Immunization of Early Adolescent Females with Human Papillomavirus Type 16 and 18 L1 Virus-Like Particle Vaccine Containing AS04 Adjuvant

PurposeIn female individuals 15–25-years of age, the AS04-containing human papillomavirus (HPV)–16/18 vaccine is highly immunogenic and provides up to 100% protection against HPV-16/18 persistent infection and associated cervical lesions up to 4.5 years. Optimal cervical cancer prevention will require prophylactic vaccination against oncogenic HPV 16 and 18 before the onset of sexual activity in early adolescent girls. To establish the feasibility of vaccination in girls 10–14 years of age, we compared the immunogenicity and safety in early adolescent female individuals to those 15–25 years in whom vaccine efficacy has been demonstrated.MethodsWe enrolled 773 female participants aged 10–14 years and 15–25 years to receive the HPV-16/18 L1 VLP AS04 vaccine, which was administered at months 0, 1, and 6. Serum samples were collected at months 0 and 7; antibodies to HPV 16 and 18 VLPs were measured by enzyme-linked immunosorbent assay. Vaccine safety was assessed at 7 or 30 days after each dose; serious adverse events were recorded during the entire study period.ResultsBoth age groups achieved 100% seroconversion for HPV 16 and 18. Participants in the group aged 10–14 years were not only noninferior to those 15–25 years in terms of HPV 16 and 18 seroconversion rates but also had approximately twice as high geometric mean titers. The vaccine was generally safe and well tolerated.ConclusionsThese findings suggest that HPV vaccination during early adolescence is generally safe, well tolerated, and highly immunogenic. The observed higher antibody titers in the group 10–14 years of age are likely to result in longer antibody persistence. Overall, these data support the implementation of prophylactic HPV vaccination in this age group.     

A preliminary report--heparin counteracts indomethacin effect on ductus arteriosus in very low birthweight infants.

OBJECTIVE: We report a clinical observation showing that continuous exposure to heparin via a central venous catheter is associated with patent ductus arteriosus treatment failure with indomethacin in very low birthweight infants. STUDY SELECTION: A clinical observational case report in infants weighting <1501 g. DATA EXTRACTION: This study compares the rates of patent ductus arteriosus treatment failure during a) the index period from June 2, 2003, to August 22, 2003, when all very low birthweight infants with a peripherally inserted central venous catheter received continuous infusion of heparinized parenteral nutrition; b) the baseline period of 1 yr before the index period; and c) the postindex period of 1 yr after the index period. DATA SYNTHESIS: The rate of patent ductus arteriosus treatment failure with indomethacin increased significantly during the index period compared with the baseline (odds ratio, 7.0; 95% confidence interval, 1.41-34.7; p = .017) and postindex periods (odds ratio, 33.8; 95% confidence interval, 4.72-243; p = .0005). The result was confirmed in logistic multivariable regression analysis. CONCLUSION: This observation, based on a case series and their controls, serves as a basis for a new hypothesis suggesting that continuous exposure to heparin through heparinized central venous infusion significantly increases patent ductus arteriosus treatment failure with indomethacin. This hypothesis needs to be tested in a randomized controlled trial.     

Incremental cost‐effectiveness of double‐reading mammograms

Background. Double reading is a widely used criterion standard in breast cancer screening despite a lack of evidence of the costeffectiveness of the second reading. This study evaluates the incremental costeffectiveness of such a strategy.Design. Costeffectiveness analysis: Nationwide populationbased semiannual screening program for women aged 50–59 in Finland. Participation rate was 91%. All mammograms (95,423) performed during 1990–1995 in three screening centers of the Finnish Cancer Society were read by two radiologists with gradings recorded. The effectiveness of the double reading was the difference in cancers detected in the double compared to that of the single reading. Incremental costs of the double reading for the health care and nonhealth care and the time costs were estimated. The main outcome measure was the incremental cost per additional cancer found as a result of the doublereading strategy.Results. The total number of cancers detected with the double and single reading were 290 and 261, respectively. A significantly higher ratio of carcinoma in situ was the causative pathology in cancers detected only by the second reader. The cost per cancer detected with a single reading was US$ 18,340. The incremental cost of any additional cancer found was US$ 25,523, that is, a 39% higher cost per additional cancer found by double reading.Conclusions. The additional cost per cancer detected by double reading is not drastically higher than with single reading. However, the additional cost per life year saved may be much higher.     

Serotonergic activation after 2-week intrastriatal infusion of L-dopa and slow recovery of circling in rats with unilateral nigral lesions

A unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease was used to determine an effective dose to abolish circling behaviour of the continuous intrastriatal infusions of L-dopa via osmotic minipumps into the lesioned striatum. This 2-week L-dopa treatment evoked a dose-dependent decrease in the contralateral rotations induced by acute intraperitoneal L-dopa and carbidopa that was sustained at least for 10 weeks. The minimum effective dose of intrastriatal L-dopa was 3 microg/hr. Striatal [3H]-spiperone binding was significantly increased by the 6-OHDA lesion, reflecting a permanent, lesion-induced, up-regulation of dopamine D2 receptors. Furthermore, striatal dopamine and its metabolites as well as the level of tyrosine hydroxylase were significantly reduced by 6-OHDA. None of these parameters were restored by the 2-week L-dopa infusions but, unexpectedly, the rotational response did not become normalized after discontinuation of L-dopa infusions. Nigral 6-OHDA lesions suppressed ipsilateral striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations, and 5-HT uptake sites while tryptophan hydroxylase was not changed in the striatum. When studying the cause of the sustained circling behaviour, we found that intrastriatal L-dopa infusion dose-dependently elevated striatal tryptophan hydroxylase much above the levels of intact side and 5-HT uptake sites to the level of intact side, but the striatal 5-HT levels exhibited no significant recovery while 5-HIAA levels were partially restored. These data support the view that a long-term ipsilateral activation of the serotonergic innervation occurs after L-dopa infusions into the lesioned striata.     

A peptide inhibitor of vascular adhesion protein-1 (VAP-1) blocks leukocyte-endothelium interactions under shear stress

Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule mediating leukocyte interactions with blood vessels during leukocyte extravasation. Molecularly VAP-1 is a cell-surface-expressed ecto-enzyme belonging to the group of semicarbazide-sensitive amine oxidases (SSAO; EC 2.4.6.3), which deaminate primary amines. Here we asked whether peptides displaying a suitable free amine group could be a substrate or inhibitor of SSAO and thus regulate VAP-1-mediated leukocyte adhesion. On the basis of a molecular model of VAP-1, we designed synthetic peptides that fit to the substrate channel of VAP-1. One of these lysine-containing peptides effectively inhibits VAP-1-dependent lymphocyte rolling and firm adhesion to primary endothelial cells under physiologically relevant shear conditions. The same peptide inhibits the SSAO activity of endothelial and recombinant VAP-1 in a selective and long-lasting manner. We also show that all enzymatically active VAP-1 is displayed on the cell surface. Our results suggest that, in addition to soluble amines, specific cell-surface-bound molecules containing free NH(2) groups in a suitable position may modulate the enzymatic activity of SSAO. Moreover, the inhibitory peptide diminishes leukocyte interactions with endothelial cells under conditions of shear, and thus it may be useful to treat inflammatory conditions.     

Maternal Genetic Variants of IL4/IL13 Pathway Genes on IgE With "Western or Eastern Environments/Lifestyles"

Purpose

We investigated maternal genetic effects of four IL-4/IL-13 pathway genes as well as their interactions with the "Western or Eastern lifestyles/environments" on IgE in Karelian children.

Methods

This study included 609 children and their mothers. Total IgE levels in children and mothers were measured and 10 single nucleotide polymorphisms (SNPs) in IL-4, IL-4Ra, IL-13, and STAT6 were genotyped in mothers and their children.

Results

The maternal G allele of IL-13 130 (rs20541) was significantly (P=0.001) associated with decreased IgE in children in the Karelian population (Pooling Finnish and Russian children), as well as in Finnish (P=0.030) and Russian children (P=0.018). The IgE levels were significantly (P=0.001) higher in Russian children whose mothers were homozygous for the G allele of the IL-4Ra 50 (rs1805010) SNP than that in Russian children of mothers who were AG heterozygotes or AA homozygotes. After accounting for children''s genotypes, we observed interactive effects on children''s IgE for maternal IL-13 130 genotypes (P=0.014) and maternal IL-4Ra 50 genotypes (P=0.0003) with "Western or Eastern" lifestyles/environments. With the adjustment for multiple comparisons using a false discovery rate (FDR) of 0.05, the interactive effect of the maternal IL-4Ra50 SNP was significant.

Conclusion

Maternal genetic variants in IL-4/IL-13 pathway genes, such as IL-13 130 and IL-4Ra50, influenced IgE levels in school children that were independent of the children''s genetic effects. These effects differ in "Western or Eastern" environments.     

Wheezing due to rhinovirus infection in infancy: Bronchial hyperresponsiveness at school age

Background: Characteristics related to decreased lung function and increased bronchial responsiveness after early childhood wheezing requiring hospitalization are not fully established.
Methods: Seventy-nine children with wheezing requiring hospitalization at age <2 years were prospectively followed up and re-investigated at age 5.6–8.8 years when the measurements of baseline lung function and bronchial responsiveness to exercise were performed.
Results: At early school age, 23% of children had decreased lung function, and 13% had increased bronchial responsiveness to exercise. Predictors of decreased lung function were maternal history of smoking during pregnancy (odds ratio [OR], 12.8; 95% confidence interval [CI]: 1.2–139.6), parental history of asthma (OR, 4.3; 95%CI: 1.1–17.1), and female gender (OR, 4.0; 95%CI: 1.2–13.7). Increased bronchial responsiveness was associated with rhinovirus infection-induced wheezing in infancy (OR, 6.5; 95%CI: 1.2–36.3), and early cat or dog exposure leading to sensitization (OR, 26.6; 95%CI: 1.3–525.2). Inhaled anti-inflammatory therapy was common in children with rhinovirus infection-induced wheezing in infancy ( n  = 13/19; P  = 0.001 vs children with other/no confirmed virus infection etiology for wheezing in infancy, n  = 16/60), which may have improved lung function and attenuated bronchial responsiveness in them.
Conclusions: After early childhood wheezing requiring hospitalization, one-fourth of children will have decreased lung function and one-eighth of children will show increased bronchial responsiveness at school age. Gender, heredity of asthma, and antenatal exposure to tobacco smoke are predictors of decreased lung function, whereas rhinovirus infection etiology of wheeze and early animal exposure leading to sensitization are associated with increased bronchial responsiveness later in childhood.     

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.     

Doctor-managers as decision makers in hospitals and health centres

PURPOSE: This paper describes factors influencing doctor-managers' decision making in specialised health care, health centres and at different levels of management. DESIGN/METHODOLOGY/APPROACH: Data were collected as part of a survey on physicians graduating in 1977-1991 as drawn from the register of the Finnish Medical Association. The study sample was formed by selecting all physicians born on odd days (n=4144) from the baseline group (n=8232). The category of doctor-managers comprised physicians reporting as their main occupation: principal or assistant principal physician of hospital, medical director or principal physician of health centre, senior ward physician of hospital, and health centre physician in charge of a population area. FINDINGS: Independent of gender, all doctor-managers responding to the survey reported that the most important base for decision making was personal professional experience. Position in organisation (first-line manager, principal physician) had no impact on the base of decision making. Doctor-managers in primary health care utilised knowledge on norms and knowledge available from their organisation in support of their decision making to a greater degree compared with doctor-managers in specialised health care. RESEARCH IMPLICATIONS: Evolution discourse from public administration is not yet receiving much response in Finnish doctor-managers' activities, instead, they still act as clinicians. ORIGINALITY/VALUE: Facing the growing challenges of the future, the paper shows that doctor-managers should reconstruct their orientation and to act more like managers.