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Biomedical subjects

M Cicardi

Publications and source records attributed to M Cicardi.

At least 73 records · Page 4Linked to original sources
PubMed1989

Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon.

The molecular genetic basis of C1 inhibitor (C1 INH) deficiency in a patient with type I hereditary angioneurotic edema was studied. This patient was found to have an abnormally short C1 INH mRNA together with a normal message. Restriction fragment length polymorphism of the C1 INH gene was detected by Southern blot analysis of the patient's DNA after digestion with Pst I or Sac I, and hybridization with a full-length C1 INH cDNA. Hybridization of the same blot with three different fragments of the full-length cDNA suggested that exon VII and portions of both flanking introns were deleted in the C1 INH gene. Northern blot analysis of RNA from cultured monocytes, using a probe corresponding to exon VII, also indicated that the abnormal C1 INH mRNA had a deletion of these nucleotides. To confirm the hypothesis that the short C1 INH mRNA contained a deletion, the involved segment of the patient's C1 INH mRNA was amplified using the polymerase chain reaction (PCR). PCR amplification yielded two C1 INH DNA fragments of different lengths (380 and 160 bp). Southern blot and sequence analysis of both DNA fragments clearly revealed that the smaller 160-bp DNA was derived from the abnormal message and had a deletion of nucleotides corresponding to exon VII.

Angioedema↗
PubMed1988

Haemostasis contact system and fibrinolysis in hereditary angioedema (C1-inhibitor deficiency).

Factors of the classical complement pathway, the contact system and fibrinolysis were evaluated both with functional and immunochemical methods, in patients with inherited deficiency of C1-inhibitor. Evaluations were performed under basal conditions, during acute attacks and during prophylaxis with low doses of anabolic steroids. Patients in the basal state showed no significant abnormalities of any of the parameters that we investigated. During acute attacks a slightly reduced prekallikrein concentration was registered. During treatment with low doses of danazol and stanozolol, protein C and plasminogen were found to be increased. Our data suggest that C1-inhibitor deficiency per se does not lead to a derangement of the fibrinolysis and coagulation contact system, and that the kinin system may be involved during acute attacks of angioedema.

Adolescent↗
PubMed1987

Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema.

Hereditary angioneurotic edema (HANE) results from deficiency of complement 1 inhibitor (C1 INH). In type I HANE, C1 INH is present in serum at levels 5-30% of normals. Using cultured monocytes and biosynthetic labeling of proteins, C1 INH was detected in supernatants of cells from HANE patients at levels 20% of those detected in normals. The intracellular reduction of C1 INH in patients' monocytes approached 50%. The study of C1 INH messenger RNA (mRNA) by Northern blot analysis indicated that in HANE patients' monocytes a message of normal size is present at about half the concentration of that from normal cells. One of the patients analyzed showed the presence of a genetically inherited abnormal mRNA (1.9 kb) in addition to the normal mRNA (2.1 kb). Southern blot analysis of DNA from peripheral blood leukocytes did not show any difference in quantity or in sizes of endonuclease restriction fragments between patients and normals. The defect(s), therefore, in type I HANE is pretranslational, but is not due to a deletion or to a major chromosomal rearrangement.

Angioedema↗
PubMed1987

Restriction fragment length polymorphism of the C1 inhibitor gene in hereditary angioneurotic edema.

Hereditary angioneurotic edema (HANE) results from the deficiency of the inhibitor of the first component of human complement (C1-INH). It is inherited as an autosomal dominant trait. Heterogeneity of this defect has been shown at the protein and mRNA level. Southern blot analysis of genomic DNA was performed after digestion with six different restriction endonucleases in 24 families affected with type 1 HANE (low antigenic and functional C1-INH levels) and five with type 2 (low functional C1-INH levels and normal or elevated levels of dysmorphic C1-INH). Blots were hybridized with a C1-INH cDNA probe of 1,227 bp. With one enzyme (Pst I), two different patterns of restriction fragment length polymorphism (RFLP) were detected. One was present in one kindred with type 1 HANE and the other appeared the same in one type 1 and in one type 2 family, thus indicating that each RFLP resulted from a different mutation. Analysis of a total of 34 members of these three families suggested that the polymorphisms are tightly linked to the mutation responsible for the disease. Using a 170-bp probe we showed that the three different mutations leading to these polymorphisms are located in the same region of the C1-INH gene. These data suggest that different mutations in the same region of the C1-INH gene are responsible for C1-INH deficiency in these families. Most of these mutations are probably point mutations or other "minor" defects and do not appear to be due to major deletions or rearrangements.

Angioedema↗
PubMed1986

In vivo study of the complement system during infusion of radiographic contrast media.

It has been claimed that activation of the complement system may play a role in reaction to radiographic contrast media (RCM) infusion. In order to clarify the effects of RCM on the complement system, three different parameters (CH50, C3a, and C1 inhibitor) were measured in 20 patients undergoing intravenous pyelography for diagnostic purposes. We found no significant changes in C3a levels, but CH50 and C1 inhibitor fell significantly at the different sampling times; however, the decreases lost significance when the data were corrected for hemodilution with the total protein content of each sample as a reference. We conclude that RCM infusion does not activate the complement system.

Complement Activation↗
PubMed1986

The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency.

The metabolism of 125I-labeled C1 inhibitor (C1INH) and C1q was studied in five patients with B cell lymphoproliferative disorders, C1INH deficiency, and angioedema. C1INH catabolism was markedly accelerated in these patients. The fractional catabolic rate (FCR) was 0.053 of the plasma pool per hour compared to that of normal subjects (0.025) or patients with hereditary angioneurotic edema (HANE) (0.035). The catabolism of two dysfunctional proteins Wel and Ta was studied. Protein Wel was catabolized at an accelerated rate (0.041) compared to that in patients with HANE (0.029) or in normal subjects (0.020). In contrast, the FCR of protein Ta was 0.012, which is similar to that in normal patients and in patients with HANE. The extravascular to plasma ratio (E/P) of the normal C1INH in patients was 1.55 compared to 0.60 in normal patients. This is consistent with the rapid extravascular sequestration of the C1INH. The synthesis rate of the C1INH was 0.29 mg/kg/hr in patients that is similar to that in control subjects. The metabolism of C1q was studied in two normal control subjects and three patients. The FCR of C1q was 0.051 in patients compared to 0.023 in control subjects. The E/P was increased in patients (2.8) compared to E/P in control subjects (0.6). The acquisition of C1INH deficiency results from increased consumption of C1INH in vivo.

Adult↗
PubMed1986

Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11.

C1 inhibitor is a heavily glycosylated plasma protein that regulates the activity of the first component of complement (C1) by inactivation of the serine protease subcomponents, C1r and C1s. C1 inhibitor cDNA clones have been isolated, and one of these (pC1INH1, 950 base pairs) has been partially sequenced. Sequence analysis demonstrates that the C1 inhibitor is a member of the serpin "superfamily" of protease inhibitors. In the region sequenced, C1 inhibitor has 22% identity with antithrombin III, 26% with alpha 1-antitrypsin and alpha 1-antichymotrypsin, and 18% with human angiotensinogen. C1 inhibitor has a larger amino-terminal extension than do the other plasma protease inhibitors. In addition, inspection of residues that are invariant among the other protease inhibitors shows that C1 inhibitor differs at 14 of 41 of these positions. Thus, it appears that C1 inhibitor diverged from the group relatively early in evolution, although probably after the divergence of angiotensinogen. Southern blot analysis of BamHI-digested DNA from normal individuals and from rodent-human somatic cell hybrid cell lines (that contain a limited but varied human chromosome complement) was used to localize the human C1 inhibitor gene to chromosome 11.

Amino Acid Sequence↗
PubMed1986

Immunoreactive precipitation of C1 inhibitor protein from plasma of normal subjects and of patients with hereditary angioedema after isoelectric focusing.

C1-inhibitor is an acid glycoprotein, isoelectric point 3.5-3.6. Plasma of some patients with a variant form of hereditary angioedema contains high levels of functionless C1-inhibitor-albumin complex with an isoelectric point at 4.5-4.6. Therapy with Danazol, which increases C1-inhibitor levels, does not modify the isoelectric focusing pattern of such protein in patients with hereditary angioedema.

Adult↗
PubMed1985

Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins.

The syndrome of acquired angioedema and C1-inhibitor deficiency is associated with B-cell lymphoproliferative disease. It is characterized by accelerated consumption of C1q and C1 inhibitor in vivo and by low levels of serum C2 and C4. Four patients with B-cell malignant diseases (IgA myeloma, macroglobulinemia, chronic lymphocytic leukemia, and B-cell lymphoma, respectively) and acquired C1-inhibitor deficiency were found to have circulating antiidiotypic antibodies to the monoclonal immunoglobulin expressed on the surface of their B cells (three patients) or in the cytoplasm of their bone-marrow cells (one patient). Two of the four patients had circulating M components, and their antiidiotypic antibodies reacted with the M components. In three patients studied the percentage of B cells bearing C1q was 18, 24, and 35 per cent, as compared with 2.3 +/- 1.7 per cent (mean +/- S.D.) in six normal controls. These results suggest that an interaction between the idiotype of monoclonal immunoglobulins and antiidiotypic antibodies causes increased consumption of C1q and C1 inhibitor in patients with acquired angioedema and C1-inhibitor deficiency. We propose that the subsequent activation of the early components of complement leads to increased vascular permeability and to angioedema and that these patients have a disease caused by antiidiotypic antibodies.

Aged↗
PubMed1985

Acquired C1 inhibitor deficiency with angioedema symptoms in a patient infected with Echinococcus granulosus.

A patient with echinococcosis, acquired deficiency of the inhibitor of the activated first component of complement and angioedema symptoms has been studied. These symptoms started 7 months after the surgical removal of an echinococcus liver cyst. Eight years later, when the complement was investigated, a marked deficiency of the C1 inhibitor, C1, C4 and CH50 was present. The patient was therefore successfully treated with tranexamic acid. After 4 years, the woman needed another operation because of a relapse of echinococcosis; afterwards she was symptom-free without medications, while the complement profile remained unchanged. Circulating immune complexes were detected by the conglutinin method. The patient's serum was demonstrated to possess an anticomplementary activity without affecting the C1 inhibitor when incubated with normal human serum at 37 degrees C. At present, 16 years after the onset of the symptoms, there are no signs of lymphoproliferative disease.

Angioedema↗
PubMed1985

Studies of complement activation in ARDS patients treated by long-term extracorporeal CO2 removal.

To investigate the role of complement activation in the adult respiratory distress syndrome (ARDS) and in the complications of extracorporeal circulation (ECC), several parameters (CH50, C3 split products, C3a, C5a, PMN aggregating activity, carboxypeptidase activity) of the complement profiles of 23 ARDS patients were measured. Twenty patients were treated by long-term extracorporeal support. Before connection to ECC, marked leukocytosis (18,250 +/- 5,950) and significantly high plasma C3a levels (p less than 0.005) were observed. After connection, C3a levels increased further, up to values eight times higher than the basal ones. The WBC count transiently decreased to 41% of prebypass levels after 15 minutes of ECC. At the same time C3 split products appeared and PMN aggregating activity was shown in 52% of the patients. C5a levels remained normal during bypass, even in two samples in which PMN aggregating activity was detected. Later decreases in CH50 titers (p less than 0.001) and carboxypeptidase activity (p less than 0.005) were observed. Complement activation was no longer evident after the 24th hour of bypass. We conclude that there is a low-degree complement activation in ARDS, and ECC is a further strong stimulus for complement activation. This phenomenon appears, however, to be self-limited.

Adolescent↗
PubMed1983

Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives.

17 alpha-Alkylated androgens are highly effective in preventing attacks in HAE patients. These drugs, however, seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumors. In order to assess the risk-benefit balance of the long-term therapy with androgen derivatives, a follow-up investigation was performed in 13 HAE patients. The results of this study indicate that long-term treatment (15 to 47 mo) with low doses of danazol or stanozolol does not induce significant hepatic damage detectable by laboratory tests or liver biopsy. However, the limited number of patients, although in a rather long period of observation, still suggests a careful control and the use of minimal effective doses.

Adult↗
PubMed1983

Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema.

The metabolism of normal C1 inhibitor and two dysfunctional C1 inhibitors (Ta and WeI) was studied in 10 normal subjects and 8 patients with hereditary angioneurotic edema (HANE), 4 with low antigen concentration (type 1) and 4 with dysfunctional protein (type 2). The fractional catabolic rate of the normal C1 inhibitor in normal subjects was 0.025 of the plasma pool/hour, whereas in HANE subjects it was significantly elevated at 0.035 of the plasma pool/hour. The synthesis of normal C1 inhibitor was decreased in patients with type 1 HANE (0.087 mg/ kg per h compared with 0.218 mg/kg per h). The fractional catabolic rate of dysfunctional protein WeI was similar to normal and showed a slightly accelerated catabolism in patients with HANE, whereas the dysfunctional protein Ta had a strikingly decreased fractional catabolic rate in normals and subjects with HANE. The present study is compatible with reduced C1 inhibitor synthesis in patients with type 1 HANE consistent with a single functional C1 inhibitor gene. The lower than anticipated levels of C1 inhibitor in HANE type 1 appears to result from (a) the single functional gene and (b) increased catabolism of the protein, perhaps related to activation of C1 or other proteases.

Adolescent↗
PubMed1982

Effect of treatment with 17 alpha-alkylated androgens on C4 conversion products in hereditary angioedema studied by crossed immunoelectrophoresis.

During agarose electrophoresis C4 in the normal human serum is converted into cleavage products of Beta 1 and Beta 2 mobility. By contrast in the serum of untreated patients with hereditary angiodema C4 gives only one Beta 2 peak on crossed immunoelectrophoresis. The normal C4 electrophoretic pattern is restored in serum of patients treated with stanazolol but not with danazol despite the same C1-esterase inhibitor (C1 INH) activities and C4 serum concentration. We suggest that stanazolol besides having specific effect on C1 INH activity can interfere with other protease inhibitors affecting C1 activation.

Adult↗
PubMed1982

[Pathological effects of recently isolated complement derived peptides].

The C3a and C5a polypeptides release, under conditions of complement activation, causes a change in PMN shape and adhesiveness with formation of leukoemboli in microvascular districts. Those modified granulocytes produce oxygen radicals with toxic activity. This mechanism seems to play a role in different pathological situations like pulmonary distress in hemodialysis, leukapheresis, cardiopulmonary by-pass and extent of necrosis in acute myocardial infarction. The same mechanism has been largely investigated in Adult Respiratory Distress Syndrome (A.R.D.S.). In this condition the leukoembolization toxicity seems to be the most important pathogenetic factor of the alveolo-capillary membrane damage which is the base of the disease.

Animals↗