An animal model involving the subcutaneous implantation of tissue cages into guinea pigs and subsequent infection with Staphylococcus aureus was used to study factors pertinent to foreign body infection. Whereas 10 8 colony-forming units (cfu) of S. aureus strain Wood 46 did not produce any abscesses in the absence of foreign material, 10 2 cfu was sufficient to infect 95070 of the tissue cages despite the presence of polymorphonuclear leukocytes (PMNLs) in sterile tissue cage fluid. Opsonization of S. aureus by tissue cage fluid was adequate during the first hour of infection, but opsonic coating of the organisms decreased at 20 hr after the induction of infection. PMNLs from sterile tissue cage fluid showed decreased phagocytic and bactericidal activities when compared with PMNLs from either blood or peritoneal exudate obtained after short-or long-term stimulation (P < 0.001).The enhanced risk of bacterial infections in the vicinity of a foreign body -such as sutures and metallic or polymeric implants -has been repeatedly documented in cardiovascular [1][2][3], orthopedic [4][5][6], plastic reconstructive [7], and general [8] surgery. Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli are most frequently implicated as the etiologic agents [9]. Foreign body infection proceeds by two possible routes: early infection, due to local bacterial contamination during surgery [4], and late infection, after occasional seeding of microorganisms by the hematogenous route [6]. Both types of infections, once established, rarely heal, and excision of the foreign body remains the only effective treatment.
We studied the possible role of granulocyte neutral proteases as mediators of airway destruction in patients with cystic fibrosis (CF) who were infected with Pseudomonas aeruginosa. We measured the enzymatic activities of bronchial secretions on purified radioactively labeled complement component three (C3), elastin, and a granulocyte elastase-specific substrate. Bronchial secretions from 18 patients with CF who were infected with P aeruginosa had a significantly higher mean value for C3 cleaving, elastolytic, and granulocyte elastase-like activity than did two control groups. High enzymatic activities were observed in patients with CF who have advanced bronchial disease (that had been determined by a clinical scoring system). Kinetics of proteolysis of radioactively labeled C3 and inhibition profiles of the activities of the three enzymatic activities studied suggest that they are mainly derived from granulocytes. In addition, 20 of 31 strains of P aeruginosa isolated from patients with CF inactivated purified o l-antiprotease in vitro. We postulate that granulocyte neutral proteases and P aeruginosa may act synergistically in the airways of patients with CF and may contribute to the destruction of elastin and inactivation of C3.Cystic fibrosis is a fatal hereditary disease, in which the leading cause of death is respiratory failure [I]. Patients with cystic fibrosis (CF) usually have a long history of purulent bronchitis leading to progressive destruction of small bronchioles and followed by involvement of the large airways [2]. The pathogens most frequently associated with these respiratory-tract infections are Staphylococcus aureus and Pseudomonas aeruginosa [2,3]. Clinical and pathological observations suggest that progressive airway destruction is accelerated during infections with P aeruginosa [2]. However, little information is available regarding the mechanisms involved in progressive bronchiolar and bronchial damage and the persistence of P aeruginosa in bronchial secretions.Bronchial secretions from patients with CF con- [4,5]. These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11]. It is also well established that they are released extracellularly during phagocytosis [12]. Furthermore, P aeruginosa may secrete an elastase that destroys the two main inhibitors protecting the lung and its airways from the activity of PMN neutral proteases: al-antiprotease [13][14][15][16] and the bronchial mucosal proteinase inhibitor [17]. In addition, this bacterial elastase is also active on C3[18] and elastin [15].We therefore measured the enzymatic activities of bronchial secretions from patients with CF (who were infected with P aeruginosa) on purified human C3, bovine elastin, and a granulocyte elastase-specific substrate. Two groups of patients with bronchial secretions r...
Spontaneous inhibitors of factor VIII (FVIII) are pathogenic IgG autoantibodies of restricted isotypic heterogeneity found in the plasma ofpatients presenting with bleeding episodes and low levels of FVM. We now report the presence of a natural FVIII-neuralizing activity in 85 of500 plasma samples (17%) from healthy donors. FVIII-inhibitory activity was present in F(ab')2 fragments of purified IgG and was dosedependent. The titer of anti-FVIII antibodies in normal plasma ranged between 0.4 (threshold of detection) and 2.0 Bethesda units. Anti-FVIII IgG was also detected in normal plasma by using an ELISA. Anti-FVIH antibodies from healthy individuals did not exhibit restricted isotypic heterogeneity. Mean levels of FVIII activity did not differ significantly between individuals with and without detectable anti-FVIU antibodies in plasma. Natural anti-FVIII IgG inhibited FV1I activity in pools of normal plasma and in plasma of certain donors in the pool but did not inhibit FVII activity in autologous plasma. These observations demonstrate that polyclonal IgG antibodies against procoagulant FVHI are present in healthy individuals. The antibodies are natural IgG autoantibodies and/or antibodies directed against epitopes associated with a so far unidentified allotypic polymorphism of the human FVIII molecule.The presence of autoantibodies to factor VIII (FVIII) has so far exclusively been investigated in the plasma of patients with spontaneously occurring severe bleeding episodes in whom circulating autoantibodies are associated with low levels of FVIII. The inhibitors are IgG autoantibodies of restricted isotypic heterogeneity (1) that bind to selective sites on the FVIII molecule, resulting in inhibition of FVIII procoagulant activity (2-4).Natural IgM and IgG autoantibodies reacting with a wide array of serum proteins and hormones, and nuclear and cellular antigens are found in normal human serum (5). In the present study, we found that the plasma of 17% of 500 healthy blood donors contained FVIII-neutralizing activity. Anti-FVIII activity was present in F(ab')2 fragments from the IgG fraction of the plasma samples with inhibitor activity. FVIIIneutralizing activity of anti-FVIII IgG from a given donor differed with the individual source of FVIII used in the neutralization assay. Blood was collected in 0.13 M sodium citrate, 1:9 (vol/vol), and immediately centrifuged at 2500 x g for 15 min at room temperature. Plasma was divided and stored at -800C for no longer than 4 weeks.Pooled plasma and IgG from the 420 healthy donors lacking detectable anti-FVIII activity in plasma were used as negative controls.FVIII Assays. FVIII activity was measured in a one-stage assay by a manual activated partial thromboplastin reagent (APTT) method using human plasma depleted of FVIII (containing <1% FVIII and normal levels of factor V; coagulation time in APTT, >200 sec) (General Diagnostics, Morris Plains, NJ) as substrate and human brain partial thromboplastin and Kaolin (5 mg/ml) as activators. The clotting time of four ...
A growing body of literature documents that intravenous immunoglobulin prophylaxis and therapy is becoming applied to a steadily growing list of new indications. Some of these new indications have led to the use of intravenous immunoglobulin therapy in doctors offices, far from the hospital environment. Being stable products purified from blood or plasma donations, intravenous immunoglobulins must be considered as biological products in addition to their status as pharmaceutical products. This makes the study of adverse reactions reach beyond a mere drug safety surveillance programme into the realms of good manufacturing procedures guaranteeing not only intravenous tolerance but also sterility with regard to transfusion transmitted agents. The initially perceived adverse effects, stemming from complement activating aggregated immunoglobulin G, had the effect of slowing down widespread introduction of intravenous immunoglobulin therapy in the late 1970s. These adverse effects have now been eliminated with amendment of the appropriate manufacturing steps. However, new adverse effects, such as hyperviscosity, aseptic meningitis or renal insufficiency, have been observed which can be assigned to certain comnpounds of intravenous immunoglobulin, to administration regimens or to special patient characteristics. Adverse effects can be divided into 3 types: immediate adverse effects (those that occur during the infusion, e.g. anaphylactoid reactions); delayed adverse effects (those that occur hours to days after initiation of the infusion, e.g. renal, pulmonary, dermatological adverse effects, hyperviscosity, aseptic meningitis, arthritis, cerebral infarction, haemolysis and leucopenia) and; late adverse effects (e.g. transmission of infectious agents). We conclude from our analysis, that in general, intravenous immunoglobulin may be considered a well tolerated medical agent provided the indication for use is chosen carefully and use is monitored by a physician familiar with contraindications, risks, adverse effects and their appropriate management.
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