Immunoregulatory role of maternal idiotypes. Ontogeny of immune networks.

Specific idiotypie can be induced in randomly chosen rabbits by preimmunization with anti-idiotypic antibodies (Ab2). Rabbits that synthesize anti-anti-idiotypic antibodies (Ab3) when injected with antigen produce antibodies that display idiotypic specificities that are also found on the starting idiotype. When female rabbits actively producing Ab3 are crossed with naive males, a significant proportion of the offsprings (approximately 40%) produce antibodies that were idiotypically cross-reactive with the starting idiotype, as compared to 3% of the controls. This conclusion was obtained using 5 female rabbits and their 32 surviving offspring. Maternal idiotypes have therefore strong immunoregulatory properties and influence the emergence of the available idiotypic repertoire.

Evolution of immunoglobulins: structural homology of kappa and lambda Bence Jones proteins.

The amino acid sequence of a human lamba chain has been determined. There are many identities in sequence with human kappa chains, but this intraspecies homology is less than the interspecies homology of kappa light chains of man and mouse. Structural relationships suggest a common evolutionary origin and early differentiation of light- and heavy-chain genes.

Immunoglobulin structure: variation in amino acid sequence and length of human lambda light chains.

Variation and conservation in the primary structure of human lambda light chains is revealed by complete amino acid sequence of three Bence Jones proteins. These proteins differ in amino acid sequence in from 38 to 48 positions; they are of unequal length in the amino-terminal half of the chain but have identical sequence in the last 105 amino acids.

Macroglobulin structure: homology of mu and gamma heavy chains of human immunoglobulins.

The amino acid sequence of fragments obtained by cyanogen bromide cleavage of the mu-chain of a human gammaM-globulin is homologous to the NH(2)-terminal sequences of the gamma-chain of human and rabbit gammaG-globulins and is related to that of human light chains. This supports the hypothesis that light and heavy chains evolved from a common ancestral gene.

Idiotypic manipulations: hierarchy in idiotype expression in rabbits immunized against Micrococcus luteus.

Idiotypic cross-reactions were analyzed among three series of anti-peptidoglycan antibodies of the Micrococcus luteus system. The reference idiotype Ab1 was an antibody fraction isolated from an isoelectric focusing preparative column. Cross-reactive idiotypes, Ab1', were induced through the immunization chain (Ab1-Ab2-Ab3). Idiotypic antibodies of Ab1-F1 type were obtained from offspring of female rabbits, actively producing Ab3 during pregnancy. Finally, Ab1 CRI were cross-reactive idiotypes with Ab1 found in a random population of rabbits immunized with M. luteus. Three idiotopes could be characterized within Ab1 antibody. Ab1' usually expressed two of these idiotopes, but never the third specificity which is "private" to Ab1. Ab1-F1 shared one or two idiotopes with Ab1 and Ab1' antibodies. Only one common idiotope appeared to be present on Ab1 CRI. Finally, this idiotope, IdX, could be detected by radioimmunoassay in 20% of rabbits immunized with micrococcal vaccine. It appears that a recurrent idiotype of anti-peptidoglycan antibodies can be preferentially amplified through idiotypic manipulations. On the other side, cascade immunizations lead to the expression on Ab1' and on some Ab1-F1 of a second idiotypic specificity, shared with Ab1. This hierarchy of idiotype expression may well be important in the regulation of antibody synthesis through idiotypes.

Interchangeability of ceftizoxime and cefoxitin: a clinical perspective.

Ceftizoxime and cefoxitin, two parenteral broad-spectrum cephalosporin antibiotics, were compared in a prospective, randomized, double-blind study to determine if they are clinically equivalent in the treatment of infections of the urinary or respiratory tracts, the intra-abdominal cavity, or skin and skin structure. Since the pharmacokinetic properties of ceftizoxime permit less frequent dosing than cefoxitin and, in consequence, lower daily doses, a second objective was to compare the cost of intravenous use of these antibiotics in hospital practice. Patients were assigned at random to treatment with either 4 to 8 gm/day of cefoxitin or 2 to 4 gm/day of ceftizoxime. Within each treatment group, they were stratified according to the site of the infection. Cure rates were similar with ceftizoxime (96% of 134 patients) and cefoxitin (92% of 132 patients). There were no statistically significant differences with respect to site or severity of infection. An analysis of the cost of the drugs and the labor to administer them showed ceftizoxime to be less expensive ($263 to $389/day) than cefoxitin ($394 to $638/day).

Efficacy of ceftizoxime administered twice daily in hospitalized patients with respiratory tract infections.

The efficacy and safety of ceftizoxime administered twice daily were evaluated in 215 hospitalized patients with documented lower respiratory tract infections. The majority of patients received 1 to 2 gm of ceftizoxime intramuscularly or intravenously every 12 hours; the mean dosage was 2 gm/day, and the mean duration of therapy was 8.9 days. Clinical cure was achieved in 204 (95%) of the 215 patients with lower respiratory tract infection. One hundred and thirty-eight patients were both clinically and bacteriologically evaluable. The clinical response rates, by organism, were: Streptococcus pneumoniae, 100% (50/50); Haemophilus influenzae, 96% (25/26); gram-negative bacilli (Escherichia coli, Proteus mirabilis, Enterobacter sp, Serratia sp, Pseudomonas sp, Klebsiella sp, Citrobacter sp, and Morganella morganii), 86% (32/37); and Staphylococcus aureus, 92% (12/13). In the other 77 patients with clinical symptoms, no pathogen was isolated or insufficient follow-up data were collected to assess bacteriologic response. Adverse reactions, which were infrequent, were similar to those reported in other US trials of the drug. The findings indicate that ceftizoxime, 1 to 2 gm BID, is effective and safe in the treatment of lower respiratory tract infections in hospitalized patients. This low-dose regimen can significantly reduce the cost of cephalosporin therapy.

Clinical efficacy of cefonicid in the treatment of staphylococcal infections.

Cefonicid is a parenteral cephalosporin with a half-life of 4.5 hours, which permits once-daily dosing. The efficacy of cefonicid in the treatment of established staphylococcal infections was reviewed in all patients with infections due to staphylococci who were treated with cefonicid during the US clinical development program. Two hundred evaluable cases were identified, of which 95 had other pathogens as well. Cefonicid was clinically effective in 92% of skin and soft tissue infections, 74% of bone and joint infections, 83% of respiratory tract infections, and 95% of urinary tract infections. None of the three evaluable patients with Staphylococcus aureus endocarditis responded to cefonicid. Thus, based on current evidence, cefonicid is not effective in the treatment of established staphylococcal endocarditis. However, for the treatment of staphylococcal infections at other sites, cefonicid is comparable to other cephalosporins, most of which must be administered more frequently than cefonicid and thus are less cost-effective.

Five cephalosporins: pharmacokinetics and their relation to antibacterial potency.

In a group of adult volunteers, pharmacokinetic profiles of five cephalosporins were correlated with their minimal inhibitory concentrations (MICs90) against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter aerogenes. Subjects received the following intravenous regimens in a randomized, crossover fashion: (1) 0.5 gm, 1 gm, or 2 gm of cefazolin; (2) 2 gm of cephalothin; (3) 1 gm of cephapirin; (4) 1 gm of cefoxitin; or (5) 0.5 gm of cefamandole. The 500-mg dose of cefazolin produced serum concentrations that exceeded those of any of the other cephalosporins at 0.5, 1, 2, 4, and 6 hours after administration. The area under the curve for this dose of cefazolin was at least twice that of any of the other antibiotics. Two hours after a 500-mg dose of cefazolin, serum levels exceeded the MIC90 for all seven groups of pathogens; at six hours, the 500-mg dose of cefazolin continued to achieve serum levels above the MIC90 against the majority of bacterial groups. In contrast, at two hours after administration none of the other cephalosporins maintained serum levels above the MIC90 for all pathogens; at six hours, the levels of cephapirin were adequate to inhibit the two streptococci, but serum levels of all other cephalosporins were inadequate to inhibit any of the pathogens. These data indicate that a 500-mg dose of cefazolin maintains serum levels above the MICs90 longer than any of the other cephalosporins tested and support the use of a 500-mg dose of cefazolin every eight hours for surgical prophylaxis and treatment of most community-acquired infections. Such a comparatively low dosage offers substantial savings to both patient and hospital.

The religion of the therapist: its meaning to Orthodox Jewish clients.

How do Orthodox Jewish clients feel about the religious identity of their therapists? Do they have any preferences; and if so, why? The research reported here was designed to answer these questions. Semi-structured in-person interviews were conducted with a sample of Orthodox Jewish clients of out-patient mental health clinics and private practitioners. The findings of this study revealed a wide range of diverse meanings attached to the therapist's religious identity by Orthodox Jewish clients. The implications of the findings for clinical practice with Orthodox Jewish clients as well as other religious minority group clients are discussed. The overall findings suggest that religious differences in the therapeutic relationship can and do play a critical role in the treatment process.

Isolation and characterization of homogenous rabbit antibodies to Micrococcus lysodeikticus with specificity to the peptidoglycan and to the glucose-N-acetylaminomannuronic acid polymer.

The antibody response of rabbits to Micrococcus lysodeikticus is characterized by the production of a high concentration of antibodies which manifest markedly reduced heterogenicity. The specificity of these antibodies was studied and it revealed that M. lysodeikticus contains 2 major antigens: both the glucose-N-acetyl-aminomannuronic acid polymer obtained by formamide extraction of the cell walls and peptidoglycan solubilized by ultrasonic treatment gave precipitin reactions with hyperimmune antisera. By means of inhibition studies of the glucose-mannose polymer specificity, glucose appeared as the immunodominant sugar in the majority of antibodies studied. Inhibitions studies also confirmed that both the glycan and peptide moieties constitute antigenic determinants of M. lysodeikticus peptidoglycan. Antibodies to the glucose-mannose-polymer and the peptidoglycan were specifically fractionated by use of immunoadsorbents formed from lysozyme solubilized cell walls and activated Sepharose. Both antibody specificities showed a limited heterogeneity by isoelectric focusing. Finally, because antisera to M. lysodeikticus are a rich source of antibodies to peptidoglycan, emphasis is placed on the possible usefulness of this system for studies of clonal dominance.

Idiotypic regulation of the immune system by the induction of antibodies against anti-idiotypic antibodies.

Anticarbohydrate antibodies (Ab1) were isolated from a rabbit hyperimmunized with Micrococcus lysodeikticus and injected into allotype-matched rabbits in order to obtain specific anti-iodiotypic antibodies (Ab2). Ab2 was isolated by means of a Sepharose column coupled to the anticarbohydrate antibodies and was injected into two allotype-matched rabbits. These latter rabbits produced specific anti-anti-idiotypic antibodies (Ab3) probably sharing idiotypic specificities with Ab1. However, these Ab3 did not react with the antigenic carbohydrate moiety of bacteria. The two rabbits that had produced Ab3 were then immunized with M. lysodeikticus and synthesized anticarbohydrate antibodies (Ab1') bearing idiotypic specificities similar to those of Ab1. The immune repertoire which is effectively expressed in one individual depends not only on the antigenic stimulation but also on the previous idiotypic history of the individual. These data support the concept that the immune system is a functional idiotypic network.

Idiotypic lymphocytes in the rabbit: occurrence and nature of idiotypic lymphocytes in normal and hyperimmunized rabbits.

Rabbits were hyperimmunized with Micrococcus Pysodeicticus, leading to homogeneous antibody responses. Peripheral blood lymphocytes were taken from the rabbits before and monthly (during 3 months) after the start of the immunization. The cells were stored frozen. Lymphocytes were tested with anti-idiotypic conjugates for the presence of surface idiotypic structures. The nature of the idiotype-positive cells was determined with respect to the presence of IgM or T-cell antigenic determinants on their surface. A sharp rise and fall in the percentage of idiotypic lymphocytes was found, ranging between 1/40,000 and 1/1,000. Initially almost all idiotypic lymphocytes were IgM-positive. In the blood taken 2 months after the start of the immunization 20% of the idiotypic cells belonged to the T-cell population and 10% were negative for both IgM and T-cell antigenic determinants.

Coagulopathy associated with extended-spectrum cephalosporins in patients with serious infections.

Patients enrolled in two double-blind multicenter studies were evaluated for the development of hypoprothrombinemia during treatment with cephalosporins. Patients with pneumonia or peritonitis received ceftizoxime, cefotaxime, or moxalactam. The incidence of hypoprothrombinemia was greater in patients with peritonitis (12 of 49) than in those with pneumonia (5 of 96; P less than 0.05). Overall, moxalactam was associated with a higher incidence of hypoprothrombinemia (13 of 52) than either ceftizoxime (1 of 43; P less than 0.05) or cefotaxime (3 of 50; P less than 0.05), and moxalactam patients incurred the highest average increase in prothrombin time (3.7 s) as compared with either ceftizoxime (0.5 s; P less than 0.05) or cefotaxime (0.9 s; P less than 0.05) patients. The occurrence of hypoprothrombinemia in moxalactam patients with peritonitis was not related to dosage, duration of therapy, age, sex, race, or renal or hepatic function. The degree of ileus was, however, strongly related to the development of coagulopathy in moxalactam-treated patients only.