C1 esterase inhibitor concentrate for capillary leakage syndrome following bone marrow transplantation

The prognosis of patients with severe capillary leakage syndrome (CLS) after bone marrow transplantation (BMT) is dismal despite aggressive use of intensive care therapy. Because the activated classical pathway of complement and relatively low levels of C1 esterase inhibitor (C1 INH) activity are known features in these patients, we evaluated the efficacy of a therapy using purified, human C1 INH concentrate. Severe CLS was defined as increase in body weight by more than 3% within 24 h combined with generalized edema, impaired hemodynamic system (tachycardia and/or decreased blood pressure), and non-responsiveness to furosemide. Of 142 patients, 22 developed severe CLS. The first seven patients whom we diagnosed with this complication were assessed as control patients. Fifteen patients with severe CLS were treated with C1 INH concentrate using a cumulative dose of 180 units/kg body wt. (initial dose: 60 units/kg, followed by two doses at 30 units/kg and four doses at 15 units/kg, every 12 h). The survival rate of patients with CLS was 57% at 1 year after BMT in the C1 INH treatment group, compared with 14% in the control group (p = 0.008). Eight of 15 treated patients are alive at a median of 9 months (range: 4-55) after BMT. The plasma levels of the complement activation parameters C4d and C5a were 3 +/- 1.1 mg/dl (mean +/- S.D.) and 0.3 +/- 0.1 microgram/l, respectively, prior to BMT, increasing to 8.2 +/- 2.1 mg/dl and 1.3 +/- 0.4 micrograms/l, respectively, at diagnosis of CLS. After infusion of C1 INH concentrate the plasma levels of C5a and C4d normalized. The activity of C1 INH rose to 139 +/- 10% of normal human plasma NHP pool (mean +/- S.D.) after infusion. The CH50 values were not significantly altered. The fluid status normalized within 11 days in 14 of 15 treated patients. The results of this study suggest that therapy with C1 INH concentrate improves the prognosis of patients with CLS after BMT. This has to be confirmed in a randomized, controlled trial.     

Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations

We studied the inflammatory reaction related to cardiopulmonary bypass in 24 neonates (median age 6 days) undergoing the arterial switch operation for simple transposition of the great arteries, with respect to the development of postoperative capillary leak syndrome. Complement proteins, leukocyte count, tumor necrosis factor-alpha, and histamine levels were determined before, during, and after cardiopulmonary bypass. Additionally, protein movement from the intravascular into the extravascular space during cardiopulmonary bypass was assessed by the measurement of plasma concentrations of proteins with molecular weights ranging from 21,200 to 718,000. Capillary leak syndrome developed in 13 of the 24 neonates. Patients with capillary leak syndrome, as compared with those without, had preoperatively higher C5a levels (C5a, 3.0 +/- 0.6 microgram/L vs 0.9 +/- 0.2 microgram/L) (mean +/- standard error of the mean) (p < 0.05) and higher leukocyte counts (leukocytes, 17.9 +/- 2.1 X 10(3) cells/ml versus 11.7 +/- 0.8 X 10(3) cells/ml) (p < 0.05), suggesting in these neonates a preoperative inflammatory state. Preoperative clinical and operative data were identical in both patient groups. Before cardiopulmonary bypass, serum protein concentrations were similar in all patients. Ten minutes after institution of cardiopulmonary bypass, protein concentrations fell to significantly lower values in patients with capillary leak syndrome than in those without: albumin (19% +/- 1.5% vs 30% +/- 6% of the prebypass value, p < 0.05), immunoglobulin G (17% +/- 1.5% vs 29% +/- 5.5%, p < 0.001), and alpha 2-macroglobulin (15% +/- 1.2% vs 25% +/- 4%, p < 0.02). During cardiopulmonary bypass, albumin concentrations remained significantly lower in patients with capillary leak syndrome than in those without, whereas hematocrit values were similar in both groups. During cardiopulmonary bypass, patients with capillary leak syndrome also had lower concentrations of complement proteins C3 and C4 but not C1 inhibitor. C3d/C3 ratio and C5a levels were similar in both patient groups. In contrast, histamine liberation during cardiopulmonary bypass was significantly more pronounced in patients with capillary leak syndrome than in those without (725.2 +/- 396.7 pg/ml vs -54.1 +/- 58.4 pg/ml, p < 0.05). Tumor necrosis factor-alpha levels after protamine administration were also significantly higher in patients with capillary leak syndrome (38.1 +/- 10.0 pg/ml vs 15.3 +/- 3.4 pg/ml, p < 0.05). Leukocyte count during and after cardiopulmonary bypass was similar in both patient groups. This study demonstrates increased protein leakage as early as 10 minutes after initiation of.     

C1-esterase inhibitor prevents early pulmonary dysfunction after lung transplantation in the dog

The success of lung transplantation to a large extent depends on effective protection of the graft from ischemic injury after reperfusion. Although mechanisms have not been clarified, the pathologic findings of ischemic injury after reperfusion are similar to adult respiratory distress syndrome, a condition in which the blood coagulation contact system is activated. This study evaluates the effect of C1-esterase inhibitor (C1-INH), the main inhibitor of the blood coagulation contact system, on short-term lung function in a dog model of orthotopic lung transplantation. Twelve lung transplantations were performed after 24 h of ischemic time. Dogs were randomly assigned to receive either vehicle (Control) or C1-INH. After the lung transplantation in the control group, Pao2 decreased by 84% and both the AaPO2 and the Qs/Qt% increased (340 and 530%, respectively, p < 0.01); these parameters remained unchanged in the C1-INH group. The hypoxemia observed in control animals was associated with decreased blood coagulation contact factors, complement consumption, increased expression of adhesion glycoproteins in leukocytes, and extensive intraalveolar and interstitial neutrophil infiltration. In contrast, C1-INH administration prevented hypoxemia, the decrease in blood coagulation contact factors, the activation of the complement system, the increase in expression of leukocyte adhesion molecules, and inflammatory cell infiltrate. This study has demonstrated that in a dog model of lung transplantation, the administration of C1-INH prevents early pulmonary dysfunction, and it suggests that activation of blood coagulation contact system and complement are important mechanisms causing ischemic injury after reperfusion.     

Responses of gibbons (Hylobates lar) to their mirror images

BACKGROUND: Hepatitis G virus (HGV) is a blood-borne flavivirus that may cause acute and chronic transfusion-transmitted infections. Patients with complement component 1 (C1) inhibitor (C1-INH) deficiency may acquire blood-borne infections through infusion of plasma concentrates. STUDY DESIGN AND METHODS: Serum samples from 84 patients with C1-INH deficiency (19 who received unmodified C1-INH concentrates, 23 who received steam-heated concentrates, and 42 untreated patients) were tested for HGV RNA and hepatitis C virus (HCV) RNA by a nested polymerase chain reaction (PCR). The samples were also tested for antibodies to the E2 envelope protein of HGV (anti-HGV) and to HCV with enzyme-linked immunosorbent assays. RESULTS: Nine (11%) patients had serum HGV RNA; that is, 7 (17%) of 42 patients previously treated with C1-INH concentrates and 2 of 42 previously untreated patients. HGV RNA was as common in the 19 patients treated with unmodified concentrates as in the 23 given steam-heated concentrates (16 vs. 17%, p = 0.60). Anti-HGV was more common among the recipients of unmodified concentrates than among those given steam-heated concentrates (26 vs. 0%, p = 0.014). HCV RNA was more frequently detected in treated patients than in untreated patients (33 vs. 7%, p = 0.005) and in the 19 recipients of unmodified concentrates than in the 23 treated with steam-heated concentrates (58 vs. 16%, p = 0.003). Only one HGV RNA-seropositive patient had elevated serum aminotransferase activity, compared to 11 with HCV RNA. CONCLUSION: HGV was transmitted by both unmodified and steam-heated concentrates, but it caused persistent viremia in a minority of the cases and was rarely associated with liver disease.     

A novel isoform of the neurofibromatosis type-1 mRNA and a switch of isoforms during murine cell differentiation and proliferation

There are different recommendations for the handling of blood samples for analyses of the kallikrein-kinin or complement system, respectively. C1 inhibitor (C1-INH) takes a crucial part in both systems. In order to establish recommendations for blood specimen collection and transport for making the diagnosis of hereditary angioedema (HAE), the effect of time, temperature and different additives on C1-INH function and antigen was determined. We used blood samples from normals and patients suffering from HAE type I. Plasma containing EDTA, heparin, sodium citrate or polybrene-EDTA, and serum were assayed after incubations at 4 degrees C or 37 degrees C for 6 or 24 h. In addition, pooled serum was incubated for up to 5 days at room temperature. A modest decrease in C1-INH function was observed as an effect of storage-time in samples from normals (p = 0.039) and a substantial decrease was seen for the HAE patients (p = 0.0002). No significant effect of temperature (4 degrees C or 37 degrees C) was found. Clotting did not reduce C1-INH activity. Plasma containing heparin or polybrene interfered with the functional assay, yielding falsely high and low values, respectively. C1-INH functional assay performed within 24 h in serum, EDTA-treated or citrated plasma discriminated well between HAE patients and normals. This was also the case for serum kept at room temperature for up to 5 days, although a modest fall in C1-INH function was seen in the incubation period. For practical purposes we recommend serum as the sample of choice, preferably received within 48 h.     

Rapid activation of the complement system by cuprophane depends on complement component C4

Hemodialysis with cuprophane dialyzer membranes promotes rapid activation of the complement system, which is thought to be mediated by the alternative pathway. Complete hereditary deficiency of complement C4, a classical pathway component, in two hemodialysis patients provided the opportunity to investigate a possible role of the classical pathway. In two hemodialysis patients with both C4 isotypes, C4A and C4B, and in one patient with C4B deficiency complement activation occurred immediately after the onset of hemodialysis, with peak levels of C3a and terminal complement complex (TCC) after ten to fifteen minutes. In patients with complete C4 deficiency, C3a and TCC remained unchanged for fifteen minutes and increased thereafter, reaching the highest level after thirty minutes. The leukocyte nadir was also delayed from fifteen to thirty minutes. In vitro incubation of normal, C4A- or C4B-deficient serum with cuprophane caused complement activation after fifteen minutes. In contrast, no activation was observed in sera of four C4-deficient patients. The addition of normal serum or purified human C4 restored the capacity for rapid complement activation. In one patient with severe immunoglobulin deficiency, C3a and TCC levels increased only moderately after 25 minutes of cuprophane dialysis. This patient's serum also exhibited delayed complement activation in vitro, which was normalized after pretreatment of cuprophane with immunoglobulins. Preincubation of normal serum with MgEGTA, a blocker of the classical pathway, inhibited rapid complement activation through cuprophane. As basal levels of C4a are markedly increased in hemodialysis patients (3450 +/- 850 ng/ml) compared to healthy controls (224 +/- 81 ng/ml), no further elevation of C4a was detectable during cuprophane hemodialysis. Incubation of normal serum with cuprophane, however, caused a slight increase in C4a after five minutes. These results indicate that the initial deposition of complement C3b on the cuprophane membrane, necessary for activation of the amplification loop of the alternative pathway, is mediated by the classical pathway C3-convertase C4b2a. We propose an extended concept of complement activation through cuprophane, which is based on four steps: (a) binding of anti-polysaccharide antibodies, (b) classical pathway activation, (c) alternative pathway activation and (d) terminal pathway activation.     

C1 inhibitor-C1s complexes are internalized and degraded by the low density lipoprotein receptor-related protein

Like other serpin-enzyme complexes (SECs), proteinase-complexed C1 inhibitor (C1-INH) is rapidly cleared from the circulation and thought to be a neutrophil chemoattractant, suggesting that complex formation causes structural rearrangements exposing a domain which is recognized by specific cell surface receptors. However, the cellular receptor(s) responsible for the catabolism and potential mediation of chemotaxis by C1-INH-protease complexes remained obscure. To determine whether the SEC receptor mediates the binding and potential chemotaxis of C1-INH.Cs, we performed binding assays with HepG2 cells, neutrophils, and monocytes, and the results show that C1-INH.Cs neither bind to these cells nor cause a chemotactic response of neutrophils and monocytes. Furthermore, C1-INH.Cs, the COOH-terminal C1 inhibitor peptide, or the tetrameric C1-INH.Cs.Cr. C1-INH complex were found to be significantly less effective in competing with the SEC receptor ligand 125I-peptide 105Y for the binding to HepG2 cells than unlabeled 105Y, indicating that the SEC receptor does not sufficiently recognize C1-INH-protease complexes. The asialoglycoprotein receptor was also ruled out to be responsible for the removal of the heavily glycosylated C1-INH.Cs complex, since asialoorosomucoid did not compete for the clearance of C1-INH. 125I-Cs and asialoglycoprotein receptor knockout mice showed no alterations in the C1-INH.125I-Cs clearance rate. We found that C1-INH.125I-Cs complexes were efficiently degraded by normal murine fibroblasts expressing the low density lipoprotein receptor-related protein (LRP) and cellular degradation was significantly reduced by chloroquine and the receptor-associated protein, which is a potent inhibitor of the binding of all known ligands to LRP. Moreover, receptor-associated protein inhibited the in vivo clearance of C1-INH.125I-Cs and murine fibroblasts genetically deficient for LRP did not degrade C1-INH.125I-Cs. Our results demonstrate that C1-INH. Cs complexes do not stimulate neutrophil or monocytic chemotaxis but are removed by LRP, further underscoring its role as a serpin-enzyme complex clearance receptor.     

Association of TAP1 and TAP2 with systemic sclerosis in Japanese

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal stem cell disorder resulting in insufficient and defective haematopoesis associated frequently with aplastic anaemia (AA). A deficiency of the glycosyl phosphatidylinositol (GPI)-anchored complement activation regulatory proteins CD55 and CD59 is responsible for an increased sensitivity of erythrocytes to complement attack leading to chronic intravascular haemolysis with haemoglobinuria. In this study we investigated the effects of complement activation caused by anti-thymocyte globulin (ATG) treatment on the PNH clone in a patient affected with the PNH/AA-syndrome. Fluid phase complement components C3, C4, C6 and terminal complement complex (TCC) were assayed by ELISA. CD55, CD59 and cell-associated TCC were monitored by flow cytometry. ATG treatment resulted in profound systemic complement activation which led to a decrease in the levels of native C3 and C4 to 65% and 40%, respectively, of the original levels on day 5 and of C6 and TCC to 61% and 23%, respectively, on day 10. A return to pre-treatment levels was observed for C3 by day 15, for C6 by day 30 and for C4 by day 90. Flow cytometry revealed that the deficiency in the GPI-anchored protein was restricted to granulocytes, while lymphocytes remained unaffected. Cell-bound TCC increased by 1.67-fold and 2.37-fold on day 5 and day 10, respectively, decreasing to 1.40-fold and 1.30-fold on day 15 and day 30, respectively. The percentage of PNH granulocytes as identified by the absence of the CD55- and CD59-antigens exhibited a temporary decrease from 72% on day 0 to 65% on day 5 and 59% on day 10 and returned thereafter to the original percentage of 70% by day 15 and exceeding this level to 76% on day 30 and 79% on day 90. We report profound activation of the classical pathway of the complement cascade and the terminal complement complex by the globulin leading to a transient decrease of the PNH clone, presumably due to subsequent lysis of the PNH cells devoid of complement regulatory proteins.     

Endotoxin-induced pulmonary dysfunction is prevented by C1-esterase inhibitor

In septic shock, hypotension, disseminated intravascular coagulation, and neutrophil activation are related to the activation of the blood coagulation contact system. This study evaluates in dogs the effect of the C1-esterase inhibitor (C1-INH), a main inhibitor of the blood coagulation contact system, on the cardiovascular and respiratory dysfunction associated with endotoxic shock. Two groups were included: controls, which received Escherichia coli endotoxin, and a C1-INH group in which C1-INH was infused before E. coli endotoxin administration. In both groups, endotoxin produced hypodynamic shock; however, the decrease in the systolic index and the ventricular systolic work indexes were greater in controls than the C1-INH group. In controls, the arterial O2 partial pressure decreased by 30% and the alveolo-arterial O2 difference increased by 625%, these parameters remained unchanged in the C1-INH group. Hypoxemia was associated with increased intrapulmonary shunt, decreased blood coagulation contact factors, and decreased C3c. In contrast, C1-INH administration prevented endotoxin-induced hypoxemia, the increase in intrapulmonary shunt, and the decrease in blood coagulation contact factors. This study shows that, in dogs with endotoxic shock, pulmonary dysfunction is associated with an activation of the blood coagulation contact phase system. An inhibition of this system by C1-INH prevented the hypoxemia induced by endotoxic shock.     

An estimate of the total UV-B exposure for outdoor workers during a south-east Queensland summer

BACKGROUND: Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. METHODS: Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. RESULTS: C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p < 0.01). Univariate analysis (log rank test) showed that low concentrations (< or = lower quartile) of C3 (p < 0.001) and C3bc (p < 0.05), haemolytic complement activity of the alternative pathway (p < 0.01) and classic pathway (p < 0.05), and decompensated cirrhosis (p < 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p < 0.02). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.     

Alterations in fibrinolytic and protein C pathways in gynaecological surgery: low molecular weight heparin prophylaxis

Several parameters of fibrinolytic and protein C pathways were evaluated in three groups of patients with high (HR), moderate (MR) and low (LR) postoperative thrombotic risk undergoing major gynaecological surgery. The HR and MR groups were subjected to low molecular weight heparin (LMW) prophylaxis. A significant increase in plasminogen activator inhibitor type 1 (PAI-1) antigen and activity levels was observed in the HR patient group in comparison with the MR and LR groups in the preoperative and early postoperative period. In all the groups studied, the maximum increase in the levels of PAI-1 was seen on day 1 after surgery. However, the D-dimeric levels reached the highest level on day 7. A significant increase in activated protein C:alpha 1 antitrypsin (APC:alpha 1AT) complex levels was observed in the HR group in comparison with the LR group, and a strong decrease in protein C inhibitor in the early postoperative period was detected in all the groups. In spite of heparin prophylaxis, 2 HR patients were diagnosed as deep vein thrombosis (DVT) during the postoperative period. Both patients showed pre-operative levels of PAI-1 antigen or activity and APC:alpha 1AT complexes above the mean + 1 SD of the pre-operative levels in the HR group. In conclusion, in HR patients a hypofibrinolytic and hypercoagulable state was detected in the pre-operative and early postoperative periods. The prophylactic LMW heparin dose used in the present report (20 mg/day x 7) was insufficient to prevent DVT in the HR group. At present our HR patients are given higher doses of LMW heparin (40 mg/day x 7).     

Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy

We investigated hemostatic parameters in a prospective study of 16 patients who received bone marrow transplants (BMT). We found a significant rise in the levels of fibrinogen, plasmin-alpha2 antiplasmin inhibitor complex, tissue-plasminogen activator.plasminogen activator inhibitor complex (t-PA.PAI), von Willebrand factor antigen, and thrombomodulin on day 14 after transplant compared with values before transplant. Protein C and thrombin-antithrombin III levels did not change significantly. No significant changes in prothrombin time ratio, activated partial thromboplastin time, or protein S were detected. Patients who had grades II-IV graft-versus-host disease (GVHD) (n = 6) showed a significantly higher level of t-PA.PAI on day 14 compared with those with grades 0-I GVHD (n = 10) (P = 0.0062). Three patients with grades II-IV GVHD developed thrombotic microangiopathy (TMA) on days 19, 19 and 62. In these patients, we noted significantly lower levels of fibrinogen (P = 0.0383), and significantly higher levels of t-PA.PAI (P = 0.0008) and thrombomodulin (P = 0.0001) on day 14 compared with those patients who did not develop TMA. These results suggest that prothrombotic states and endothelial damage may be caused by the conditioning regimen and/or acute GVHD during BMT; thrombomodulin values on day 14 post BMT may be useful in surveillance for TMA because of endothelial cell injury.     

Functional determination of C1-inhibitors in human blood]

The author describes the method of assessment of the C1-inhibitor, the principle being activation of plasma prekallikrein by Hageman factor fragment (HFf) to the active enzyme kallikrein which splits the specific chromogenic substrate NO-Pro-Phe-Arg-pNA. In the presence of acetone the influence of C1-INH is eliminated and the assessed amount of kallikrein corresponds to the prekallikrein plasma level. In a parallel estimation without acetone after formation of the C1-INH complex the residual amount of kallikrein is assessed. The difference between the two levels is proportional to the formed enzyme-inhibitor complex. The method was tested on plasma of healthy donors and the results were compared with assessment of C1-INH by a modification of Schapira's method (6) (correlation coefficient r = 0.88) and with Cullmann's method (8) (r = 0.61). The advantage of the proposed method is that it does not require commercially unavailable enzyme preparations, that it uses as activating agent HFf concentrate, prepared in the laboratory and that along with the C1-INH level also the plasma level of prekallikrein is assessed.     

Stimulatory effect of melanin-concentrating hormone on luteinising hormone release

We investigated the cytokine profile and peak levels of interleukin (IL) -6, IL-8, IL-10 and tumour necrosis factor (TNF) -alpha levels in 42 patients after allogeneic bone marrow transplantation (BMT). Eleven of them developed veno-occlusive disease (VOD) of the liver. Fourteen patients had moderate-to-severe acute graft-versus-host disease (aGvHD), 10 isolated bacteraemia and 7 had no major complication. Those who developed severe VOD (n=6) showed a short, very high IL-8 peak (median: 6632 pg/ml, range: 5546-10,000 vs. 280 pg/ml, 0-2042 in controls, p<0.01) 1-4 d after diagnosis of the liver disease. Five of these patients had high peak levels of IL-6. Five patients with mild VOD showed a lower increase in the cytokines tested. Bilirubin levels, at day of IL-8 peak, did not differ statistically between mild and severe VOD. The highest levels of IL-10 were found in those with aGvHD. IL-8 levels were also increased, but not to the same extent as in patients with severe VOD (p=0.01 vs. VOD). In patients with bacteraemia, very high levels of IL-6 were seen. In patients without major complications, the levels of cytokines were low. In conclusion, high levels of IL-8 occurred in severe VOD of the liver, which may be of value to determine prognosis.     

Potentiation of C56-initiated lysis by leucocyte cationic proteins, myelin basic proteins and lysine-rich histones

Synthetic polycations such as poly-L-lysine (PLL) have recently been shown to enhance C56-initiated lysis by neutralization of serum-derived inhibitors of the C567 complex, collectively designated C567-INH. In the present report we have examined the effect of several naturally occurring polycations on C56-initiated lysis. Lysosomal granule extracts from rabbit peritoneal exudate cells were found to potentiate C56-initiated lysis via counteraction of C567-INH in the fluid phase; this was dependent upon the amount of C567-INH present and independent of cell concentration. The basic proteins of guinea-pig, bovine, and monkey myelin as well as lysine-rich histones also potentiated EC567 formation, but this effect seemed to occur predominantly at the cell surface. The presence of biologically derived cationic proteins at sites of complement activation during inflammation thus might lead to enhanced tissue damage by favouring the formation of cell-C567 intermediates by either or both of these mechanisms.     

Contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan

To assess the contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan, we compared 10 major clinical features among 7 patients with type B fulminant hepatitis (type B group), 13 patients with non-A, non-B fulminant hepatitis with evidence of hepatitis C virus infection (type C group) and 10 patients without evidence of hepatitis C virus infection (NANB group). Duration from first symptom to coma and that from onset of jaundice to coma was significantly longer in the type C group (median = 39 and 25 days, respectively) and in the non-A, non-B group (median = 29 and 12 days, respectively) than in the type B group (median = 9 and 2 days, respectively) (p < 0.01). The maximum median AST level was significantly lower in the type C (1,689 U/L) and non-A, non-B groups (1,353 U/L) than in the type B group (5,780 U/L) (p < 0.05). Serum transaminase levels showed a single peak in six of seven of the type B patients, whereas they formed two or more peaks in all of the type C patients and in most of the non-A, non-B group (p < 0.05). Six of seven in the type B group, 6 of 13 in the type C group and 4 of 10 in the non-A, non-B group survived (p < 0.05). We found no significant difference in any of the 10 clinical features between the type C and non-A, non-B groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlations of C1q- and C3d-bearing circulating immune complexes with immunopathological disease activity in lupus nephritis patients

The serum levels of circulating immune complexes (CIC) measured by three different types of enzyme immunoassay (EIA) using monoclonal anti-C1q and antibodies and C1q as solid phase reagents were compared with clinical disease activity and immunohistological glomerular lesions in 29 SLE patients. Three types of CIC measured by these assays (anti-C1q CIC, anti-C3d CIC and C1q SP CIC) showed significantly higher levels in patients than in controls and were significantly associated with the clinical and serological disease activities. Anti-C1q CIC showed good correlation not only with mesangial IgG depositions (P < 0.01), but also with that of C1q (P < 0.05). C1q SP CIC also showed a weak correlation with mesangial C1q deposition (P < 0.05). Serum levels of anti-C3d CIC increased with the degree of mesangial IgG and complement depositions. Analysis of the clinical course of a patient with active SLE revealed a more rapid decrease of anti-C1q CIC and anti-C3d CIC along with the improvement of disease activity, including the mesangial lesion, than that of C1q SP CIC. According to these results, the CIC detected with assays using monoclonal antibodies against complement fragments, especially the anti-C1q assay, is likely to provide specific information regarding the clinical, serological and immunohistological disease activity in lupus nephritis.     

Impact of size mismatch and left ventricular function on performance of the St. Jude disc valve after aortic valve replacement

BACKGROUND: The hemodynamic function of the St. Jude valve may change relative to changes in left ventricular function after aortic valve replacement for aortic stenosis. From theoretical reasons one may hypothesize that prosthetic valve hemodynamic function is related to left ventricular failure and mismatch between valve size and patient/ventricular chamber size. METHODS: Forty patients aged 24 to 82 years who survived aortic valve replacement for aortic stenosis with a standard St. Jude disc valve (mean size, 23.5 mm; range, 19 to 29 mm) were followed up prospectively with Doppler echocardiography and radionuclide left ventriculography preoperatively and 9 days, 3 months, and 18 months after the operation with assessment of intravascular hemolysis at 18 months. Follow-up to a maximum of 7.4 years (mean, 6.3 years) was 100% complete. RESULTS: Left ventricular muscle mass index decreased from 198 +/- 62 g.m-2 preoperatively to 153 +/- 53 g.m-2 at 18 months (p < 0.001), paralleled by a significant increase in left ventricular ejection fraction, peak ejection rate, and peak filling rate; only 18% of the patients had normal left ventricular muscle mass index and only 32% normal ventricular function (normal left ventricular ejection fraction, peak ejection rate, peak filling rate, early filling fraction, and late filling fraction during atrial contraction) at 18 months. Prosthetic valve peak Doppler gradient dropped from 20 +/- 6 mm Hg at 9 days to 17 +/- 5 mm Hg at 18 months (p < 0.05). Reduction of left ventricular muscle mass index was unrelated to peak gradient and size of the valve. Peak gradient at 18 months rose with valve orifice diameter of 17 mm or less (by 6 mm Hg), orifice diameter/body surface area of 9 mm.m-2 or less (by 5 mm Hg), left ventricular enddiastolic dimension (by 23 mm Hg per 10 mm increase), and impaired ventricular function (by 3 mm Hg). All but 2 patients (5%) had intravascular hemolysis; none had anemia. Two patients with moderate paravalvular leak had the highest serum lactic dehydrogenase levels; 4 patients with trivial leak had higher serum lactic dehydrogenase levels than those without leak. Serum lactic dehydrogenase levels rose with moderate paravalvular leak, impaired ventricular function, and valve orifice diameter. Six patients with trivial or moderate paravalvular leak had a cumulative 7-year freedom from bleeding and thromboembolism of 44% +/- 22% compared with 87% +/- 5% for those without leak (p < 0.05). CONCLUSIONS: The peak gradient of the St. Jude aortic valve dropped marginally over the first 18 postoperative months in association with incomplete left ventricular hypertrophy regression and marginal improvement of ventricular function. Mismatch between valve size and ventricular cavity size or patient size and impaired function of a dilated ventricle significantly compromised the performance of the St. Jude valve. Probably explained by platelet destruction or activation, paravalvular leak was related to bleeding and thromboembolic complications.     

Keratosis follicularis spinulosa decalvans: report of a new pedigree

Soluble interleukin-6 receptor (sIL-6R) has previously been shown to potentiate the activity of interleukin (IL)-6, which may display antitumor activity. We evaluated sIL-6R and IL-6 levels in the sera of 24 patients following transplantation (allogeneic, n=17; autologous, n=7). Five patients developed acute graft-versus-host disease (AGVHD), three had early graft rejection, and three had an early relapse following bone marrow transplantation (BMT). Soluble IL-6R levels were evaluated at day - 10, day 0, day of engraftment, and during BMT-related complications, using IL-6R-specific monoclonal antibodies (mAb) and double-sandwich ELISA. In normal controls, sIL-6R and IL-6 levels were 20+/-3 ng/ml and 0.01+/-0.005 ng/ml, respectively. Soluble IL-6R levels increased in direct correlation with engraftment in the uneventful allogeneic transplants (17.7+/-2.1 ng/ml at day 0 to 49.7+/-2.6 ng/ml at day of engraftment, n=6, P<0.05) as well as in the autologous transplants (26.8+/-2.82 at day 0 to 66.4+/-12.9 at day of engraftment, n=5, P=0.01). In contrast, IL-6 levels declined with time during the conditioning period and showed only a modest elevation following BMT. Increased levels of sIL-6R and IL-6 were found in the patients who developed AGVHD (23.8+/-4.2 and 0+/-0 ng/ml at day 0 to 79+/-6.9 and 0.26+/-0.04 ng/ml, respectively, at time of AGVHD, n=5, P=0.01). No correlation was found between the severity of AGVHD and sIL-6R levels. In the three patients with early relapse, sIL-6R levels increased from 30+/-0 ng/ml at day 0 to 90 ng/ml (P=0.05) and IL-6 levels increased from 0 to 0.16+/-0 ng/ml, respectively. The mean elevation of sIL-6R in the patients with early relapse and AGVHD was significantly higher than the mean elevation in the patients with the relatively smooth engraftment (P<0.05). Contrary to these findings, in the three patients with graft rejection, sIL-6R levels decreased while IL-6 was found to be elevated. Basic disease, conditioning regimen, type of transplant, GVHD propylaxis, and T cell depletion had no effect on sIL-6R or IL-6 levels. In summary, sIL-6R levels positively correlated with engraftment. Both sIL-6R and IL-6 levels were found to be significantly elevated in patients who developed AGVHD or early relapse following BMT. Therefore, the sIL-6R level may be used as a tool for assessing engraftment and transplant-related complications following BMT.     

Clinical neuropsychological aspects of motor disorders in patients with post-CVA epilepsy

The study included 22 patients with poststroke epilepsy (group 1) and 30 patients with stroke without epilepsy (group 2). A bilateral decrease of the time of central conduction (TCC) through pyramidal path (both on the paretic and intact side) was revealed in group 1. This was not observed in patients of group 2 with similar gravity of motor disorders (p < 0.01). Tendency to TCC decrease was also observed in patients without epileptic disorders by day 5-6 after ischemic stroke. However, TCC values were increased in such patients by day 10-14. Low indices persisted for a long time in patients with poststroke. There was also an increase of delta index of facilitation (the difference between TCC in rest and in muscle effort). It was also found that motor disorders in the group of patients with poststroke epilepsy were characterised by higher muscular tone than in poststroke patients with the same degree of the paresis.