Antiproteinuric effect of angiotensin-converting enzyme inhibition and C5b-9 urinary excretion in membranous glomerulonephritis

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have an antiproteinuric effect in membranous glomerulonephritis (MGN). However, no studies have investigated whether this antiproteinuric effect is influenced by urinary C5b-9 excretion, a marker of immunological activity in this disease. METHODS: Eleven patients with biopsy-proven MGN were treated with captopril for 8 weeks. The evolution of several clinical and biochemical parameters, including 24-h urinary protein excretion was evaluated every 4 weeks. Urinary C5b-9 excretion was measured at the onset and at the end of captopril treatment. RESULTS: Patients with MGN had significantly higher C5b-9 excretions than a group of 14 healthy controls (89 +/- 23 vs 3.7 +/- 1.4 ng/mg UCr; P < 0.001). A significant correlation was found between urinary C5b-9 and the magnitude of proteinuria, both at the onset and at the end of treatment. After 8 weeks of captopril treatment, proteinuria had decreased from 8 +/- 1.8 to 5.2 +/- 1.3 g/day (P < 0.05). Four weeks after captopril discontinuation, proteinuria rose to 7.3 +/- 1.7 g/day (P < 0.05). A marked variability in the antiproteinuric response was observed, ranging from 0 to 85% with respect to baseline values. No correlation between decrease in proteinuria and baseline urinary C5b-9 levels was observed. Several patients with elevated urinary C5b-9 levels had captopril-induced decrease in proteinuria. CONCLUSIONS: ACE inhibition induces an antiproteinuric effect in patients with MGN. The urinary C5b-9 excretion does not predict the magnitude of this response.     

A novel 22q11.2 microdeletion in DiGeorge syndrome

BACKGROUND: Decreased red blood cell survival contributes to the anemia of chronic renal failure patients. Because patients on chronic dialysis therapy are frequently exposed to excessive complement activation, we investigated the susceptibility of this patient population to erythrocyte C5b-9 deposition, complement-mediated lysis, and ghost formation. METHODS: We developed a flow cytometric assay using antibodies to both glycophorin and the C5b-9 complex to detect C5b-9 deposition on intact erythrocytes and erythrocyte ghosts. Serum C5b-9 levels and C5b-9 deposition on erythrocyte ghosts were measured by enzyme-linked immunosorbent assay. RESULTS: A significant increase in C5b-9 deposition on intact erythrocytes was demonstrated in patients with advanced chronic renal failure (2.2 +/- 0.5%) and in patients on chronic maintenance hemodialysis (2.3 +/- 0.4%) compared with normal volunteers (0.9 +/- 0.1%, P = 0.005 vs. chronic renal failure, P < 0.001 vs. chronic hemodialysis patients). There was also a significantly higher percentage of C5b-9-positive erythrocyte ghosts in patients with advanced chronic renal failure (20.6 +/- 5%) and in chronic hemodialysis patients (15.5 +/- 3.1%) compared with normal controls (2.6 +/- 0.9%, P < or = 0.001 vs. advanced chronic renal failure and chronic hemodialysis patients). Treatment of erythrocyte preparations with cobra venom factor, which activates the complement cascade, resulted in dramatic increases in the percentages of C5b-9-positive erythrocyte ghosts in patients with chronic renal failure (49.9 +/- 6.9%) and in chronic hemodialysis patients (45.0 +/- 4.2%) compared with normal volunteers (22.3 +/- 2.7%, P < 0.001 vs. chronic renal failure and chronic hemodialysis patients). Erythrocyte membrane expression of the complement regulatory proteins CD59 and CD55 did not significantly differ between normal controls and hemodialysis patients. Plasma C5b-9 levels after cobra venom factor stimulation were higher in chronic renal failure patients (538 micrograms/ml) compared with normal controls (345 micrograms/ml, P < 0.001). CONCLUSIONS: Patients with chronic renal failure and on hemodialysis therapy are susceptible to erythrocyte C5b-9 deposition with subsequent lysis and ghost formation. Susceptibility to complement-mediated erythrocyte injury may contribute to the anemia of chronic renal disease.     

Renography before heart transplantation in patients with cardiomyopathy

In patients with ischemic cardiomyopathy (CM), abnormal renograms may result not only from circulatory failure (which should reverse after transplantation) but also from intrinsic renal disease (which contraindicates heart transplantation). Here, the outcome of heart transplantation was related to preoperative renograms, and the differentiating and prognostic value of renography was analyzed. METHODS: The study population consisted of 50 patients with ischemic CM expecting heart transplantation. Anatomical renal pathology was excluded in all patients. Dynamic renal scintigraphy was performed with 99mTc-mercaptoacetyltriglycine. Background-subtracted renograms were inspected visually and characterized numerically. Mean parenchymal transit time (mPTT), renal tracer content at 15 min (RTC15) and retention index (RI) were determined. The parametric renogram values were related to a normal reference group of 64 patients. The preoperative renograms were matched with the postoperative outcome. RESULTS: Three characteristic types of symmetrical findings in the kidneys were found: no pathological findings, mildly delayed peak and excretion phase and severely delayed peak and excretion phase. Pathological renograms were observed in 36 of 50 (72%) patients. The mean parametric renogram values in ischemic CM were as follows: Group A (normal kidney function), mPTT = 142+/-26.6 sec, RTC15 = 22.3%+/-4.6% and RI = 24.7+/-11.9; Group B (mild dysfunction), mPTT = 210+/-44.0 sec, RTC15 = 42.6%+/-10.3% and RI = 101.4+/-50.5; Group C (severe dysfunction), mPTT = 320+/-94.2 sec, RTC15 = 79.6%+/-15.9% and RI = 347.7+/-194.7; and reference patients (normal kidney function), mPTT = 137+/-31.1 sec, RTC15 = 22.8%+/-3.8% and RI = 24.6+/-7.9. Postoperative serum creatinine levels were <1.5 mg/dl in all Group A patients, between 1.5 and 2.5 mg/dl in 78% of Group B patients and >2.5 mg/dl in 75% of Group C patients. CONCLUSION: Renography revealed abnormal kidney function when structural pathology was excluded. The renographic abnormalities in ischemic CM did not reflect simply the circulatory failure. The numerical grading of renograms allowed patient stratification, suggestive of possible renal insufficiency after cardiac transplantation and immunosuppressive therapy. With further experience, renography may become a useful tool for predicting postoperative outcome in ischemic CM.     

Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass

Plasma concentrations of the complement activation products C3b, iC3b, and C3c; the terminal C5b-9 complement complex; and the granulocyte proteins calprotectin, myeloperoxidase, and lactoferrin were assessed in two groups of patients undergoing aortocoronary bypass procedures. In 10 patients operated on, the bypass circuits were coated by the Carmeda Bio-Active Surface and systemic heparinization was reduced to 1.5 mg/kg; in another 10, the systems were uncoated and the dosage of systemic heparinization was 4 mg/kg. In both groups, significant complement activation was observed after the onset of cardiopulmonary bypass, but the maximum levels of C3b, iC3b, and C3c and the terminal C5b-9 complement complex were significantly lower in the heparin-coated group. In both groups, a significant increase in calprotectin, myeloperoxidase, and lactoferrin release was observed by the end of operation. The maximum myeloperoxidase levels were significantly lower in the heparin-coated group than those in the uncoated group (p = 0.03). There was a correlation of borderline significance between the formation of terminal C5b-9 complement complex and lactoferrin release, as well as between the formation of terminal C5b-9 complement complex and myeloperoxidase release (p = 0.05). The postoperative blood loss did not differ significantly between the two groups. We conclude that coating by end point-attached and functionally active heparin allows a significant reduction in the amount of systemic heparinization, and significantly reduces complement and granulocyte activation.     

Myocarditis in children with dilated cardiomyopathy: incidence and outcome after dual therapy immunosuppression

BACKGROUND: The true incidence and prognosis of myocarditis in children with acute dilated cardiomyopathy (DCM) at presentation remains uncertain. This study examines the incidence of lymphocytic myocarditis in a consecutive cohort of children with acute DCM at presentation and outcome after dual therapy immunosuppression with cyclosporine and steroids. METHODS: Twenty-nine consecutive children with acute DCM underwent early endomyocardial biopsy. Children with "definite" myocarditis comprised group I (n = 9) and were treated with cyclosporine and prednisolone. Group II (n = 2) had "borderline" myocarditis, and group III (n = 18) nonspecific histologic findings. Outcome was assessed by echocardiographic measurement of left ventricular end-diastolic dimension and fractional shortening, with follow-up endomyocardial biopsy in group I subjects. RESULTS: Myocardial inflammation with or without myocardial necrosis (groups I and II) was present in 38% of all cases. There were no initial clinical, electrocardiographic, or echocardiographic features to distinguish patients in group I from patients in group III. At presentation, the mean +/- SEM left ventricular end-diastolic dimension and fractional score-Z scores of group I patients were 4.6 +/- 1.7 and -5.1 +/- 0.8, respectively, compared with 0.8 +/- 0.3 and -0.9 +/- 0.4, respectively, at withdrawal of immunosuppression (p < 0.001 for both). Both of these parameters did not differ significantly from normal controls at least follow up. Two group I patients had a biopsy-proven relapse after withdrawal of therapy that responded to reinstitution of immunosuppression. At latest follow-up, all nine group I patients had regained normal left ventricular function compared with four of 18 group III patients (p < 0.001). CONCLUSION: Lymphocytic myocarditis is frequent in children with dilated cardiomyopathy and cannot be predicted from noninvasive investigations. The use of cyclosporine and steroids is associated with a favorable outcome, and a controlled trial of dual therapy immunosuppression in children is therefore warranted.     

Preoperative application of glucocorticosteroids efficaciously reduces the primary immunological response in kidney transplantation

Early acute rejection episodes have a considerable influence on long-term prognosis of renal transplants. Therefore the aim of primary immunosuppressive therapy must be effective suppression of the immunological response following antigen recognition. Owing to their pharmacological properties, intravenously given glucocorticosteroids are suitable for the alteration of the primary immunological response. However, even after intravenous administration, glucocorticosteroids have a latency of hours prior to reaching maximum activity. In a prospective clinical study, 111 patients undergoing renal transplantation were preoperatively treated with 500 mg methylprednisolone for immunosuppressive induction. A historical group of 40 patients who had received the same dose as intraoperative bolus, was used for comparison. Postoperative immunosuppression did not substantially differ between the two groups. The incidence of acute rejections within 30 d after transplantation was a clinical parameter of the study. The mitogenic cytokine induction was measured in blood samples which were collected intraoperatively and on days 1, 2, and 5 after transplantation. Cytokine release served as an in vitro parameter for the immunological responsiveness of the transplant recipient. In the group under study, the incidence of acute rejections was 21% (23/111) and, in contrast, 43% (17/30) in the historical group (p < 0.05). 89% of the patients in the group being studied showed normal renal function after 1 yr, compared to 78% in the reference group (n.s.). Following preoperative (mean 5.09 h) administration of glucocorticosteroids, mitogenic cytokine induction (IL-1 beta, IL-2, sIL-2R and IFN-gamma) was almost completely blocked at the time of transplantation. A prospective, randomized study has just been started to evaluate the effect of preoperative administered glucocorticosteroids on the incidence of acute rejections and long-term allograft survival.     

The transducing pathway of Ca2+ influx during progesterone-initiated acrosome reaction of guinea pig sperm

Although idiopathic membranous nephropathy (IMN) is thought to represent a diffuse glomerulopathy, it was found that three of 31 children histologically diagnosed as IMN showed focal and segmental deposition of immunoglobulin G (IgG) and C3 on the glomerular capillary walls. The present study attempted to comparatively investigate clinical and pathological features of the diffuse group and the focal segmental group in 31 IMN children. Immunofluorescence study revealed that 28 of 31 IMN exhibited diffuse granular deposition of IgG along glomerular capillary walls. In contrast, focal and segmental deposition of IgG and C3 was noted in three children with IMN. In addition, focal and segmental electron-dense deposits were identified in these cases. In two children of the focal segmental group, immunofluorescent patterns of IgG deposition were unchanged even at the second biopsy. The focal segmental form of IMN tended to occur in younger children than diffuse IMN. However, other clinical parameters such as the range of proteinuria, hematuria, serum albumin and prognosis did not show any significant differences between both groups. Electrophoretic profiles of urinary proteins on sodium dodecylsulfate-polyacrylamide gel electrophoresis were not different between both groups. It is proposed that the focal segmental form of IMN may have a distinctive glomerulopathy from the typical form of IMN.     

Sodium excretion in children with lithogenic disorders

INTRODUCTION: The causes of nephrolithisis are multifactorial and have not yet been enough investigated [1]. Hypercalciuria is the most common cause of metabolic nephrolithiasis [2-4]. Close relationship between urinary calcium and urinary sodium has been a subject of reported observations in the past, showing that high urinary sodium is associated with high urinary calcium [5-7]. Hyperoxaluria, hyperuricosuria and cystinuria are also metabolic disorders that can lead to nephrolithiasis. Recent studies have indicated that urinary elimination of cystine is influenced by urinary sodium excretion. Based on these observations it has been hypothesised that patients with high urinary sodium excretion are at high risk of urinary stone disease. The purpose of the study was to investigate sodium excretion in a 24-hour urine and first morning urine collected from children with lithogenic metabolic abnormalities (hypercalciuria, hyperoxaluria, hyperuricosuria, cystinuria), both with nephrolithiasis and without it, in order to determine its significance in urinary calculi formation. PATIENTS AND METHODS: Urinary sodium excretion was investigated in 2 groups of children: patients with lithogenic metabolic abnormalities, but without urinary stone disease (L group) and patients with nephrolithiasis (C group). Both groups were divided into 2 subgroups: patients with hypercalciuria and without it. There were 22 patients in group L (mean age 11.97 +/- 4.13 years), of whom 17 formed a hypercalciuric subgroup and 5 formed a non-hypercalciuric subgroup (3 patients with hyperuricosuria and 2 patients with hyperoxaluria). Group C consisted of 21 patients with nephrolithiasis (mean age 12.67 +/- 3.44 years), of whom 6 formed a hypercalciuric subgroup and 15 formed a non-hypercalciuric group (2 patients with cystinuria and 13 patients without lithogenic metabolic abnormalities). Control group consisted of 42 healthy age-matched children. All subjects had a normal renal function. A detailed history and clinical examination were done, and ultrasonography was performed in all patients. A 24-hour urine, first morning urine and serum specimen were analysed for sodium, potassium, calcium, uric acid, urea and creatinine. Fractional excretion of sodium, as well as urinary sodium to creatinin ratio and urinary sodium to potassium ratio, were calculated from the findings. Sodium and potassium levels were determined by flame photometry, calcium was measured by atomic absorption technique (Beckman Atomic Spectrophotometer, Synchron CX-5 model, USA), uric acid by carbonate method and creatinine by Jaffe technique. Cystine and dibasic amino acids were quantified by ion chromatography. Urinary oxalate excretion was determined by enzyme spectrophotometry. Hypercalciuria was defined by 24-hour calcium excretion greater than 3.5 mg/kg per day and/or calcium to creatinine ratio greater than 0.20 [8]. Uric acid excretion was expressed as uric acid excretion factored for glomerular filtration, according to Stapleton's and Nash's formula [9]. Normal values were lower than 0.57 mg/dl of glomerular filtration rate in 24-hour samples. Mean values were statistically analyzed by Pearson's linear correlation and analysis of variance (ANOVA). RESULTS: Urinary sodium concentration values including urinary sodium to potassium ratios, are shown in Table 1. We found that urinary sodium excretion was significantly increased in patients of both L and C groups when compared with controls (p < 0.05). Further analysis of the subgroups showed that urinary sodium excretion was significantly higher only in patients with hypercalciuria of both L and C groups in comparison to controls (p < 0.05) (Table 2). A significant positive correlation was found between 24-hour urinary sodium to creatinine ratio and urinary calcium to creatinine ratio (r = 0.31; p < 0.001) (Graph 1), as well as between urinary sodium to potassium ratio in 24-hour and first morning urine (r = 0.69; p < 0.001) (Graph 2). (A     

Immunosuppressive therapy and hepatitis C virus infection: the clinical course of liver disease

In a retrospective long-term follow-up study the clinical course of liver disease was examined in renal allograft recipients with hepatitis C virus (HCV) infection and negative hepatitis B surface antigen under immunosuppressive therapy. We compared 42 anti-HCV antibody (anti-HCV) positive patients (study group) to 213 anti-HCV negative patients (control group). All patients received immunosuppressive therapy. Measurements were made of the following: aminotransferases, bilirubin, albumin, gammaglobulins, ascites, spleen diameter, HCV RNA, and anti-HCV antibody. We found all but four anti-HCV positive patients to be HCV RNA positive prior to transplantation. There were no differences in overall mortality or mortality secondary to liver disease or sepsis. Normal liver enzymes were found in 13 (31%) anti-HCV positive and in 137 (64%) anti-HCV negative patients during the whole mean observation period of 65 months (range 10-215). Aminotransferase activity decreased in anti-HCV positive and negative patients during the observation period. Liver function with regard to synthesis and excretion was normal in anti-HCV negative and anti-HCV positive patients. No signs of portal hypertension were observed in the anti-HCV positive group. Neither the different immunosuppressive regimens nor the antirejection therapy led to differences between anti-HCV positive and negative groups with respect to liver function and did not alter the clinical course. We conclude that HCV infection in patients under immunosuppressive therapy causes only a mild liver disease, as determined by clinicochemical and clinical parameters, and that mortality rate is not increased.     

Immunohistochemical localization of C3d fragment of complement and S-protein (vitronectin) in normal and diseased human kidneys: association with the C5b-9 complex and vitronectin receptor

The localization of C3d, a fragment produced by C3 activation and S-protein (vitronectin), a regulatory factor of C5b-9, was studied immunohistochemically in normal human kidney and renal biopsies from patients with several types of glomerulonephritis. Immunofluorescent staining of the normal kidneys showed that C3d was present along the glomerular basement membrane (GBM), tubular basement membrane (TBM) and arterioles, and that S-protein was present in the GBM, mesangium, TBM, and arterioles. Immunoelectron microscopy of isolated basement membranes showed that C3d was localized exclusively on the epithelial side of the GBM, and that S-protein was present along both the epithelial and endothelial sides. In nephritic tissues, glomerular staining of C3d, C5b-9, and S-protein was increased when compared with that in normal tissues. S-protein, frequently co-localized with C3d and C5b-9 neoantigen, was intensely positive in the immune deposits of glomerular capillaries and the mesangial area, overlapping the background staining of GBM and mesangial matrix. S-protein and its receptor were occasionally co-localized in the glomeruli. These findings indicate that C3d and S-protein are normally present in the glomeruli. Co-staining of C3d, C5b-9 neoantigen, and S-protein within the immune deposits of nephritic kidneys suggests in situ binding of S-protein to locally-formed C5b-9 complex, or merely co-distribution of S-protein with the complex, rather than trapping of large molecular SC5b-9 complex from the circulation.     

Clinical subgroup of autoimmune hepatitis type 1 sustaining remission without additional drugs

BACKGROUND/AIMS: Many patients with autoimmune hepatitis type 1 need additional non-steroidal immunosuppressants to maintain remissions, but the indication should be limited to avoid the unnecessary side effects. The aim of this study is to clarify the clinical subgroups of autoimmune hepatitis type 1 sustaining remission without additional drugs. METHODOLOGY: We studied 20 patients with autoimmune hepatitis type 1, in whom complete remissions were achieved in the natural course or by prednisolone alone. Remissions were maintained with none or less than 10 mg/day of prednisolone. RESULTS: In the course (average: 6 years), 8 patients (40%) remained in remission for more than three years. In the remitted group, initial values of serum gamma-globulin (p<0.05) and serum immunoglobulin G (p<0.01) were lower than those in the relapsed group. The group with less than 30 mg/ml of gamma-globulin and 3000 mg/dl of immunoglobulin G showed a significantly lower relapse rate than the other one (p<0.01). CONCLUSIONS: There is a clinical subgroup of autoimmune hepatitis type 1 that sustains remission with low-dose prednisolone alone. Additional immunosuppressive drugs may not be needed to maintain remissions in such patients.     

Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.     

Overexpression, purification, and characterization of the cloned metallo-beta-lactamase L1 from Stenotrophomonas maltophilia

OBJECTIVES: The purpose of this study was to assess whether the presence or absence of myocardial viability during dobutamine echocardiography (DE) predicts survival in patients with coronary artery disease (CAD) and severe left ventricular (LV) dysfunction. BACKGROUND: In patients with CAD, the presence of myocardial viability during DE identifies viable myocardium and predicts recovery of LV systolic function after revascularization. However, there is little data on the relation between myocardial viability and clinical outcome in patients with CAD and severe LV dysfunction. METHODS: We studied 318 patients with CAD and a LV ejection fraction (EF) < or =35% who underwent DE and were followed for 18+/-10 months. Patients were classified into four groups. Group I (n=85) consisted of patients who had evidence of myocardial viability and subsequently underwent revascularization. Group II (n=119) consisted of patients with myocardial viability who did not undergo revascularization. Group III (n=30) consisted of patients who did not have myocardial viability and underwent revascularization. Finally, group IV (n=84) patients lacked myocardial viability and did not undergo revascularization. RESULTS: The four groups had similar baseline characteristics and rest LVEF. During follow-up there were 51 deaths (16%). The mortality rate was 6% in group I, 20% in group II, 17% in group III and 20% in group TV (p=0.01, group I vs. other groups). CONCLUSIONS: In patients with CAD and severe LV dysfunction who demonstrated myocardial viability during DE, revascularization improved survival compared with medical therapy.     

Amplification and detection of a Y-chromosome DNA sequence by fluorescence in situ polymerase chain reaction and flow cytometry using cells in suspension

In this part of Malaysia, consent of splenectomy is virtually unobtainable, so we studied the outcome of ITP without this treatment option. Thirty-two adult patients were seen, but 7 defaulted before therapy evaluation. Of the remaining 25, 17 achieved a complete remission with prednisolone, but in only 8 was this prolonged. Twelve patients, who failed to respond to prednisolone or who required > 15 mg/day as maintenance, were offered splenectomy, but all fused. Of these 12: one has died from an intracranial haemorrhage; three others have defaulted while on no treatment with platelet counts of < 16 x 10(9)/1; one has had a baby who died from intracranial bleeding. The other seven patients have platelet counts ranging from 4 - 202 x 10(9)/1 with moderate bleeding on doses of prednisolone of 0-60 mg/day: long-term corticosteroid side-effect are evident in all but one of them. This study demonstrates that ITP patients who refuse splenectomy have a high morbidity.     

Complement activation during CAPD

Complement activation was monitored in 20 CAPD patients and 20 normal individuals using markers of the alternative (Bb fragment), classical (C4d fragment), common (iC3b) and terminal pathways (SC5b-9, the soluble form of the membrane attack complex, MAC), together with C3, C4 and factor B. CAPD plasma SC5b-9 was higher than normal although this was not due to increased complement activation in the plasma. The calculated cleavage for C3, C4 and factor B to iC3b, C4d and Bb respectively, due to spontaneous activation, was similar in both groups. C3, C4 and factor B in dialysate were less than 1% of plasma concentration, consistent with vascular leakage, whereas iC3b, Bb and SC5b-9 were at higher concentrations, suggesting generation in the peritoneum by the alternative pathway. 2.4% C4d is consistent with leakage of this small molecule but may indicate slight classical activation. It is concluded that complement activation occurs in the peritoneum during CAPD. MAC and the anaphylatoxins which are also generated may contribute to an increased risk of infection and other inflammatory complications.     

Postoperative inflammatory response after autologous and allogeneic blood transfusion

BACKGROUND: Allogeneic blood transfusions cause immunosuppression. The aim of this study was to determine whether complement anaphylatoxins, cytokines, or both are released in the recipient, after blood transfusions in general, and after autologous blood transfusions in particular. METHODS: Thirty-one patients having total hip joint replacement surgery were randomized to receive either allogeneic red blood cells (n = 15) or predeposited autologous whole blood transfusion (n = 16). Plasma concentrations of the anaphylatoxins C3a and C5a, the terminal C5b-9 complement complex, and cytokines IL-6 and IL-8 in the recipients were repeatedly analyzed before, during, and after surgery. RESULTS: Significantly increased concentrations of IL-6 and IL-8 appeared in both groups, with a significantly greater increase in the autologous blood group. Patients in both groups developed a moderate but significant increase of C3a without a significant difference between them. C5a and terminal C5b-9 complement complex were not greatly changed. CONCLUSIONS: The study showed a greater increase in cytokine concentration after autologous blood transfusion than after allogeneic blood transfusion. The lower response in the latter may result from transfusion-induced suppression of cellular immunity.     

A molecular perspective of the genetic relationships of G-protein coupled melatonin receptor subtypes

OBJECTIVE: To compare the efficacy, tolerance and recurrence rate of endometriosis after 5-year follow-up of treatment with Gestrinone and Buserelin, respectively. STUDY DESIGN: A prospective study with randomized follow-up of 5 years duration (minimum) for each patient was done. We included 43 cases of endometriosis diagnosed by laparoscopy or laparotomy and treated them with Gestrinone (Group G, n = 25 cases) or Buserelin intranasal spray (Group B, n = 18) for 6 months. RESULTS: General data: Age, height, weight of patients and AFS score of endometriosis were without significant differences in either group. Specific data: A) Global clinical efficacy was good or excellent in 74% (16/25) of group G and in 78% (14/18) of group B without significant differences. B) Global clinical tolerance was good in 50% of the patients in group G and in 0% in group B (p < 0.001). C) Global evaluation after 5-year follow-up showed "success" only for 36% of patients in group G and in 33% in group B (no significant differences), with "failure" in 40% and 33%, respectively (no significant differences). CONCLUSIONS: 1) Gestrinone and Buserelin intranasal spray are valid treatments for the remission of endometriosis, with "success", "failure" and "clinical recurrence" rates similar after a follow-up of 5 years of initial treatment. 2) The most significant androgenic effect of Gestrinone was the presence of acne. Vascular effects were also considered as very undesirable effects according to the comments of patients. On the contrary, the effects of analogs are generally better tolerated.     

Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy

BACKGROUND: Myocardial ischemia and reperfusion (MI/R)-induced tissue injury involves necrosis and apoptosis. However, the precise contribution of apoptosis to cell death, as well as the mechanism of apoptosis induction, has not been delineated. In this study, we sought to define the contribution of the activated terminal complement components to apoptosis and necrosis in a rat model of MI/R injury. METHODS AND RESULTS: Monoclonal antibodies (mAbs; 18A and 16C) raised against the rat C5 complement component bound to purified rat C5 (ELISA). 18A effectively blocked C5b-9-mediated cell lysis and C5a-induced chemotaxis of rat polymorphonuclear leukocytes (PMNs), whereas 16C had no complement inhibitor activity. A single dose (20 mg/kg i.v.) of 18A blocked >80% of serum hemolytic activity for >4 hours. Administration of 18A before myocardial ischemia (30 minutes) and reperfusion (4 hours) significantly reduced (91%) left ventricular free wall PMN infiltration compared with 16C treatment. Treatment with 18A 1 hour before ischemia or 5 minutes before reperfusion significantly reduced infarct size compared with 16C treatment. A significant reduction in infarct size (42%) was also observed in 18A-treated rats after 30 minutes of ischemia and 7 days of reperfusion. DNA ladders and DNA labeling (eg, TUNEL assay) demonstrated a dramatic reduction in MI/R-induced apoptosis in 18A-treated compared with 16C-treated rats. CONCLUSIONS: Anti-C5 therapy in the setting of MI/R significantly inhibits cell apoptosis, necrosis, and PMN infiltration in the rat despite C3 deposition. We conclude that the terminal complement components C5a and C5b-9 are key mediators of tissue injury in MI/R.     

Association of class I HLA antigens with invasive meningococcal disease

BACKGROUND: The majority of meningococcal infections are characterized by nasopharyngeal carriership. In some patients invasive disease with a mild course develops, while some cases have a lethal outcome. The reasons of this wide variation range are not clear. The objective of the present work was to assess whether the development of invasive meningococcal disease or its prognosis are associated with HLA class I. METHODS AND RESULTS: The group of patients was formed by 40 patients (29 females, 11 males, mean age 16 years, range 8 months to 52 years). In 28 patients the disease was caused by N. meningitidis group C, in 9 cases group B, in three cases the serotype was not assessed. The etiology was confirmed by cultivation or latex agglutination. Twenty-three patients had a mild course of the disease, 8 a medium severe one, 9 patients a severe clinical course (score according to Stiehme, Damrosch and Rosenblat). The patients were compared with 227 non-related blood donors (114 women, 113 men, 18 to 50 years old). In patients and controls 24 lymphocytic HLA antigens class I were identified as to type. Typing was done using the standard microlymphocytotoxic test in the NIH modification. The results were processed by statistical methods using Fisher's exact test and the 2 x 2 test with Yates correction. In patients with a mild course HLA antigens B7 and B12 predominate (p = 0.03; p = 0.02), in medium severe cases antigen A11 (p = 0.03), in patients with the most severe course antigen A9 (p = 0.04). In invasive infections caused by N. meningitidis serotype B antigen B17 predominates (p = 0.05). CONCLUSIONS: The severity of meningococcal invasive infections is associated with HLA class I. Invasive disease caused by N. meningitidis serotype B are more likely to occur in carriers of HLA B17. No relationship was found between HLA class I and invasive disease caused by N. meningitidis regardless of serotype and with serotype C.