Infant immune response to human rotavirus serotype G1 vaccine candidate reassortant WI79-9: different dose response patterns to virus surface proteins VP7 and VP4

BACKGROUND: Rotavirus is the leading cause of morbidity from gastroenteritis in the developed world and the leading cause of mortality from viral gastroenteritis (estimated 600000 deaths) worldwide. G1 is the most prevalent human serotype. Reassortant rotavirus between simian rotavirus RRV or bovine rotavirus WC3 and human strain rotaviruses have been extensively tested as candidate vaccines. Rotavirus (RV) reassortant strain WI79-9 consists of a human (strain WI79) G1 serotype VP7 surface protein on a bovine (strain WC3) background. It is a key component of a pentavalent (G1, G2, G3, G4 and P1) WC3 reassortant vaccine candidate, RotaTeq, now being tested in Phase III clinical trials. METHODS: We studied 84 infants between the ages of 2 and 8 months who received 3 oral doses of WI79-9. Serum neutralizing antibody was measured to the human (WI79 serotype P1 G1) and bovine (WC3 serotype P7 G6) parent RV after each dose. A significant response was defined as a > or =3-fold rise in antibody titer between the predose and postdose sera. RESULTS: In two separate cohorts of vaccinees given three doses of WI79-9 reassortant rotavirus, 68 to 75% of infants demonstrated a significant response to WC3 (VP4, P7) after Dose 1, fewer (24 to 39%) responses were detected after Dose 2 and rare (0 to 4%) additional responses occurred after Dose 3. The cumulative response rate to WC3 after three doses was 95% in both trials. In contrast 23 to 37% had a significant response to WI79 (VP7, G1) after Dose 1, and 57 to 61% had a significant response after Dose 2. Additional significant responses after Dose 3 led to a cumulative response of 70 to 84%. CONCLUSION: Two doses of G1 reassortant WI79 were necessary to induce significant antibody responses to human G1 (VP7) antigen in >50% of infants. Three doses were required to achieve significant antibody responses to VP7 in >70% of infants.     

Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers

BACKGROUND AND METHOD: As genetic alterations in the gene for the peroxisome proliferator-activated receptor gamma (PPARgamma) have been described and PPAR agonists have been shown to redifferentiate thyroid cancers in animal models, we performed a pilot study in five patients with thyroglobulin-positive and I scan-negative thyroid cancers using the PPARgamma agonist rosiglitazone. RESULTS: Although thyroglobulin levels increased in four of the five patients after 3 months of treatment with rosiglitazone, the I scan remained negative in four patients and became only faintly positive in one patient for two lung metastases that could be correlated with metabolically active lung metastases shown by F-fluorodeoxyglucose positron emission tomography (F-FDG PET) and by computed tomography (CT). F-FDG PET, performed in four patients, revealed metastases of significant size in two patients, including the patient mentioned above and in a second patient confirmed by surgery. CONCLUSIONS: Treatment with rosiglitazone increased the production of thyroglobulin in some patients with thyroid cancers, but only rarely restored scintigraphically significant iodine trapping. It remains to be shown whether longer treatment periods might result in a more efficient redifferentiating effect.     

Sociability trait and serotonin metabolism in the rat social interaction test

Social behaviour is the basis of one of the most generally accepted independent dimensions of personality. The purpose of the present study was to find out whether the social activity of individual rats, expressed in the social interaction test of anxiety, is consistent, and associated with monoamine levels. Four social interaction tests with 10 days intervals were carried out in 20 rats, and the animals were decapitated 4 days after the last test. There was no consistent correlation between performances in single tests, but the social interaction time in each test correlated strongly with the mean values of social activity in all or the other three tests. Social interaction time of rats correlated moderately but significantly with their partner's social activity in the test. The average social interaction time correlated strongly with 5-HIAA levels in the frontal cortex (r = -0.67, P < 0.01). Neither exposure of rats singly to the social interaction test box nor the test procedure had any effect on monoamine levels. When animals were decapitated immediately after a single social interaction test, there was a negative correlation between the social interaction time and 5-HIAA and 5-HT levels in the septum, but not in the frontal cortex or hippocampus. Thus, social behaviour is a stable trait, expression of which depends in part upon the partner's social behaviour. This trait is negatively associated with 5-HT metabolism in the frontal cortex. Social activity of rats in a particular test situation may rather be related to 5-HT metabolism in the septum.     

Effect of hyperglycaemia on glucose concentration of human nasal secretions

Glucose is not detectable in airways secretions of normoglycaemic volunteers, but is present at 1-9 mmol x l(-1) in airways secretions from people with hyperglycaemia. These observations suggest the existence of a blood glucose threshold at which glucose appears in airways secretions, similar to that seen in renal and salivary epithelia. In the present study we determined the blood glucose threshold at which glucose appears in nasal secretions. Blood glucose concentrations were raised in healthy human volunteers by 20% dextrose intravenous infusion or 75 g oral glucose load. Nasal glucose concentrations were measured using modified glucose oxidase sticks as blood glucose concentrations were raised. Glucose appeared rapidly in nasal secretions once blood glucose was clamped at approx. 12 mmol x l(-1) ( n =6). On removal of the clamp, nasal glucose fell to baseline levels in parallel with blood glucose concentrations. An airway glucose threshold of 6.7-9.7 mmol x l(-1) was identified ( n =12). In six subjects with normal glucose tolerance, blood glucose concentrations rose above the airways threshold and nasal glucose became detectable following an oral glucose load. The presence of an airway glucose threshold suggests that active glucose transport by airway epithelial cells normally maintains low glucose concentrations in airways secretions. Blood glucose exceeds the airway threshold after a glucose load even in people with normal glucose tolerance, so it is likely that people with diabetes or hyperglycaemia spend a significant proportion of each day with glucose in their airways secretions.     

Endothelin-A receptor blockade in porcine pulmonary hypertension

Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET(A)) receptor activation. We hypothesized that ET(A) blockers (EMD 122946 and BQ 610) would reduce hypoxia-induced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n = 12) or heat-killed GBS (n = 11). ET(A) blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET(A) blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (>100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (<25%) changes in SAP or SVRI. Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO(2) did not change with GBS but decreased with BQ 610. ET(A) receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET(A) blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infection-associated), and the specific ET(A) antagonist used.     

The effectiveness of risk-based intrapartum chemoprophylaxis for the prevention of early-onset neonatal group B streptococcal disease

OBJECTIVE: Our purpose was to evaluate the effectiveness of a risk-based intrapartum antibiotic prophylaxis strategy for the prevention of early-onset neonatal group B streptococcal disease. STUDY DESIGN: Cases and controls were selected from infants born to women with one or more risk factors: preterm labor or rupture of membranes, prolonged rupture of membranes (>18 hours), fever during labor, or previous child with group B streptococcal disease. Cases were matched with controls by birth hospital and gestational age. Data abstracted from medical records were analyzed to estimate the effectiveness of intrapartum antibiotic prophylaxis. RESULTS: We analyzed data from 109 cases and 207 controls. Nineteen (17%) case versus 69 (33%) control mothers received an acceptable regimen of intrapartum antibiotic prophylaxis. In adjusted analyses, the effectiveness of intrapartum antibiotic prophylaxis was 86% (95% confidence interval, 66%-94%). When the first dose of antibiotics was given > or =2 hours before delivery, the effectiveness increased to 89% (95% confidence interval, 70%-96%); when it was given within 2 hours of delivery, the effectiveness was 71% (95% confidence interval, -8%-92%). Effectiveness was lowest in mothers with intrapartum fever (72%, 95% confidence interval, -9%-93%). On the basis of a 70% prevalence of maternal risk factors expected among cases in the absence of intrapartum antibiotic prophylaxis, we estimate that the risk-based strategy could reduce early-onset group B streptococcal disease by 60%. CONCLUSIONS: The risk-based approach to intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease. To achieve the maximum preventive effect, the first dose of antibiotics should be administered at least 2 hours before delivery.