Immunogenicity of Haemophilus influenzae type b capsular polysaccharide vaccines in 18-month-old infants

Haemophilus influenzae vaccine containing polyribosyl ribitol phosphate (PRP) or PRP covalently linked to diphtheria toxoid (PRP-D) was given to 94 healthy infants 17 to 22 months of age at the same time, but not at the same site, as a diphtheria-tetanus-pertussis booster. Systemic reactions were similar in the two vaccine groups and resembled those expected with the diphtheria-tetanus-pertussis injection alone. Six (13%) and seven (14%) of the PRP and PRP-D recipients, respectively, had minor local reactions to the Haemophilus vaccine. Among the 77 children who were not already naturally immune (ie, anti-PRP antibody concentration of less than or equal to 0.15 micrograms of protein per milliliter) before vaccination, PRP-D was significantly more effective than PRP in inducing protective levels of antibody. Only 15 (43%) of the 35 nonimmune PRP recipients achieved a concentration of greater than or equal to 0.15 microgram/mL and only seven (20%) reached a concentration greater than or equal to 1.0 micrograms/mL following vaccination. In contrast, 34 (81%) of the 42 nonimmune recipients of PRP-D had a concentration of greater than or equal to 0.15 microgram/mL following vaccine and 32 (62%) had a concentration of greater than or equal to 1.0 micrograms/mL (P less than or equal to .001). These results suggest that more than one-half of nonimmune 18-month-old infants will not respond to PRP with protective levels of antibody. In light of the current data, recommendation for revaccination at 24 months of age for those immunized at any younger age is appropriate.     

Effects of nitric oxide synthase inhibition on blood flow and survival in experimental skin flaps.

The aim of the present study was to examine the effect of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) on skin and flap blood flow, NOS activity and flap survival in an ischaemic dorsal flap model in the rat. Fifty-four rats were used in the study. l-NAME or the inactive enantiomere d-NAME was given intravenously either pre-, per- and postoperatively or only postoperatively. Controls received saline treatment. Blood pressure and skin and flap blood flow were monitored. NOS activity was measured in intact skin before and after l-NAME and d-NAME infusion and in flap tissue 48h postoperatively. Forty-eight hours postoperatively flap survival was determined in all rats. l-NAME treatment caused: (1) a marked attenuation of constitutive Ca(2+) dependent NOS activity in intact skin (p<0.001), (2) an increase in blood pressure (p<0.05), (3) a decrease in blood flow in intact skin and in skin flaps (p<0.05), and (4) a decrease in flap survival (p<0.05). In saline and d-NAME treated animals no change in blood pressure, blood flow or NOS activity in intact skin was noted. In conclusion this study shows that l-NAME attenuates constitutive Ca(2+) dependent NOS activity in intact skin, decreases skin and flap blood flow and decreases the survival of skin flaps. These results indicate that constitutive nitric oxide synthase is important for basal blood flow in skin and flap tissue and for the survival of skin flaps.     

Pharmacokinetics of vancomycin in adult cystic fibrosis patients.

Although the depositions of many antibiotics are altered in cystic fibrosis patients, that of vancomycin has not been studied. To assess vancomycin pharmacokinetics, 10 adult cystic fibrosis patients were given a parenteral dose of vancomycin (15 mg/kg) during the first 72 h of hospitalization for acute bronchopulmonary exacerbation. Blood samples were obtained at 0, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 15, and 24 h. The mean (standard deviation) weight, measured creatinine clearance, and Taussig clinical score were 51 (13) kg, 130 (39) ml/min/1.73 m2, and 64 (13), respectively. Multicompartmental pharmacokinetic parameters were best described by a two-compartment model. The mean (standard deviation) volume of distribution, total body clearance, and terminal elimination rate constant were 0.58 (0.15) liter/kg, 91 (19) ml/min/1.73 m2, and 0.123 (0.05) h-1, respectively. These values were consistent with vancomycin pharmacokinetic parameters obtained in previous studies of healthy adult volunteers. Vancomycin dosages predicted by using a two-compartment Bayesian model were approximately 15 mg/kg every 8 to 12 h. There were poor correlations between clinical score or creatinine clearance and any pharmacokinetic parameter (r values of < 0.32). The coefficient of correlation between urine flow rate and total body clearance was 0.7 (P < 0.05). Adult cystic fibrosis patients exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus cystic fibrosis does not alter vancomycin pharmacokinetics.     

Endotoxin toxicity in rats with 6-sulfanilamidoindazole arthritis.

Seven oral administrations of 6-sulfanilamidoindazole (6-SAI) to 10- to 12-month-old rats sensitized the animals to endotoxin, with dosages as small as 2.5 microgram causing death in 80% of animals. Endotoxin in a dosage of 3,000 microgram was not lethal for nonmedicated control animals. 6-SAI-treated 1-month-old rats were not as sensitive to endotoxin as aged animals. The sulfonamide-induced sensitivity to endotoxin could not be passively transferred and could not be explained by blockade of the reticuloendothelial system or impairment of endotoxin detoxification. 6-SAI administration was associated with both depletion of liver glycogen and lowering of blood glucose concentration without changes in blood lactic acid concentration. Disseminated intravascular coagulation is believed to be involved in the pathogenesis of shock and death as evidenced by: (i) concomitant decreases in plasma fibrinogen concentration and elevations in fibrin degradation products after endotoxin challenge; (ii) protection against lethal actions of endotoxin by pretreatment with heparin. Treatment of 6-SAI-medicated rats with glucocorticoids before endotoxin challenge protected the animals against lethal doses of endotoxin and prevented deposition of fibrin thrombi in the glomerular capillaries.     

Molecular basis for serological cross-reactivity between enteroviruses.

The recognition sites for human antibodies which are cross-reactive between different types of enteroviruses were determined and characterized. Serum samples obtained from 58 patients with culture-confirmed enteroviral infections were analyzed in enzyme immunoassays against two sets of overlapping synthetic peptides covering residues 31 to 96 of poliovirus 1 VP1 (Mahoney strain) and residues 31 to 148 of coxsackievirus B1 VP1 (position based on alignment with poliovirus 1 VP1, Mahoney strain). A major antigenic region eliciting cross-reactive antibodies could be located to residues 37 to 51 of VP1. Furthermore, a single peptide covering residues 42 to 55 almost completely inhibited the binding of human antibodies to heat-inactivated enteroviruses, indicating that residues 42 to 55 of VP1 contain a major region eliciting cross-reactive antibodies. By using peptide analogs in which each residue within positions 42 to 55 of VP1 was sequentially substituted by Ala or Gly, we were able to determine the most essential residues for human antibody binding in 38 of the convalescent-phase patient serum samples. In a majority of the serum samples, the most essential residues for antibody binding were found to be Pro-42, Ala-43, Leu-44, Thr-45, Ala-46, Glu-48, Thr-49, and Gly-50. All of these residues are conserved, according to known enterovirus sequences, with the divergent echovirus 22 excepted. In conclusion, we could demonstrate that the essential residues for binding of cross-reactive antibodies are well conserved within the enterovirus family. These findings provide a molecular basis for the observed antibody cross-reactivity within the enterovirus group.