Mechanisms for pneumococcal meningitis and a new vaccine platform to raise a serotype-independent protection in the host

Streptococcus pneumoniae is a highly relevant pathogenic bacterium, responsible for a large fraction of deaths and disease morbidity in the world. The pneumococcus remains the leading cause of life-threatening pneumonia, septicemia and meningitis beyond neonatal age, despite global implementation of vaccination programs. Due to its extraordinary adaptability, S. pneumoniae has developed evasion strategies against most therapeutic interventions. In addition to escaping vaccine conferred immunity, antibiotic resistance trends are continuously on the rise. The pneumococcal polysaccharide capsule is an important virulence factor with around 100 distinct capsular serotypes identified so far, that vary in invasiveness. Among other major virulence factors of the pneumococcus are the cytotoxin pneumolysin, pneumococcal pili, and adhesin factors PspA and PspC. Vaccine-induced pressure drives capsular switching, and acquisition of resistance genes is promoted by antimicrobial pressure, complicating treatment strategies. The clinical management of pneumococcal meningitis is particularly troublesome, which is reflected in persistently high rates of permanent neurological sequalae among survivors. Therefore, there is an urgent need to scrutinize the pathogenesis of invasive pneumococcal disease (IPD), to identify new adjunctive therapeutic or prophylactic targets, and improve clinical outcomes. The work presented in the thesis aims to contribute to an improved understanding of key virulence mechanisms in the development of pneumococcal meningitis. These include bacterial invasion of the brain, bacterial interactions with fundamental cellular components of the brain, and bacteria-induced disruption of the brain’s fluid dynamics. Moreover, we propose a new vaccine platform to prevent pneumococcal colonization and infection in a serotype-independent manner. Pneumococcal invasion of the brain through the blood-brain barrier, and the potential therapeutic effect of blocking the endothelial cell host receptors PECAM-1 and pIgR, was investigated in paper I. In combination with antibiotics, antibody blockade successfully prevented bacterial invasion of the brain, and protected the brain from damage, in a murine bacteremia-derived meningitis model. The feasibility to modulate host responses as adjunctive therapy was demonstrated. Bacteria-host communication between the pneumococcus and human neuronal cells was shown to occur directly and indirectly in paper II. Neuronal cell injury was induced by pneumolysin and pilus-I interactions with cytoskeletal β-actin. Inhibition of the interaction, using a β-actin antibody, partially protected against cellular damage. The pneumococcal-induced pathophysiology of the brain’s waste clearance system, the glymphatic system, and consequent neurofunctional damage, was characterized in paper III. A rat meningitis model, where bacteria were intracisternally administered together with a tracer dye, was employed, to study the accumulation of fluid and bacterial components in the brains CSF compartment. The findings of the study attest to the benefit of using lumbar drainage to alleviate intracranial pressure as adjunctive therapy in bacterial meningitis. Finally, in paper IV, pneumococcal vesicles were evaluated for their capacity to induce cross-protection against several pneumococcal serotypes, in a mouse immunization model. We found that the vesicles gave an excellent homologous and heterologous protection. The conserved lipoproteins MalX and PrsA were found to be the major components in the vesicles that conferred heterologous cross-protection. We suggest that vesicles represent promising novel vaccine targets to protect against pneumococcal diseas

Relationship between growth and feeding in infancy and body mass index at the age of 6 years

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To assess the relationship between size and growth measurements in infancy to body mass index (BMI) at 6 y. DESIGN: A longitudinal observation study on randomly chosen infants' growth and consumption in infancy. Follow-up until the age of 6 y. SUBJECTS: A total of 90 children who were born healthy and full-term. MEASUREMENTS: Weight and height were measured at maternity wards and healthcare centers in Iceland throughout infancy and at 6 y. Food records were made every month during infancy. At 2, 4, 6, 9 and 12 months, food was weighed to calculate food and nutrient intake. RESULTS: Weight gain from birth to 12 months as a ratio of birth weight was positively related to BMI at the age of 6 y in both genders (B=2.9+/-1.0, P=0.008, and B=2.0+/-0.9, P=0.032 for boys and girls, respectively). Boys in the highest quartile of protein intake (E%) at the age of 9-12 months had significantly higher BMI (17.8+/-2.4 kg/m(2)) at 6 y than the lowest (15.6+/-1.0 kg/m(2), P=0.039) and the second lowest (15.3+/-0.8 kg/m(2), P=0.01) quartile. Energy intake was not different between groups. Together, weight gain at 0-12 months and protein intake at 9-12 months explained 50% of the variance in BMI among 6-y-old boys. CONCLUSION: Rapid growth during the first year of life is associated with increased BMI at the age of 6 y in both genders. In boys, high intake of protein in infancy could also contribute to childhood obesity

Conservation Properties of the Hamiltonian Particle-Mesh method for the Quasi-Geostrophic Equations on a sphere

The Hamiltonian particle-mesh (HPM) method is used to solve the Quasi-Geostrophic model generalized to a sphere, using the Spherepack modeling package to solve the Helmholtz equation on a colatitude-longitude grid with spherical harmonics. The predicted energy conservation of a Poisson system is shown to be approximately retained and statistical mean-eld theory is veried

A functional central limit theorem for a Markov-modulated infinite-server queue

The production of molecules in a chemical reaction network is modelled as a Poisson process with a Markov-modulated arrival rate and an exponential decay rate. We analyze the distributional properties of $M$, the number of molecules, under specific time-scaling; the background process is sped up by $N^{\alpha}$, the arrival rates are scaled by $N$, for $N$ large. A functional central limit theorem is derived for $M$, which after centering and scaling, converges to an Ornstein-Uhlenbeck process. A dichotomy depending on $\alpha$ is observed. For $\alpha\leq1$ the parameters of the limiting process contain the deviation matrix associated with the background process.Comment: 4 figure

Iron status in 6-y-old children: associations with growth and earlier iron status

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To investigate the iron status of 6-y-old children and its association with growth and earlier iron status. DESIGN: In a cross-sectional study, children's body size measurements were recorded and blood samples taken near their sixth birthday. SUBJECTS: A sample of 188 children, randomly selected in two previous studies, was contacted, and 139(74%) agreed to participate. RESULTS: No children had iron deficiency anaemia, one was iron-deficient (serum ferritin (SF) or =15 microg/l (258+/-31%; n=49) (P=0.001). MCV at 2 y predicted weight gain from 2 to 6 y (B+/-s.e.=1.721+/-0.581; P=0.005; adj. R2=0.153) (n=44); also, children with SF or =15 microg/l (n=35) gained 9.6+/-2.8 kg (P=0.007), furthermore a difference was seen in proportional weight gain from 2 to 6 y between children with depleted iron stores at 2 y and not, or 156+/-13 vs 169+/-18% (P=0.038). CONCLUSION: The results suggest that low iron status at 1 and 2 y might lead to slower growth up to 6 y of age. Low iron status at 1 and 2 y and/or slower growth from 1 and 2 y up to 6 y might contribute to worse iron status at 6 y, while faster growth in early childhood is related to lower iron status

The Association of the Social Relationships CAP with Depression in Psychiatric In-patients: An Outcome Study

Background: Depression is a worldwide problem but studies have shown that after patients with depressive symptoms are in remission, difficulties in social relationships may persist. There is a need for future research on the relationship between social function and depressive symptoms in order to facilitate development of new clinical interventions. Objectives: This study aimed to identify what factors contribute to the relationship between depressive symptoms and social relationships and what factors predict improvement in depressive symptoms during psychiatric hospitalization. Methods: This longitudinal cohort study was based on a secondary analysis of RAI-MH data from the Ontario Mental Health Reporting System (OMHRS). Depressive symptoms were measured with the Depressive Symptoms Rating Scale (DRS) and social relationships difficulties were evaluated with the interRAI Social Relationships CAP. The sample comprised of 125,120 patients from acute, long stay, addiction, psychiatric crisis units and forensic units. Sub-sample of patients with depressive symptoms and mood disorder was created (N = 38,823). Results presented in a descriptive analysis for both samples and bivariate and multivariate analysis for the sub-sample. Logistic regression analysis was performed to predict rates of improvement of depressive symptoms. Results: The study revealed that many factors predict outcome of depressive symptoms. Difficulties in social relationships, older age, multi-morbidity, functional impairments, trauma, and poor physical health predict decreased odds of improvements but longer hospital stay, individual therapy and family/couples therapy predict increased odds of improvements. Conclusions: The interRAI Social Relationships CAP provides a valuable tool to address social issues in patient care, assist clinical staff in care planning and provide mental health authorities information for policy making

Iodine intake and status in Iceland through a period of 60 years

Iodine deficiency is considered to be one of the most common nutrition disorders in the world and the world's greatest single cause of preventable brain damage. Despite a worldwide application of successful iodine supplementation programs over the last four decades, iodine deficiency remains a major public health problem throughout the world. All European countries except Iceland have experienced this health and socioeconomic threat to a greater or lesser extent. The fact that mild to severe iodine deficiency persists in many European countries may have important public health consequences, including impaired intellectual development of infants and children. Iceland has in the past been known for its high iodine status, based on results from studies of iodine status from 1939, 1988, and 1998 suggested to be due to high fish consumption. Fish together with milk and other dairy products are the main sources of iodine in the Icelandic diet, but iodized salt is not commonly used. In recent years fish and dairy intake has decreased, especially among young people. In this paper, historical data on iodine status and iodine intake in Iceland is reviewed and the need for further studies as well as possible need for public health actions evaluated

Associations of iron status with dietary and other factors in 6-year-old children

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To investigate the associations of iron status at 6 years of age with dietary and other factors. DESIGN: In a cross-sectional study, children's dietary intakes (3-day weighed food record) were recorded, body size was measured and blood samples were taken near their sixth birthday. SUBJECTS: A sample of 188 children, from two previous studies (cohorts 1 and 2), was contacted, and 139 (74%) agreed to participate. RESULTS: Multiple regression analyses with dietary and other factors showed that meat and fish consumption, multivitamin/mineral supplement intake (both positively) and cow's milk product consumption (negatively) were associated with log serum ferritin (SF) (adjusted R (2)=0.125; P=0.028; n=129), and juices and residence (rural>urban) with haemoglobin (Hb) (adjusted R (2)=0.085; P=0.034; n=127). Of 21 multivitamin/mineral consumers, none had depleted iron stores compared to 21 iron-depleted of 108 non-consumers (P=0.024). Children living in rural areas (10,000 inhabitants) (82.1+/-3.2 fl; n=103) (P=0.048). Multiple regression analyses with dietary and other factors and growth showed in cohort 1 that residence (rural>urban), weight gain 0-1years (negatively), and meat and fish intake (positively) were associated with Hb (adjusted R (2)=0.323; P=0.030; n=51), meat and fish (positively) with both log SF (adjusted R (2)=0.069; P=0.035; n=52) and MCV (adjusted R (2)=0.064; P=0.035; n=52), and in cohort 2 cow's milk product consumption (negatively) was associated with log SF (adjusted R (2)=0.119; P=0.017; n=41) and residence (rural>urban) with MCV (adjusted R (2)=0.102; P=0.025; n=41). CONCLUSIONS: Consumption of meat and fish and possibly also juices, as well as multivitamin/mineral intake might affect iron status in 6-year-old children positively, whereas cow's milk product consumption might affect iron status negatively. Slower growth in the first year of life and rural residence are positively related to iron status of 6-year-olds

Nutrition and Iron Status of 1-Year Olds following a Revision in Infant Dietary Recommendations

A previous study showed low iron status in 12-month-old Icelandic infants associated most strongly with cow's milk intake and growth. Infant dietary recommendations were revised in 2003. This study investigated nutrition and iron status in a new infant cohort. Subjects/Methods. Randomly selected infants were prospectively investigated for diet, anthropometry, and iron status (n = 110–141). Results. Breastfeeding initiation rate was 98%; 38% of 5-month olds were exclusively and 20% of 12-month olds partially breastfed. Formula was given to 21% of 6-month olds and 64% of 12-month olds, but cow's milk to 2.5% and 54.4% of 6- and 12-month olds, respectively. Iron depletion (serum ferritin < 12 μg/L) affected 5.8%, 1.4% were also iron deficient (MCV < 74 fl), and none were anemic (Hb < 105 g/l). Iron status associated negatively with growth and breastfeeding duration and positively with meat and formula intake at 9–12 months, but not with cow's milk. Conclusion. Improved iron status might be explained by a shift from cow's milk to formula in the diet of Icelandic 6–12-month olds. Dietary changes altered associations between foods and iron status

Protein intake from 0 to 18 years of age and its relation to health: a systematic literature review for the 5th Nordic Nutrition Recommendations.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The present systematic literature review is a part of the 5th revision of the Nordic Nutrition Recommendations. The aim was to assess the health effects of different levels of protein intake in infancy and childhood in a Nordic setting. The initial literature search resulted in 435 abstracts, and 219 papers were identified as potentially relevant. Full paper selection resulted in 37 quality-assessed papers (4A, 30B, and 3C). A complementary search found four additional papers (all graded B). The evidence was classified as convincing, probable, limited-suggestive, and limited-inconclusive. Higher protein intake in infancy and early childhood is convincingly associated with increased growth and higher body mass index in childhood. The first 2 years of life is likely most sensitive to high protein intake. Protein intake between 15 E% and 20 E% in early childhood has been associated with an increased risk of being overweight later in life, but the exact level of protein intake above which there is an increased risk for being overweight later in life is yet to be established. Increased intake of animal protein in childhood is probably related to earlier puberty. There was limited-suggestive evidence that intake of animal protein, especially from dairy, has a stronger association with growth than vegetable protein. The evidence was limited-suggestive for a positive association between total protein intake and bone mineral content and/or other bone variables in childhood and adolescence. Regarding other outcomes, there were too few published studies to enable any conclusions. In conclusion, the intake of protein among children in the Nordic countries is high and may contribute to increased risk of later obesity. The upper level of a healthy intake is yet to be firmly established. In the meantime, we suggest a mean intake of 15 E% as an upper limit of recommended intake at 12 months, as a higher intake may contribute to increased risk for later obesity.Nordic Council of Minister