02-19.6), and age > 65 (OR = 6.3; 95% CI = 1.18-33.7). CONCLUSIONS: In this first multicenter retrospective study of the Polish AAV patients, we have shown that their demographic characteristics, disease manifestations, and predictors of fatal outcome follow the same pattern as those from other European countries, with men possibly suffering from more severe course of the disease.

Is Taurolidine a candidate for treatment of rheumatoid arthritis?

OBJECTIVE: To study the therapeutic potential of taurolidine (TRD), a derivative of taurine with known anti-inflammatory and anti-proliferative properties, in various experimental models of synovitis. METHODS: In vitro: fibroblast-like synoviocytes (RA FLS) isolated from the synovial tissue of patients with rheumatoid arthritis (RA) were cultured in the presence of either TRD or polyvinylpyrrolidine (PVP), the pharmaceutical stabilizer of TRD, which was used as a control. Proliferation of RA FLS and cytokine (IL-6 and IL-8) release were measured. In vivo: (A). The effect of systemic TRD treatment on the development of collagen-induced arthritis (CIA) in female DBA1/J mice was investigated. Mice were treated either with intraperitoneal injections of 1 ml of 2% Taurolin Boehringer Ingelheim (TRD +PVP) or with PVP as placebo. The incidence of arthritis, myeloperoxidase (MPO) activity in periarticular tissue, as well as serum concentration of IgG specific to collagen II (IgG alphaCII) were determined. (B). The effect of intra-articular TRD treatment was studied in rabbits with antigen-induced monoarthritis (AIA). After the induction of AIA of right knees rabbits were treated either with intra-articular injections of 0.5 ml of 2% Taurolin or 0.5ml PVP ( placebo). The animals were examined for clinical signs of arthritis and diameter of joints was measured. After termination of the experiment, the arthritic knees were examined and histopathology of the joints was assessed. In addition, serum amyloid A (SAA) concentration was measured. RESULTS: n vitro: TRD exerted cytotoxic effect on RA FLS when applied at concentrations >100 microM. TRD at non-cytotoxic concentrations, inhibited PDGF-triggered RA FLS proliferation, reduced IL-1beta - stimulated production of IL-6 and slightly decreased intracellular content of IL-8. In vivo: (A). Intraperitoneal treatment with Taurolin significantly reduced the incidence (30%) of CIA when compared to the control mice (79%). However, Taurolin failed to control the development of CIA in mice with high serum level of IgG alphaCII (>1000 U).(B). Intra-articular application of 2% Taurolin resulted in amelioration of AIA in all treated rabbits (reduced diameter of arthritic joints and smaller rise of SAA level as compared to the control animals). Histopathologic evaluation revealed pannus formation in both groups and extensive necrotic lesions of synovial tissue treated with TRD, suggesting synoviorthesis-like effect. CONCLUSION: Results from AIA and from in vitro RA FLS studies suggest that intra-articular administration of TRD could be used as a "pharmacological scalpel" to remove the inflamed synovium. Our data confirmed anti-inflammatory and anti-proliferative properties of TRD in all experimental models encouraging further studies which should evaluate its therapeutic potential in RA.

Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion.

Aprotinin reduces blood loss after cardiac operations and decreases the bleeding time. The mechanism of action of aprotinin that produces these effects is not clear. During simulated extracorporeal circulation the contact and complement systems, platelets, and neutrophils are activated. We investigated the effect of aprotinin on kallikrein-C1-inhibitor complex and C1-C1-inhibitor complex formation, neutrophil degranulation, and platelet release and aggregation during simulated extracorporeal circulation. Fresh heparinized human blood was recirculated at 37 degrees C for 2 hours in a spiral coil membrane oxygenator-roller pump perfusion circuit. Changes in platelet count, leukocyte count, platelet response to adenosine diphosphate, and plasma levels of beta-thromboglobulin, kallikrein-C1-inhibitor complexes, C1-C1-inhibitor complexes, and neutrophil elastase were measured before and at 5, 30, 60, and 120 minutes of recirculation at 0, 0.015, 0.03, 0.06, and 0.12 mg/ml doses of aprotinin. Platelet counts decreased to 36% +/- 12% of control values at 5 minutes and increased to 56% +/- 13% at 120 minutes without aprotinin. Aprotinin did not affect platelet counts, but it did prevent the decrease in sensitivity of platelets to adenosine diphosphate and it attenuated beta-thromboglobulin release. In the absence of aprotinin, kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively to 0.53 +/- 0.14 U/ml and 2.38 +/- 0.33 U/ml, respectively, at 120 minutes. Kallikrein-C1-inhibitor complexes were completely inhibited and C1-C1-inhibitor complexes were partially inhibited at aprotinin concentrations of 0.03 mg/ml or greater. Release of neutrophil elastase was partially but not completely inhibited at the highest dose of aprotinin and was 50% inhibited at a dose of 0.03 mg/ml. Because activation of the fibrinolytic system does not occur in this system, the changes were independent of the inhibition of plasmin. We conclude that aprotinin in high doses completely inhibited kallikrein-induced activation of neutrophils and partially inhibited complement-induced activation. Aprotinin did not directly affect platelet adhesion or aggregation, but it indirectly preserved platelet sensitivity to agonists and also attenuated release of alpha-granule contents. The data indicate that in the presence of aprotinin platelet function was partially preserved, kallikrein production was totally inhibited, complement activation was partially inhibited, and neutrophil release was partially inhibited, thus attenuating the "whole body inflammatory response" associated with cardiopulmonary bypass.

Gamma interferon administration to patients with atopic dermatitis inhibits fibrinolysis and elevates C1 inhibitor.

Recombinant human gamma interferon was used to treat 10 atopic dermatitis patients. Recombinant gamma interferon was administered weekly for three consecutive days at 50 microg/M2 SQ for four weeks. All patients' dermatitis improved with recombinant gamma interferon therapy and plasma tumor necrosis factor-alpha levels rose with treatment. Recombinant gamma interferon treatment positively correlated with reduced total plasma fibrinolysis as measured by the fibrin lysis plate, plasmin-alpha2antiplasmin complexes, and tissue type plasminogen activator levels. Accordingly, plasminogen activator inhibitor levels increased. Treatment also was associated with a transient increase in thrombin-antithrombin III complexes. Recombinant gamma interferon resulted in a significant increase in C1 inhibitor antigen but not activity. Plasma prekallikrein, high molecular weight kininogen, and factor XII levels were not decreased. However, 5 of the 10 atopic dermatitis patients before therapy had circulating cleaved plasma high molecular weight kininogen detected on immunoblot, indicating prior kallikrein formation. The cleaved, circulating plasma high molecular weight kininogen disappeared in four out of the five original patients who were reexamined at one year after treatment. These combined data indicated that recombinant gamma interferon treatment reduced total plasma fibrinolysis. In untreated atopic dermatitis, circulating cleaved high molecular weight kininogen also may be a presenting manifestation.

[Adaptation of computed tomography and roentgenography to bone density measurements]. / Adaptacja tomografii komputerowej i rentgenografii do pomiarów densytometrycznych tkanki kostnej.

The increasing interest in issues connected with osteoporosis has recently caused the development of many new diagnostic methods which allow the measurement of bone density. The DEXA method, performed by specialised densitometers, is one of the most developed and reliable methods. However, the high cost od densitometers and DEXA investigation prevent this method from becoming easily accessible for everyday diagnosis. The adaptation of computerised tomography and rentgenography to densitometric measurements could be one of the methods by which the problem of densitometric diagnosis accessibility could be solved. Both methods are usually applied in the imaging of human tissues, working on the basis of differences in tissue X-ray absorption. X-ray absorption and density are related by linear function in the energy range used in rentgenography and tomography; therefore, quantitative information concerning density should be easily received. The procedure adapting computerised tomography and rentgenography to quantitative measurements of bone density in the lumbar spine is outlined in this work. The quantitative information is obtained from digitalised tomographic and rentgenographic images through use of a personal computer. Both methods were tested using a set of phantoms imitating the lumbar spine and the surrounding tissues. The precision and accuracy of both methods were assessed and compared to the precision and accuracy of the DEXA method. The outlined results confirm the usefulness of the described method in diagnosis.

Psychological stress in rheumatoid arthritis patients: a comparative Polish-German study: summary of the current conceptualization of the role of stress in rheumatoid arthritis.

Cultural differences in experiencing individual stress in rheumatoid arthritis (RA) patients might be observed. The aim of the study was to assess quality of life and psychological stress (distress) in RA patients, and to evaluate socio-demographic and disease specific variables predicting stress of patients. The study covered 300 Polish and 137 German RA patients. SF-36v2 scale was used to evaluate the patients' health. Psychological stress was defined as the feeling of "social isolation" and "being a burden" as demanding help in everyday activities. In both countries, the mental and physical health of patients deteriorated and about 50% of patients required support in everyday activities. 95% of Polish and 62% of German patients felt rejected from social activities. For the psychological stress perceived, functional capacity class 3 and male gender were shown to be predictive in Polish patients and living in a small town - in German patients. In the Polish group, the tertiary/bachelor level of education was linked with lower distress level. RA has a serious impact on the mental health owing to a great disease burden. Awareness of impact of the disease on quality of life and psychological stress of patients should be considered in routine clinical practice.

Mycoflora in bronchial asthma.

Examinations were done in 22 patients suffering from bronchial asthma and 10 patients with acute respiratory infection (control group). In all cases quantitative mycological and bacteriological sputum tests, mycoserological tests and cutaneous tests were performed. Presence of C. albicans was evident in 90% of sputum from asthmatics with proliferation in 45% of cases (10(4) or more of yeast cells/ml of sputum). The proliferation of the mould fungi in the sputum was not observed. Allergization with C. albicans was encountered in 25% of asthmatics and allergization with mould fungi in 36% of them. Mycoserological tests were reliable when the autoantigens of the patients flora were used. The studies of the control group call attention to possible accompanying acute invasions of C. albicans in the early days of primary acute respiratory tract infection.

[New possibilities of treating acute angioedema caused by C1-inhibitor deficiency]. / Nowe mozliwosci leczenia ostrych obrzeków naczynioruchowych u chorych z niedoborem inhibitora C1-esterazy.

The authors discuss diagnostic difficulties in 12 cases of hereditary angioneurotic edema due to C1-esterase inhibitor (C1-INH deficiency). Emphasis is on the treatment of the acute attacks with intravenous infusions of C1-inhibitor concentrate (Boehring, West Germany). This proved to be a very efficient and safe therapy, leading to a prompt disappearance of all clinical symptoms. Throughout 12 months following the infusions, indices of the liver function remained within the normal range, and anti-Hbs and anti-HIV tests were negative.

Prostacyclin for acute coronary insufficiency.

We have studied the effects of prostacyclin (PGI2) infusions in two different types of angina pectoris, i.e. effort and spontaneous angina. Contrary to sublingual nitroglycerin, intravenous infusions of PGI2 at a dose of 5 or 10 ng/kg/min offered no protection against effort anginal attacks precipitated by atrial pacing. On the other hand, in recurrent attacks of spontaneous angina at rest, infusion of PGI2 at a dose of 5 ng/kg/min led to sustained and long-lasting improvement as manifested by reduction of both anginal attacks and nitroglycerin intake. Different pathogenic mechanisms underlying the two types of angina studied could explain the results obtained. Prostacyclin might be of threapeutic interest in attacks of angina pectoris precipitated by redution of oxygen delivery to the myocardium rather than increased oxygen demand.

Protection of platelets during long-term extracorporeal membrane oxygenation in sheep with a single dose of a disintegrin.

BACKGROUND: Both short- and long-term extracorporeal membrane oxygenation (ECMO) causes platelet loss and dysfunction. Bitistatin is a reversible inhibitor of the platelet glycoprotein IIb/IIIa receptor. This study tests the hypothesis that inhibition of platelets by bitistatin during initial contact with the perfusion circuit preserves platelet number and function during long-term ECMO in sheep. METHODS AND RESULTS: Bitistatin, purified from crude snake venom, was tested for its effect on platelet count, responsiveness to ADP, release of platelet factor 4, and prevention of surface-adsorbed glycoprotein IIIa in vitro and during 24 hours of ECMO in nine splenectomized sheep. During simulated extracorporeal circulation, 0.5-1.0 microgram/ml bitistatin significantly prevented platelet adhesion, attenuated release of sheep platelet factor 4, and preserved platelet responsiveness to ADP. During ECMO at 1.8 l/min for 24 hours, a single dose of bitistatin (200 micrograms/kg) (n = 4) produced higher platelet counts (p = 0.0002) and suppressed release of platelet factor 4 (p = 0.035) for 16 hours compared with five control animals. This dose of bitistatin caused an immediate inhibition of platelet aggregation; however, between 4 and 24 hours of perfusion, platelets of bitistatin-treated animals were more responsive to ADP (p < 0.0001) compared with platelets in control animals. The amount of glycoprotein IIIa antigen extracted by Triton X-100 from the perfusion circuits was reduced in bitistatin-treated sheep. CONCLUSIONS: A single dose of bitistatin given before blood contact with the ECMO circuit briefly inhibits platelet adhesion and aggregation but thereafter preserves platelet numbers and function and suppresses alpha-granule release for 12-16 hours of ECMO.

Successful therapy of advanced arteriosclerosis obliterans with prostacyclin.

Five patients with advanced arteriosclerosis obliterans of the lower extremities, as evidenced by resting pain, ischaemic ulcers, and focal necrosis, received intra-arterial infusions of prostacyclin at doses of 5--10 ng/kg/min for 72 h. Within 2 days of termination of the infusion, pain at rest had disappeared in all patients. In three of the five, the necrosis had completely regressed and the ischaemic ulcers healed within 2 months. The other two patients showed considerable improvement. Prostacyclin therapy was not associated with changes in the radiographic appearance of the major blood-vessels. However, muscle blood-flow, as measured by xenon-133 clearance, was significantly increased both during prostacyclin infusion and for the 6 weeks of measurement after its termination.

[Netilmicin in the treatment of bacterial respiratory tract infections]. / Netylmycyna w leczeniu bakteryjnych zakazen ukladu oddechowego.

Netilmicin - a semisynthetic aminoglycoside - was administered to 33 patients with the acute or chronic lower respiratory tract or pulmonary infections in a daily dose of 5 mg/kg body weight for 10 days. A principle criterium of patients classification to netilmicin therapy were sensitive bacterial strains either in sputum or in BAL liquid. A significant clinical improvement was noted in 88% of the treated patients. However, elimination of pathogens from the sputum was achieved only in 52% of these patients. No improvement was observed in 4% of the treated patients. No adverse reactions were noted. Netilmicin proved safe and effective antibacterial agent in patients with respiratory infections.

[A preliminary assessment of the incidence of atopy at a workplace in Cracow]. / Wstepna ocena czestosci wystepowania atopii w jednym z krakowskich zakladów pracy.

Skin tests, IgE level and eosinophils percentage were determined in 337 employees of the "Hydrokop" Works in Cracow. These investigations aimed at seeking more specific markers of allergy than anamnesis and skin tests. Allergy was reported by 108 individuals (38%). Some features of atopy were confirmed in 7.5%. Skin tests were positive in 36 individuals and were related to atopy in 55%. IgE levels were 10 IU/ml--greater than 1000 IU/ml with the distribution similar to log-normal. Mean IgE concentration was relatively high (202 IU/ml, in the individuals with confirmed congenital allergy. Percentage of eosinophils exceeded 3% in 39 subjects out of which 17 reported the symptoms of allergy. IgE level and percentage of eosinophils are controversial as the markers of atopy due to the contribution of various non-allergic factors while skin tests correlate well with allergic diseases which were relatively frequent in the examined group.

Administration of gamma interferon in human subjects decreases plasminogen activation and fibrinolysis without influencing C1 inhibitor.

Recombinant gamma interferon (rHuIFN-gamma) has been recognized to increase mRNA and protein levels of C1 inhibitor (C1 INH) in various human cells. Further, when administered to patients with colon cancer, it increased plasma C1 INH levels. A prospective trial was initiated to determine whether rHuIFN-gamma could elevate plasma C1 INH levels in six normal volunteers and two patients with type I angioedema. After 1 month of observation of plasma C1 INH levels, rHuIFN-gamma was administered subcutaneously at 25 micrograms/M2 daily for 4 consecutive days. All healthy volunteers and patients experienced local erythema, headache, myalgias, and chills during the administration of rHuIFN-gamma. C1 INH, prekallikrein, high-molecular-weight kininogen, and factor XII levels in plasma were not influenced by the rHuIFN-gamma administration. One patient with hereditary angioedema (HAE) had an attack of angioedema 3 days after completion of rHuIFN-gamma therapy. During the attack, circulating cleaved high-molecular-weight kininogen, kallikrein-alpha 2-macroglobulin complexes, and an altered 50 kd form of kallikrein were detected in the patient's plasma. Additional studies showed that rHuIFN-gamma treatment resulted in decreased total fibrinolytic activity. It was found that immediately after rHuIFN-gamma treatment, tissue plasminogen activator activity and antigen levels were not significantly decreased in volunteers. Plasminogen activator inhibitor levels rose significantly, but this activity was not due to plasminogen activator inhibitor-1 antigen, whose value significantly fell. These data suggest that rHuIFN-gamma may stimulate the expression of another plasminogen activator inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)