Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor--a long-term survey.

BACKGROUND: Hereditary angioedema is a potentially life-threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short-term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures. METHODS: We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1-INH concentrate, tranexamic acid, and danazol) administered for STP. RESULTS: Comparing surgical interventions performed without pre-event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher's exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1-INH concentrate (Berinert(®) , CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher's exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP. CONCLUSIONS: STP reduces the number of postprocedural edematous episodes. C1-INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions.

C1-inhibitor autoantibodies in SLE.

The presence of anti-C1-inhibitor (anti-C1-INH) autoantibodies is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence, diagnostic value, and/or significance in systemic lupus erythematosus (SLE). In a multicentre study, we determined the levels of autoantibodies to C1-inhibitor in sera from 202 patients with SLE and 134 healthy controls. Additional clinical and laboratory parameters, such as organ involvement, as well as anti-C1q, anti-double-stranded DNA antibody, erythrocyte sedimentation rate, C-reactive protein, C3 and C4 serum complement levels have been studied in patients. The level of anti-C1-INH IgG was significantly higher (p = 0.034) in SLE patients, than in the controls. A high anti-C1-INH level of > or =0.4 U/ml (mean of controls + 2 SD) was found in 17% of the patients, but in only 4% of the controls (p = 0.0003). The SLEDAI score was significantly higher (p = 0.048) and the duration of SLE was significantly longer (p = 0.0004) among patients with elevated anti-C1-INH levels compared with patients without this autoantibody (median disease duration 8 vs. 17 years, respectively). Anti-C1-INH level was not correlated with any other laboratory parameter or organ manifestation of the disease. These findings indicate that the anti-C1-INH level is higher in SLE patients than in healthy controls and furthermore, the anti-C1-INH level correlates with the duration and activity of the disease.

Note: 4-bounce neutron polarizer for reflectometry applications.

A neutron polarizer using four successive reflections on m = 2.5 supermirrors was built and installed at the GINA neutron reflectometer at the Budapest Neutron Centre. This simple setup exhibits 99.6% polarizing efficiency with 80% transmitted intensity of the selected polarization state. Due to the geometry, the higher harmonics in the incident beam are filtered out, while the optical axis of the beam remains intact for easy mounting and dismounting the device in an existing experimental setup.

Fibronectin on the surface of human lymphocytes.

Fibronectin was detected by immunofluorescence technique on the surface of one part of separated normal peripheral blood lymphocytes by using FITC-conjugated anti-human fibronectin antibodies. Approximately one-fifth of isolated B cells and 7% of O cells contained surface-bound fibronectin but T cells failed to stain. There were no detectable free receptors for fibronectin on the surface of lymphocytes of different subsets as it was studied with FITC-labelled purified fibronectin. The percent of B and O cells bearing surface bound fibronectin was markedly decreased in patients with acute and chronic lymphocytic leukemias.

Levels of antibodies against C1q and 60 kDa family of heat shock proteins in the sera of patients with various autoimmune diseases.

Previously a strong positive correlation was found between antibodies to C1q (C1qAb) and antibodies against human heat shock protein (hsp60) and mycobacterial hsp65 in HIV infected patients. Here the levels of these antibodies were measured in the sera of patients with different autoimmune diseases (122 systemic lupus erythematosus (SLE), 55 systemic sclerosis, 33 undifferentiated connective tissue disease (UCTD), 27 primary Raynaud syndrome, 21 rheumatoid arthritis (RA), 14 polymyositis/dermatomyositis (PM/DM), and 192 healthy blood donors. The prevalence of IgG C1qAb was found to be high (P<0.0001 as compared to the healthy controls) only in the SLE group. The levels of the anti-hsp60 (P=0.0094) and anti-hsp65 (P=0.0108) antibodies were high only in the UCTD patients. No correlation was found between the C1qAb and anti-hsp antibodies in any group except a significant (P=0.011) positive correlation between C1qAb and hsp65 antibodies in the patients with UCTD. These findings indicate that the autoantibodies against C1q are heterogeneous: in different diseases different types of C1qAb may dominate.

Binding of fibronectin to human lipoproteins.

High molecular mass adhesive glycoprotein plasma fibronectin binds to isolated HDL and LDL lipoprotein fractions in a solid phase radioimmunoassay. Mean dissociation constants of interaction of fibronectin and immobilized HDL and LDL lipoproteins isolated from eight patients with type IIa and type IV hyperlipoproteinemia are 7.8 +/- 3.2 X 10(-7) mol/l and 6.8 +/- 2.6 X 10(-7) mol/l, respectively. Fibronectin can also bind to HDL and LDL isolated from six healthy subjects with mean dissociation constants of 2.07 +/- 0.45 X 10(-6) mol/l and 2.25 +/- 0.48 X 10(-6) mol/l, respectively. The binding is not dependent on the presence of divalent cations. Fibronectin-lipoprotein interaction is inhibited by soluble lipoproteins. There is no observable interaction between fibronectin and VLDL fraction. Binding of fibronectin to HDL and LDL lipoproteins can have an in vivo significance, since the interaction may play a role in the metabolism, deposition of lipoproteins into the vessel wall and in atherogenesis.

High levels of antibodies against Clq are associated with disease activity and nephritis but not with other organ manifestations in SLE patients.

OBJECTIVE: Serum concentration of antibodies to C1q (C1qAb) has been reported to be elevated in a high percentage of patients with systemic lupus erythematosus (SLE). The associations of high C1qAb levels with different clinical manifestations and the activity of the disease, however, are not definitely understood. METHODS: We measured the levels of IgG type C1qAb in the sera of 137 patients with SLE using an ELISA method. RESULTS: Serum concentrations of C1qAb were found to be higher (p < 0.0001) in SLE patients than in healthy controls. High titer (> 66 AU/ml) C1qAb was found in 40/137 (29.2%) SLE patients, and 4/192 (2.1%) healthy controls (p < 0.0001). A strong negative correlation (R = -0.4, p < 0.0001) between the age of the patients and the C1qAb titers could be detected. C1qAb levels in clinically active SLE patients significantly (p < 0.0001) exceeded those measured in the sera of patients in the inactive stage of the disease. A significant positive correlation was detected between C1qAb levels and the laboratory activity markers (anti-DNA, low C3 level) of the disease. We found a significant negative correlation between levels of C1qAb and a negative acute phase protein, alpha2-HS-glycoprotein. Renal involvement was present in 11/40 (27.5%) and 11/97 (11%) of the patients with high and low titers of C1qAb, respectively (p = 0.038). The prevalence of other organ manifestations was, however, the same in the patients with or without high titer C1qAb. CONCLUSION: These findings indicate that C1qAb measurement is a useful method for detecting the activity of SLE and predicting renal manifestations, but not other organ involvement in the disease.

Effect of various levels of T-2 toxin on the clinical status, performance and metabolism of growing pigs.

In two sets of experiments eight groups of seven-week-old pigs weighing about 9 kg were fed for three weeks a prestarter that contained 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 10.0 or 15.0 mg/kg of highly purified T-2 toxin. The feed of the two control groups was free from T-2 toxin. Average daily intakes of toxin by the pigs were 0.38, 0.81, 1.24, 1.43, 0.93, 0.81, 0.99 and 2.5 mg, respectively. The weight gains, the feed intakes, the extent of feed refusal, the parameters of energy and protein metabolism and the serum concentrations of calcium, inorganic phosphorus and magnesium were affected to different extents by the different doses of T-2 toxin, but the data indicated that feed consumption was reduced and the activity of aspartate aminotransferase was increased by the smallest amount of T-2 toxin tested.

Effect of various levels of T-2 toxin in the immune system of growing pigs.

Four groups of seven-week-old pigs weighing about 9 kg were fed for three weeks a prestarter that contained 0.5, 1.0, 2.0 or 3.0 mg/kg of highly purified T-2 toxin. The average daily intakes of toxin by the pigs were 0.38, 0.81, 1.24 and 1.43 mg, respectively. The experimental and control pigs were immunised with 5 ml aluminum hydroxide gel-absorbed purified horse globulin on the first and fourth days of the treatment period. Blood samples were withdrawn on days 7, 14 and 21 and used for the determination of the titre of anti-horse globulin antibody, for an in vitro lymphocyte proliferation test, using purified horse globulin, phytohaemagglutinin and concanavalin-A and for determinations of the immune complex, the cytotoxic reaction and the phagocytic activity and phagocytic index of circulating granulocytes. The samples taken on day 21 were also used to determine the erythrocyte count, the mean cell volume of the erythrocytes, the haematocrit, the blood haemoglobin concentration, the leucocyte count and the proportion of T lymphocytes. At the end of the experiment samples were taken from the thymus, spleen and mesenteric lymph nodes for histological examination. The diets that contained 2 and 3 mg T-2 toxin/kg caused a significant decrease in the red blood cell count, the mean corpuscular volume and the haemoglobin concentration. A significant decrease in the leucocyte count and the proportion of T lymphocytes was observed in all the treatment groups. There were also dose-dependent, significant decreases in antibody formation and in the blastogenic transformation of lymphocytes, and mild to moderate reactive processes were observed histologically in the lymphoid organs.

Effect of selenium, vitamin E and riboflavin supplementation of the feed on the humoral and cell-mediated immune responses of growing pigs.

The feed of weaned piglets of Hungarian Large White X Duroc and Dutch Landrace X Duroc genotype was supplemented with 0.5 mg selenium, 50, 100 or 150 mg vitamin E, and 2.5 or 5 mg riboflavin per kg. Feed supplementation enhanced the cytotoxic reaction and elevated the antibody titres produced against purified horse gamma globulin antigen. However, as compared to the control the differences were not significant. Feed supplementation exerted a beneficial, though varying, influence on the indices of cell-mediated immunity. The proportion of rosette-forming cells and blastogenic transformation induced by specific (horse globulin) and nonspecific (phytohaemagglutinin, PHA) mitogens underwent the most expressed and most significant increase in pigs fed 5 mg selenium, 100 mg vitamin E and 5 mg riboflavin per kg of feed. On the other hand, feed supplementation failed to enhance the responsiveness to intradermal PHA (type IV allergic reaction).

[New aspects of the pathogenesis of progressive chronic polyarthritis (rheumatoid arthritis)]. / A polyarthritis chronica progressiva (RA) pathogenesisének néhány új szempontja.

The author summarizes the newest results and knowledges which are related to the pathogenesis of polyarthritis chronica progressiva. Pursuing the composed target the feasible roles of gamma delta TcR T lymphocytes and stress proteins as well as that of CD5 positive B lymphocytes and IgG-glycosylation status are discussed. Reaching the end of the paper it is established that the solution of etiology and pathogenesis of polyarthritis chronica progressiva, in spite of the increasing theoretical knowledge, awaits for further extensive research work.

[Acute pancreatitis: inflammatory response of the body]. / Pancreatitis acuta: a szervezeti inflammatoricus válasz.

The author reviews the most important data related with the pathogenesis of pancreatitis acuta, the pathological characteristics, the clinical development of the disease, the more frequent complications are summarized. Within this scope the evolutionary mechanisms of the organ damages are discussed, the diagnostic and prognostic relations are delineated, too. Particular attention is paid to the development and regulation of the defending, preventing reactions of the organisms connected with pancreatitis acuta. The process of leukocyte emigration into the tissue being shortly summarized, the acute phase reaction of the organism and the pathophysiological, clinical significance of the acute phase reactants are likewise presented. The author deals distinctly with the physiological, pathophysiological functions of alpha 2-macroglobulin and with its significance in pancreatitis acuta. The therapeutic outlooks are in a few words touched upon. The acute phase reaction of the organism is inserted in the framework of the possible types of the protecting, preventing responses of the organism.

[Acute phase reaction of the body]. / A szervezeti "acut phasis reactio".

l" with the concept, interpretation and function of the acute phase reaction of the organism. He sums up the general constructive elements of the acute phase response of the organism, the correlations of the specific and non specific defensive mechanisms. He refers slightly in detail to the questions correlating with the structure and biologic functions of the acute phase proteins. Finally the most important criteria of the especially known acute phase proteins are presented.

[The role of the central nervous system in lupus erythematosus]. / A központi idegrendszer részvétele systemás lupus erythematosusban.

Central nervous system involvement of systemic lupus erythematosus was observed in 34 (36%) of the 94 patients studied between 1970-1990. A review of the diagnostic methods and therapy for central nervous system lupus is presented. The diagnosis of primary cerebral lupus was based on the history, physical examination and on the results of the cerebrospinal fluid analysis, CT-scan and EEG. Intractable headache (22/34), behavioural abnormalities (18/34), cranial neuropathy (16/34) occurred most frequently among neuropsychiatric symptoms. Immunoglobulin analysis of the cerebrospinal fluid proved to be the most sensitive method for detecting clinical activity (in 20/23). Central nervous system involvement was suggested by conventional serological test to a lesser degree. Alterations on CT scan and EEG were found in 17/27 and 14/26 of cases, respectively. IgM, IgA, and IgG indexes (indicators of intratechal immunglobulin synthesis) decreased when the central nervous system events subsided after successful treatment but the CT abnormalities (e. g. atrophy) were not altered.

[Diagnostic value of the determination of serum alpha2-HS-glycoprotein]. / A szérum alpha 2-HS-glycoprotein meghatározások diagnosztikus értékéröl.

Opsonic glycoprotein, alpha 2-HS-glycoprotein concentration was studied in the serum of 753 patients with various hematological, malignant, immunological, metabolic, endocrine and liver diseases and 68 healthy controls. Decreased serum alpha 2-HS-glycoprotein levels were detected in patients with acute leukemias, chronic granulocyte and myelomonocyte leukemias, lymphomas, myelofibrosis, multiple myeloma, metastatizing solid tumors, systemic lupus erythematosus, rheumatoid arthritis, acute alcoholic hepatitis, fatty liver, chronic active hepatitis, liver cirrhosis, acute and chronic pancreatitis, and Crohn's disease. Elevated levels were measured in patients with B and NANB/C hepatitis. Further decreased levels were observed in some groups with secondary infections. Serum alpha 2-HS-glycoprotein levels are affected by many factors, influencing the synthesis and elimination of the protein. The detection of serum alpha 2-HS-glycoprotein concentration has no specific diagnostic value as a marker for tumors or other diseases, however, its determination can be useful for the assessment of a non-specific regulator of the host defence.

[Effect of estrogen on the blast transformation of lymphocytes and interleukin-2 production in lupus erythematosus]. / Oestrogen hatása a lymphocyta blastos transformatióra és az interleukin-2 termelésre systemás lupus erythematosusban.

The mitogenic response of peripheral lymphocytes was investigated in 12 patients with systemic lupus erythematosus and in healthy female volunteers who were on 11 and without 9 contraceptive pills. The effect of estrogen (ethinyl-estradiol 10(-5)-10(-6)-10(-7)M) was studied on Phytohaemagglutinin and Pokeweed mitogen induced blastogenic transformation and interleukin-2 production of peripheral lymphocytes in vitro. We observed a significantly depressed Phytohaemagglutinin induced lymphoblastic transformation both in patients and women taking oral contraceptive in presence of 10(-5)M estrogen as compared to normal controls. However there was no significant alteration neither in the response of lymphocyte nor in the production of interleukin-2 using of Pokeweed mitogen. The stimulataneous inhibition of the interleukin-2 production proved to be moderate. Marked significant correlation (r greater than = 0.8) vas detected between lymphoblastic transformation and interleukin-2 production in healthy females. Correlation coefficient measured in females taking oral contraceptive (r less than = 0.64) and patients with systemic lupus erythematosus (r less than = 0.34) suggest that in these groups the inhibition of lymphoblastic transformation is due to the inhibition effect of estrogen on the interleukin-2 production.

PIP: 12 patients with systemic lupus erythematosus (SLE) (8 in the active stage) with an average age of 26 years (17-54) and 20 healthy control subjects (9 were aged 18-49 years and 11 were oral contraceptives [OC] users aged 17-44) were studied to assess the inhibiting effect of estrogen in vitro on phytohemagglutinin (PHA) and Pokeweed (PWM) mitogen induced blast transformation of lymphocytes (lymphoblastic transformation=LBT) gained from periphral blood and simultaneous interleukin-2 (IL-2) production. 8 women were taking Anteovin, 2 Ovidon, and 1 Rigevidon. The average duration of OC use was 5.2 years. 1 SLE patient did not need immunosuppressive treatment, 3 patients received corticosteroid maintenance therapy, and 4 patients were also taking 50 mg of Imuran. In 4 active SLE patients the tests were done before raising the dose of immunosuppressive drugs, and in the case of 2 other patients the administration of 75 mg and 25 mg/die Prednisolone was necessary in addition to 50 mg and 100 mg/die Imuran. LBT decreased significantly in patients and OC users. The LBT values induced by PWM were similar but not significant. The IL-2 production induced by PHA decreased in all 3 groups but not significantly. I1-2 production was 6 E/ml in patients, 5 E/ml in OC users, and 11.5 E/ml in nonusers, but the differences did not prove significant because of wide individual fluctuations. The amount of IL-2 produced by lymphocytes at PWM stimulation was almost the same in all 3 groups with or without estrogen. There was a positive, significant relationship between the extent of LBT and the amount of IL-2 produced in the healthy group of nonusers, it was less solid in the OC users, and in the SLE group trhe low correlation coefficient of .34 suggested the reduction of IL-2 through the inhibition of LBT.

[Systemic lupus erythematosus and pregnancy]. / Systemás lupus erythematosus és a terhesség.

The authors report on the successful outcome of pregnancy of a young woman with systemic lupus erythematosus. Her disease presented with severe renal involvement. The delivery was followed by lasting, complete remission. Even at the time of the report both the mother and her child are in a good health. On the occasion of this case-history the authors attempts, to summarize the present knowledge of pregnancy in systemic lupus erythematosus.

[Effect of female sex hormones on blastic transformation of lymphocytes in systemic lupus erythematosus and in healthy women]. / A nöl nemi hormonok hatása a lymphocyta blastos transformatióra systhemás lupus erythematosusban és egészséges nökben.

PIP: The susceptibility of women to autoimmune diseases is well-documented, of which systemic lupus erythematosus (SLE) is especially important. The use of oral contraceptives often activate SLE from a quiescent condition. The inductive effect of estrogen has been shown in animal studies indicating that female hormones can trigger autoimmune reaction. The effect of ethinyl estradiol, an estrogen (E), and d-norgestrel, a progesterone (P), on the mitogenic response of peripheral lymphocytes, and particularly on phytohemagglutinin (PHA)- and concanavalin-A (Con-A)-induced blastic transformation of lymphocytes (LBT) was studied in vitro. 25 patients with SLE and 27 healthy controls participated in the study. SLE was inactive in 16 patients, 7 took corticosteroids, and 3 also received 50 mg/day Imuran. 13 patients and 10 controls took contraceptives (Bisecurin, Infecundin, Ovidon, Rigevidon). The LBT value fell significantly in patients with active SLE, in contraceptive users, and the value was significantly lower in inactive patients than in those not using contraceptives. E and P separately or together significantly reduced LBT values. Contraceptives containing P only can be prescribed for women suffering from SLE, as its role in inducing the disease compared to E is negligible.^ieng

[Relapsing polychondritis associated with myelodysplasia and acute eosinophilic leukemia]. / Polychondritis recidivanshoz társuló myelodysplasiás syndroma és akut eosinophilsejtes leukaemia esete.

Authors report a case in which relapsing polychondritis had been diagnosed two years before myelodysplastic syndrome developed and terminated in eosinophilic leukemia. The observation that relapsing polychondritis may precede myelodysplasia is not in concordance with some of the previous reports regarding relapsing polychondritis as a paraneoplastic phenomenon of myelodysplastic syndrome. The terminally developed eosinophilic leukemia is not supposed to be a blastic phase of the underlying myelodysplasia, much rather a second malignant process. This opinion may be confirmed by the early presence of blast cells in the myelodysplastic process without eosinophilia. It seems interesting to note that both our patient and his daughter suffered from diseases of autoimmune origin: acquired vitiligo and subacute cutan lupus erythematodes, respectively.

[Clinical significance of antiphospholipid autoantibodies in lupus erythematosus]. / Az antifoszfolipid autoantitestek klinikai jelentösége szisztémás lupus erythematosusban.

The authors have determined the prevalence of antibodies of cofactor dependent anticardiolipin and beta 2-glycoprotein I and lupus anticoagulant and the frequency of false positive VDRL test in systemic lupus erythematosus. The aim of this retrospective study was to assess the presence of these antibodies and symptoms of antiphospholipid syndrome. The serum samples were examined by modified ELISA method for detecting of cofactor dependent anticardiolipin. The antibodies to beta 2-glycoprotein I were examined by ELISA. The lupus anticoagulant and VDRL test were performed by routine laboratory method. The authors have found that 19 of 58 patients with systemic lupus erythematosus had cofactor dependent anticardiolipin, 10 patients had antibodies to beta 2-glycoprotein I and 4 patients had positive VDRL test. 5 of 34 plasma samples were lupus anticoagulant positive. 19 patients with systemic lupus erythematosus had 14 neuropsychiatric disorders, 9 cardiovascular diseases, 7 thrombocytopenia, 6 histories of recurrent abortion and fetal loss, 5 livedo reticularis and 3 thromboembolic events in all of them had detected antibodies to cofactor dependent anticardiolipin, while these complications were diagnosed in 39 anticardiolipin negative patients much more rarely. The results of this retrospective study suggest that significant association exists between the presence of cofactor dependent anticardiolipin and symptoms of antiphospholipid syndrome in systemic lupus erythematosus.