Marjo Renko

Surfactant Protein D Gene Polymorphism Associated with Severe Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is the major respiratory tract pathogen in infancy. Host-related differences in susceptibility to severe RSV infection suggest that genetic factors may play a role. In this study, a candidate-gene approach was used to study whether the surfactant protein D (SP-D) gene polymorphism associates with severe RSV infection. DNA samples from 84 infants hospitalized for the treatment of RSV bronchiolitis and 93 healthy controls were analyzed. The controls were matched with the cases on the basis of sex, hospital district, date of birth (±2 wk) and gestational age at birth (±2 wk). Three biallelic SP-D gene polymorphisms were genotyped. Significant differences were observed in the SP-D allele frequencies for amino acid 11 between the RSV infants and their matched controls. The frequency of the allele coding for Met 11 (p = 0.033) was increased in the severe RSV group. The frequency of the homozygous genotype Met/Met for amino acid 11 was increased in the RSV group relative to the controls, whereas the heterozygous genotype tended to be less frequent among the RSV cases than in the matched controls. Conditional logistic regression analysis was used to study whether the confounders, i.e. smoking and number of children in the family, influence the association between the homozygous SP-D genotype for methionine 11 and the risk of RSV bronchiolitis. The results further confirmed this association (p = 0.028). To our knowledge, the present report provides the first evidence of a specific gene associated with susceptibility to severe RSV infection.

Association between Surfactant Protein A Gene Locus and Severe Respiratory Syncytial Virus Infection in Infants

Respiratory syncytial virus (RSV) causes seasonal epidemics of bronchiolitis among susceptible infants. Surfactant protein A (SP-A), a lung C-type lectin involved in innate host defense, opsonizes RSV and enhances phagocytosis. The candidate gene approach was used to investigate association of SP-A polymorphism with susceptibility to severe RSV infection. Genotype analysis was done for 86 infants with severe RSV infection and 95 matched control subjects. A significant difference in the frequency of SP-A2 was observed. The SP-A2 allele 1A(3) was overrepresented in RSV-infected infants, compared with control subjects (5% vs. 0.5%; P =.006), whereas allele 1A was underrepresented (1% vs. 6%; P =.011). The allele pool in which lysine was amino acid 223 was overrepresented in infants with severe RSV infection (28% vs. 18%; P =.023), whereas the allele pool in which proline was amino acid 99 was underrepresented (5% vs. 16%; P =.001). These results indicate that a genetic association exists between SP-A gene locus and severe RSV infection.

Meta-analysis of the significance of asymptomatic bacteriuria in diabetes.

OBJECTIVE To evaluate whether asymptomatic bacteriuria (ASB) is more common in patients with diabetes than among control subjects. In addition, we wanted to clarify the clinical significance of ASB in patients with diabetes. RESEARCH DESIGN AND METHODS We conducted a systematic review and meta-analysis of published data since 1966. Twenty-two studies fulfilled the inclusion criteria of the meta-analysis. RESULTS ASB was present in 439 of 3,579 (12.2%) patients with diabetes and in 121 of 2,702 (4.5%) healthy control subjects. ASB was more common both in patients with type 1 diabetes (odds ratio 3.0 [95% CI 1.1–8.0]) and type 2 diabetes (3.2 [2.0–5.2]) than in control subjects. The point prevalence of ASB was higher in both women (14.2 vs. 5.1%; 2.6 [1.6–4.1]) and men (2.3 vs. 0.8%; 3.7 [1.3–10.2]) as well as in children and adolescents (12.9 vs. 2.7%; 5.4 [2.7–11.0]) with diabetes than in healthy control subjects. Albuminuria was more common in patients with diabetes and ASB than those without ASB (2.9 [1.7–4.8]). History of urinary tract infections was associated with ASB (1.6 [1.1–2.3]). CONCLUSIONS We were able to show that the prevalence of ASB is higher in all patients with diabetes compared with control subjects. We also found that diabetic subjects with ASB more often had albuminuria and symptomatic urinary tract infections.

Vesicoureteral reflux in children with suspected and proven urinary tract infection

The aim of this study was to estimate the prevalence of vesicoureteral reflux (VUR) and clinically significant ultrasonography (US) abnormalities in a large group of children with proven and suspected urinary tract infection (UTI). The medical reports on renal US and voiding cystouretrographies (VCUG) of 2,036 children were reviewed. Renal US was performed on all children and VCUG on 1,185 children (58%). Based on the urine culture data, the UTI diagnoses were classified into five reliability classes (proven, likely, unlikely, false and no microbial data). The UTI diagnose was considered proven in 583/2036 (28.6%) and false in 145 (7.1%) cases. The prevalence of VUR was similar among those with proven and false UTI [37.4 vs. 34.8%; relative risk (RR) 1.08, 95% confidence intervals (95% CI) 0.7–1.7, P = 0.75] and decreased with increasing age (P = 0.001). Clinically significant US abnormalities occurred in 87/583 (14.9%) cases with proven UTI and significantly less often (11/145, 7.6%) in the false UTI class (RR 1.96, 95% CI 1.1–3.6, P = 0.02). Our finding supports the claim that VUR is not significantly associated to UTI and that its occurrence among children even without UTI is significantly higher than traditional estimates. This challenges the recommendations of routine VCUG after UTI.

Association of an early respiratory syncytial virus infection and atopic allergy

Background: Respiratory syncytial virus (RSV) causes postbronchiolitic wheezing but its role in allergic sensitization is controversial. The purpose of the study was to examine the effect of an early RSV infection on allergic sensitization.

Failure of Xylitol Given Three Times a Day for Preventing Acute Otitis Media

Background: Xylitol administered regularly 5 times a day after each meal is successful in preventing acute otitis media (AOM) in children, but if given only during respiratory infections it is ineffective against AOM. To find a more convenient dosing regimen, we tested whether xylitol administered 3 times a day reduces the occurrence of AOM. Methods: In this 3-month randomized, double-blind trial, 663 healthy day care children were randomized to receive either a control product (n = 331) or xylitol (n = 332). Xylitol was given in chewing gum or in a mixture 3 times a day, the daily dose being 0.5 g in the control group and 9.6 g in the xylitol group. The occurrence of the first AOM diagnosed during any period of respiratory symptoms during the follow-up was the main outcome measure. Results: At least one AOM episode was diagnosed in 98 of the 331 children who received control products (30%) and in 94 of the 332 who received xylitol products (28%). A total of 142 episodes of AOM were diagnosed in the control group compared with 156 in the xylitol group. The differences were not statistically significant. Conclusions: Xylitol given regularly 3 times a day for 3 months during the respiratory infection season failed to prevent AOM.

Impact and effectiveness of RotaTeq® vaccine based on 3 years of surveillance following introduction of a rotavirus immunization program in Finland.

Background: Finland introduced universal rotavirus (RV) vaccination in September 2009, with exclusive use of the pentavalent human-bovine reassortant RV vaccine RotaTeq® and following a vaccination schedule at 2, 3 and 5 months of age. This study monitored the impact of RV vaccination on hospitalizations due to RV acute gastroenteritis (RVGE). The results following the first 3 RV seasons after implementation of universal RV vaccination are presented. Methods: Prospective hospital-based surveillance identified children with acute gastroenteritis admitted to 2 University Hospitals (Tampere and Oulu, Finland), from December 2009 to August 2012. The surveillance covered a population of approximately 173,000 children from the 2 hospitals’ catchment areas. Stool samples were taken and analyzed centrally for RV by enzyme-linked immunosorbent assay, with genotyping by reverse transcription polymerase chain reaction. International Classification of Diseases discharge codes were collected retrospectively pre- and postvaccination. Results: During the 3-year prospective surveillance, 127 RVGE episodes were identified. Of these, 117 were in unvaccinated children and 6 were in fully vaccinated children (RotaTeq, n = 3; Rotarix, n = 3). The vaccine effectiveness against hospitalized RVGE for fully vaccinated children was 92.1% [95% confidence interval (CI): 50.0–98.7] among children eligible for the National Immunization Program. When analyzing retrospectively the Tampere and Oulu hospital databases for all children aged <16 years, hospitalizations for RVGE had decreased by 78% in the postvaccination period (2009–2012) compared with the prevaccination data (2001–2006). Conclusions: Severe RVGE requiring hospitalization was virtually eliminated in vaccine-eligible children in the 3 years following implementation of universal RotaTeq vaccination in Finland.

Medical theses as part of the scientific training in basic medical and dental education: experiences from Finland

BackgroundTeaching the principles of scientific research in a comprehensive way is important at medical and dental schools. In many countries medical and dental training is not complete until the candidate has presented a diploma thesis. The objective of this study was to evaluate the nature, quality, publication pattern and visibility of Finnish medical diploma theses.MethodsA total of 256 diploma theses presented at the University of Oulu from 2001 to 2003 were analysed. Using a standardised questionnaire, we extracted several characteristics from each thesis. We used the name of the student to assess whether the thesis resulted in a scientific publication indexed in medical article databases. The number of citations received by each published thesis was also recorded.ResultsA high proportion of the theses (69.5%) were essentially statistical in character, often combined with an extensive literature review or the development of a laboratory method. Most of them were supervised by clinical departments (55.9%). Only 61 theses (23.8%) had been published in indexed scientific journals. Theses in the fields of biomedicine and diagnostics were published in more widely cited journals. The median number of citations received per year was 2.7 and the range from 0 to 14.7.ConclusionThe theses were seldom written according to the principles of scientific communication and the proportion of actually published was small. The visibility of these theses and their dissemination to the scientific community should be improved.

Toll-like receptor 4 Asp299Gly polymorphism in respiratory syncytial virus epidemics.

The respiratory syncytial virus (RSV) antigen serves as ligand for Toll‐like receptor (TLR) 4 that is a transmembrane signaling receptor in macrophages and dendritic cells. According to current evidence single nucleotide polymorphism involving amino acid 299 influences the susceptibility to severe RSV infections. The Asp299Gly allele has been shown to influence the TLR4‐mediated signaling causing conformational change in the extracellular domain that recognizes pathogen‐associated molecular patterns. The aim was to study the association between the TLR4 Asp299Gly polymorphism and the susceptibility to severe RSV bronchiolitis in infants. Altogether 312 cases and 356 controls, selected on the basis place of residence, date of birth, gender, and gestation at birth, were studied. When adjusted for multiple dependent variables, no allele or genotype frequency difference was found between the cases and the controls. Post hoc analysis revealed that during the year 2000 epidemics, the Gly299Gly genotype associated with protection against severe RSV and during 2004 epidemics Gly299Gly genotype and 299Gly allele associated with severe RSV. To conclude, we could not confirm the association of the Gly299 allele with severe RSV. This is consistent with the evidence that the susceptibility to severe RSV infection is principally dependent on environmental and constitutional factors. We propose that the risk of severe RSV infection may additionally depend on the interaction between individual TLR4 genotype and the particular RSV group causing bronchiolitis. Pediatr Pulmonol. 2010; 45:687–692.

Cytokine responses in cord blood predict the severity of later respiratory syncytial virus infection.

BACKGROUND It has been claimed that an early respiratory syncytial virus (RSV) infection can induce asthma and recurrent wheezing. OBJECTIVE We addressed the question of whether infants contracting an early RSV infection differ from healthy children in their cytokine production at birth. METHODS In a prospective cohort study cord blood samples were collected from 1084 newborns during autumn 2001. Of 47 of these newborns with subsequent virologically confirmed RSV infection before 6 months of age, 24 had enough cells for stimulation in cord blood samples (14 of those were hospitalized). Twenty-eight children had other respiratory virus infections (16 with enough cells), and samples from 48 healthy children of the 1084 total served as control specimens. Stimulated cytokine production of mononuclear cells was measured. The responses in the groups were evaluated by means of factor analysis. RESULTS The infants hospitalized for RSV infection had higher LPS-stimulated combined IL-6 and IL-8 responses than the infants treated as outpatients (P = .005) or the healthy control subjects (P = .02). The hospitalized patients with RSV showed lower IL-1beta, IL-2, IL-4, IL-5, and IL-10 responses than those treated as outpatients (P = .02). High IL-6 and IL-8 responsiveness predicted a severe RSV infection (odds ratio, 2.20; 95% CI, 1.17-4.14; P = .01). The unstimulated cytokine responses at birth did not differ between the patients and healthy control subjects. CONCLUSION The results suggest that natural differences in innate immunity predispose children to severe RSV infection rather than the infection modifying immune responses in childhood.