Phenotype Harmonization in the GLIDE2 Oral Health Genomics Consortium.

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies (N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.

Periodontal disease is associated with carotid plaque area: the Malmö Offspring Dental Study (MODS).

BACKGROUND: Periodontal disease is associated with cardiovascular disease (CVD) but it is unknown if periodontal disease severity is associated with asymptomatic carotid plaque. The aim of the current population-based, observational study was to investigate if signs of periodontal disease are associated with the occurrence of carotid plaque and total plaque area (TPA). METHODS: The Malmö Offspring Study (MOS) is a population-based study. MOS participants underwent a thorough cardiovascular phenotyping, including carotid ultrasonography. The Malmö Offspring Dental Study (MODS) invited participants of MOS for dental examination, including periodontal charting. Multivariable regression models were used to analyse the presence of carotid plaque and TPA in relation to periodontal parameters. RESULTS: In all, 831 MODS participants were recruited, out of which 495 belonged to the children generation with mean age of 53 years, 63% had carotid plaque and 38% had moderate or severe periodontal disease. In models adjusted for CVD risk factors, the OR for having carotid plaque in subjects with vs without periodontal disease was 1.75 (95% CI: 1.11-2.78). In a linear model with TPA as dependent and number of periodontal pockets ≥ 4 mm as independent variable, the adjusted beta-coefficient was 0.34 mm2 (95% CI 0.16-0.52). CONCLUSION: Individuals within the highest quartile of periodontal pockets are expected to have 9 mm2 larger TPA compared to those without pockets. Our results suggest that intervention studies addressing periodontal disease could be useful for prevention of CVD.

1α,25-dihydroxyvitamin D3 promotes osteogenic activity and downregulates proinflammatory cytokine expression in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: The aim of this study was to assess the impact of 1α,25-dihydroxyvitamin D3 (vitamin D3) on osteogenic and inflammatory properties of human periodontal ligament (PDL) cells and investigate underlying mechanisms. MATERIAL AND METHODS: Human PDL cells, obtained from four subjects, were stimulated with vitamin D3 for 4-48 h. The bone markers osteopontin and osteocalcin and proinflammatory cytokine/chemokine expression was determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Cytokine and chemokine expression was determined after stimulation with the inflammation promoter lipopolysaccharide (LPS) in the presence or absence of vitamin D3. Alkaline phosphatase activity was assessed using p-nitrophenylphosphate substrate. RESULTS: Treatment with 30 ng/mL of vitamin D3, corresponding to an optimal plasma concentration of vitamin D, for 24 h had no effect on PDL cell number and morphology but increased PDL cell osteopontin and osteocalcin mRNA expression by about 70 and 40%, respectively, and, moreover, treatment with vitamin D3 for 48 h enhanced PDL cell alkaline phosphatase activity by about two times showing that vitamin D3 exerts pro-osteogenic effects in human PDL cells. Stimulation with LPS (1 µg/mL) for 4 h increased PDL cell interleukin (IL)-6 cytokine and chemokine ligand 1 (CXCL1) chemokine mRNA expression several fold. The LPS-induced increase in IL-6 and CXCL1 transcripts was attenuated by vitamin D3 (30 ng/mL). Treatment with vitamin D3 (3-300 ng/mL) for 24 h reduced the LPS-evoked increase in PDL cell IL-6 protein by about 50%. Vitamin D3 (30 ng/mL) had no effect on LPS-induced IL-1ß and MCP-1 mRNA expression. CONCLUSIONS: Vitamin D3 promotes osteogenic differentiation but also downregulates inflammation promoter-induced IL-6 cytokine and CXCL1 chemokine expression in human PDL cells, suggesting that vitamin D3 both stimulates bone regeneration and antagonizes inflammation in human periodontal tissue.

Human endogenous peptide p33 inhibits detrimental effects of LL-37 on osteoblast viability.

BACKGROUND AND OBJECTIVE: High levels of the antimicrobial peptide, LL-37, are detected in gingival crevicular fluid from patients with chronic periodontitis. LL-37 not only shows antimicrobial activity but also affects host-cell viability. The objective of the present study was to identify endogenous mechanisms that antagonize the detrimental effects of LL-37 on osteoblast viability, focusing on the human peptide p33 expressed on the surface of various cell types. MATERIAL AND METHODS: Human osteoblast-like MG63 cells and human hFOB1.19 osteoblasts were treated with or without LL-37 in the presence or absence of p33. Recombinant human p33 was expressed in an Escherichia coli expression system. Lactate dehydrogenase (LDH) was assessed using an enzymatic spectrophotometric assay. DNA synthesis was determined by measuring [(3) H]-thymidine incorporation. Cell number was assessed by counting cells in a Bürker chamber. Intracellular Ca(2+) was monitored by recording Fluo 4-AM fluorescence using a laser scanning confocal microscope. Cellular expression of p33 was determined by western blotting. RESULTS: LL-37 caused a concentration-dependent release of LDH from human osteoblasts, showing a half-maximal response value (EC50 ) of 4 µm and a rapid and sustained rise in the intracellular Ca(2+) concentration of osteoblasts, suggesting that LL-37 forms pores in the cell membrane. p33 (10 µm) inhibited the LL-37-induced LDH release and LL-37-evoked rise in intracellular Ca(2+) concentration, suggesting that p33 prevents LL-37-induced permeabilization of the cell membrane. Moreover, p33 blocked LL-37-induced attenuation of osteoblast numbers. Also, mucin antagonized, at concentrations representative for nonstimulated whole saliva, LL-37-evoked LDH release, whilst cationic endogenous polyamines had no impact on LL-37-induced LDH release from osteoblasts. CONCLUSIONS: The endogenous peptide p33 prevents LL-37-induced reduction of human osteoblast viability. Importantly, this mechanism may protect the osteoblasts from LL-37-induced cell damage in patients suffering from chronic periodontitis associated with high levels of LL-37 locally.

Historygrams: Enabling Interactive Global Illumination in Direct Volume Rendering using Photon Mapping.

In this paper, we enable interactive volumetric global illumination by extending photon mapping techniques to handle interactive transfer function (TF) and material editing in the context of volume rendering. We propose novel algorithms and data structures for finding and evaluating parts of a scene affected by these parameter changes, and thus support efficient updates of the photon map. In direct volume rendering (DVR) the ability to explore volume data using parameter changes, such as editable TFs, is of key importance. Advanced global illumination techniques are in most cases computationally too expensive, as they prevent the desired interactivity. Our technique decreases the amount of computation caused by parameter changes, by introducing Historygrams which allow us to efficiently reuse previously computed photon media interactions. Along the viewing rays, we utilize properties of the light transport equations to subdivide a view-ray into segments and independently update them when invalid. Unlike segments of a view-ray, photon scattering events within the volumetric medium needs to be sequentially updated. Using our Historygram approach, we can identify the first invalid photon interaction caused by a property change, and thus reuse all valid photon interactions. Combining these two novel concepts, supports interactive editing of parameters when using volumetric photon mapping in the context of DVR. As a consequence, we can handle arbitrarily shaped and positioned light sources, arbitrary phase functions, bidirectional reflectance distribution functions and multiple scattering which has previously not been possible in interactive DVR.

The antimicrobial peptide LL-37 is anti-inflammatory and proapoptotic in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: The antimicrobial peptide LL-37 is expressed in periodontal tissue, and variations in LL-37 levels have been associated with periodontal disease. The effects of LL-37 on periodontal ligament cell function have not been described before. Here, we assess anti-inflammatory properties of LL-37 and investigate the effects of LL-37 on cell differentiation, cell proliferation and apoptosis in human periodontal ligament cells. MATERIAL AND METHODS: Periodontal ligament cells were obtained from teeth extracted for orthodontic reasons. Cytokine (interleukin-6) and chemokine (monocyte chemoattractant protein-1) expression was determined by quantitative PCR, cell differentiation by alkaline phosphatase activity, cell proliferation by counting cells in a Bürker chamber, DNA synthesis by incorporation of radiolabeled thymidine and apoptosis by cell morphology and activated caspase 3 quantities. RESULTS: Treatment with 0.1 and 1 µm of LL-37 totally reversed lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and suppressed lipopolysaccharide-induced interleukin-6 expression by 50-70%. LL-37 had no effect on alkaline phosphatase activity. Incubation with 8 µm LL-37 strongly reduced cell number. DNA synthesis was attenuated by about 90% in response to 8 µm LL-37, confirming its antiproliferative effect. Cell morphology was altered in an apoptosis-like fashion in cells treated with 8 µm LL-37. Furthermore, the quantity of activated caspase 3 was increased in cells treated with 1 and 8 µm of LL-37, suggesting apoptosis. CONCLUSION: LL-37 strongly attenuates lipopolysaccharide-induced cytokine and chemokine expression and, in high concentrations, reduces cell proliferation through inhibition of DNA synthesis and by promoting apoptosis in human periodontal ligament cells.

Impact of monocytic cells on recovery of uncultivable bacteria from atherosclerotic lesions.

OBJECTIVE: Epidemiological evidence suggests that infections may contribute to atherogenesis. However, with the exception of Chlamydophila pneumoniae, cultivable bacteria have not been recovered from atherosclerotic lesions. Therefore, we aimed at developing an approach to recover uncultivable bacteria from atherectomy tissues. METHODS: We cultured homogenates from atherectomy specimens from seven nonseptic patients undergoing surgery for arterial obstruction either alone or together with THP-1 monocyte-like cells. We performed 16S rDNA analysis, biochemical tests, random amplification of polymorphic DNA PCR analysis, quantitative polymerase chain reaction (qPCR) and immunohistofluorescence to identify the cultivated bacteria. Wilcoxon signed-rank tests were used to determine whether THP-1 treatment yielded a higher number of isolates than did the untreated controls. RESULTS: We recovered more bacteria from cocultures of atherectomy specimens with THP-1 cells than atherectomy specimens cultured alone. On average, tissue homogenates incubated with THP-1 cells versus control yielded 124 vs. 22 colony-forming units, a median of 140 vs. 7, respectively (P = 0.02). We recovered 872 isolates of limited number of species, including Propionibacterium acnes, Staphylococcus epidermidis and Streptococcus infantis and the fastidious anaerobe Porphyromonas gingivalis, and confirmed its presence in tissue using double immunofluorescence imaging. qPCR demonstrated the presence of ≥3.5 × 10(3) P. gingivalis genomes per gram of atheromatous tissue. CONCLUSIONS: These results indicate that viable previously uncultivable bacterial species are present within atheromas. Our results suggest revisiting the hypothesis that infections may have a causative role in atherosclerotic inflammation and have implications for research regarding novel diagnostics and treatments for cardiovascular disease.

The human periodontal ligament cell: a fibroblast-like cell acting as an immune cell.

BACKGROUND: Periodontal ligament cells are fibroblast-like cells characterized by collagen production but also possessing some osteoblastic features. In the light of numerous studies presented during recent times, which show that human periodontal ligament cells also produce cytokines and chemokines in response to inflammation promoters, it is reasonable to suggest that periodontal ligament cells play a role as promoters of periodontal inflammation through these mechanisms. MATERIAL AND METHODS: The periodontal ligament, which harbours the periodontal ligament cells, is a part of the attachment apparatus comprised of periodontal ligament cells, extracellular matrix and fibres, attaching the root cement to the alveolar bone. Periodontal ligament cells are in close proximity to bacteria within the plaque and the pocket, and thus these cells are readily accessible to bacterial endotoxins and other promoters of inflammation. RESULTS: Cytokines and chemokines, released by periodontal ligament cells upon stimulation with inflammation promoters, reach the blood vessels easily thanks to rich vascularization of the periodontium stimulating recruitment of white blood cells to the site of inflammation. In addition to classical inflammatory cells, such as leucocytes, macrophages and mast cells, the periodontal ligament cells also contribute to periodontal inflammation via their production and release of cytokines and chemokines. CONCLUSION: Therefore, pharmacological treatment of periodontitis should aim to reduce the release of proinflammatory agents not only from classical inflammatory cells but also from periodontal ligament cells.

Differential regulation of chemokine expression by estrogen in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Estrogen modulates inflammatory responses, but the mechanisms involved have not yet been identified. Periodontal ligament (PDL) cells produce chemokines (a group of chemoattractant molecules that recruit leukocytes) and it has been suggested that estrogen modulates periodontal inflammation by regulating the expression of chemokines by PDL cells. Therefore, the objectives of this study were to investigate the regulation of chemokine ligand 2 [CCL2/monocyte chemoattractant protein 1 (MCP-1)], chemokine ligand 3 [CCL3/macrophage inflammatory protein-1α (MIP-1α)] and chemokine ligand 5 (CCL5/RANTES) by estrogen in human PDL cells. MATERIAL AND METHODS: PDL cells were obtained from the PDL of premolars, extracted for orthodontic reasons, from two boys and two girls (16 and 17 years of age). PDL cell CCL2, CCL3 and CCL5 mRNA transcripts were determined by quantitative real-time PCR. The concentrations of CCL2, CCL3 and CCL5 proteins were determined by ELISAs. RESULTS: Treatment with 0.5 µg/mL of lipopolysaccharide (LPS, from Escherichia coli) + 100 nm 17ß-estradiol (E(2) ) for 24 h reduced the expression of CCL3 mRNA by about 40% compared to PDL cells treated with LPS alone. Attenuation of CCL3 mRNA was not associated with a decrease in CCL3 protein within 48 h, suggesting a slow turnover of the CCL3 protein. Interindividual differences in the effects of E(2) on CCL5 mRNA expression were observed. E(2) (100 nm) increased the expression of CCL5 by 40-60% in PDL cells derived from two subjects but reduced the expression of CCL5 by about 30% in cells from another subject. CCL2 mRNA and CCL2 protein were highly expressed, but not regulated by E(2) . Similar data were observed in cells obtained from both boys and girls. CONCLUSION: Regulation, by estrogen, of chemokine expression in PDL cells shows a complex pattern involving the down-regulation as well as the up-regulation of chemokines, suggesting that estrogen exerts both anti-inflammatory and proinflammatory effects through these mechanisms.

LPS induces GROalpha chemokine production via NF-kappaB in oral fibroblasts.

OBJECTIVE AND DESIGN: Chemotaxis of neutrophils from blood to the inflammation process plays an important role in development of periodontal inflammation. The novel chemokine GROalpha, also named CXCL1, is a strong chemoattractant for neutrophils. Data on production and regulation of GROalpha by oral fibroblasts have not previously been presented. MATERIALS AND METHODS: GROalpha mRNA and protein levels were determined in human periodontal ligament cells and mouse gingival fibroblasts by quantitative real-time PCR and ELISA. RESULTS: We disclose that both human periodontal ligament cells and mouse gingival fibroblasts produce GROalpha in response to LPS stimulation. Stimulation with LPS for 24 h increased both mRNA for GROalpha and GROalpha protein. The steroid hormone estrogen had no effect on LPS-induced GROalpha mRNA expression. Treatment with the glucocorticoid dexamethasone attenuated LPS-induced GROalpha production, and the NF-kappaB blocker MG 132 fully prevented LPS-induced GROalpha. CONCLUSIONS: Oral fibroblasts respond to LPS stimulation by increasing GROalpha production via the transcription factor NF-kappaB, suggesting that this mechanism may be involved in development of periodontal inflammation.

Differential effects of estrogen on DNA synthesis in human periodontal ligament and breast cancer cells.

BACKGROUND: It is important to clarify the biological function of the female sex hormones estrogen and progesterone in periodontal ligament cells, as these hormones may affect periodontal health. We have previously shown that human periodontal ligament cells express estrogen receptor beta (ERbeta) but not ERalpha, whereas human breast cancer cells (MCF7) express both ERalpha and ERbeta. Data on progesterone receptor (PgR) expression in human periodontal ligament cells have not been reported. OBJECTIVES: Determine PgR expression in human periodontal ligament and MCF7 cells and to investigate how estrogen affects DNA and collagen synthesis in these two cell types showing different pattern of expression for ERalpha and beta. METHODS: Periodontal ligament cells were obtained from the periodontal ligament of premolars extracted for orthodontic reasons and MCF7 cells from the American Type Culture Collection (ATCC). PgR expression was determined by immunocytochemistry. DNA and collagen synthesis was determined by [(3)H]thymidine and L-[(3)H]proline incorporation, respectively. RESULTS: PgR immunoreactivity was observed in nuclei of MCF7 but not periodontal ligament cells. Treatment with estrogen (17beta-estradiol, E(2)) at physiological concentrations for 24 h stimulated DNA synthesis by more than two times in MCF7 cells, whereas there was no effect on periodontal ligament cell DNA synthesis. The ER blocker ICI 182780 fully reversed the stimulatory effect of E(2). Not only short-term (24 h) but also long-term (5 days) treatment with E(2) lacked effect on DNA synthesis in periodontal ligament cells. Neither periodontal ligament cell viability nor collagen synthesis was affected by E(2) treatment. Identical results were observed in periodontal ligament cells from male and female subjects. CONCLUSIONS: Human MCF7 but not periodontal ligament cells express PgR, suggesting that progesterone via PgR affects MCF7 but not periodontal ligament cells. Further, estrogen stimulates breast cancer MCF7 cell proliferation, whereas it has no effect on proliferation of periodontal ligament cells, probably reflecting cell type specific ER expression pattern in these two cell types.

Rheumatoid arthritis is already expensive during the first year of the disease (the Swedish TIRA project).

OBJECTIVE: To calculate direct and indirect costs in early rheumatoid arthritis (RA) and to characterize patients generating high and low costs respectively. METHODS: Two hundred and ninety-seven patients with recent-onset (< or = 12 months) RA were recruited. Clinical/laboratory data and 'health assessment questionnaire' (HAQ) were registered at inclusion and after 3, 6 and 12 months. After 6 and 12 months, the patients completed a questionnaire concerning health-care utilization and days lost from work. A cut-off point for direct costs was set at 34,000 Swedish kronor (euro3675) defining one-third of the patients as a high-cost group and two-thirds as low-cost group. Indirect costs were calculated for patients aged <65 yr. RESULTS: Two hundred and eleven patients completed the HAQ on both occasions. Indirect costs exceeded direct costs by a factor of 2.3. Sixty three per cent experienced work disability during the first year and were identified as the 'high-indirect-cost group'. Indirect costs accounted for >70% of total costs. Direct costs included ambulatory health care (76%), hospitalization (12%) and medication (9%). Men aged > or = 65 yr had low costs compared with younger men and women of all ages. In multiple logistic regression tests, HAQ, high levels of IgM rheumatoid factor (IgM RF) and poor hand function increased the odds of entering the high-direct-cost group, and poor hand function and pain increased the odds of entering the high-indirect-cost group. CONCLUSIONS: Substantial costs were incurred during the first year after diagnosis of early RA, mainly due to work disability. Indirect costs were two to three times higher than direct costs. High levels of IgM RF, high HAQ score, poor hand function and pain increased the odds of entering high-cost groups.

Immunocytochemical demonstration of estrogen receptor beta in human periodontal ligament cells.

Two transcription associated estrogen receptor (ER) subtypes have been identified and named ERalpha and ERbeta. In the present study we investigate the expression of these ER subtypes in cultured human periodontal ligament (PDL) cells by immunocytochemistry. ERbeta immunoreactivity was observed in the nuclei of about 40% of the PDL cells, while no ERalpha immunoreactivity was detected. In human breast cancer MCF-7 cells, serving as positive controls, both ERalpha and ERbeta immunoreactivities were demonstrated. No immunoreactivity was observed after omission of the primary antibodies. This study suggests that estrogen acts on gene transcription preferentially via ERbeta in human PDL cells.

The costs of early inflammatory joint disease: a population-based study in southern Sweden.

OBJECTIVE: To study the costs and use of healthcare for patients during the first months with early joint inflammation, in a population-based prospective referral study in Southern Sweden. METHODS: Adult patients with arthritis for < 3 months and with onset of symptoms between 1 May 1999 and 1 May 2000 were referred from primary health centres to rheumatologists. Four clinical assessments were performed during a 6-month follow-up period. The direct medical costs for inpatient stays, outpatient visits, visits to general practitioners, and visits to health professionals, as well as costs for medication, radiographs, and laboratory tests were recorded from the onset of the disease up to 6 months of follow-up. Indirect costs for sick leave were also recorded. RESULTS: Fifty-six of 71 referred patients agreed to participate. Thirteen (23%) had RA, 21 (38%) had reactive arthritis (ReA), 14 (25%) had undifferentiated arthritis, and eight (14%) had other arthritides. The median cost per patient in the entire group was USD 3362. The median cost per patient in the RA group was USD 4385, and USD 4085 in the ReA group. There was no statistically significant difference in the median costs per patient in the different diagnostic groups. Sick leave accounted for 44% of the total costs in the entire group, and 46% and 47%, respectively, in the RA and ReA groups. CONCLUSION: The costs of early arthritis are already considerable during the first months of the disease following the onset of the symptoms. The indirect costs due to sick leave accounted for nearly half of the costs.

Cost-effectiveness of interferon alfa-2b with and without ribavirin as therapy for chronic hepatitis C in Sweden.

BACKGROUND: Recent trials have shown that treatment with a combination of interferon alfa-2b and ribavirin results in sustained loss of detectable hepatitis C-virus (HCV) RNA in a higher proportion of patients than treatment with interferon alone. Combination therapy, however, is two to three times as expensive as monotherapy. METHODS: Based on data from recent randomized clinical trials and a previously published decision model, we developed a Markov model to estimate the cost-effectiveness of initial combination therapy with interferon and ribavirin versus interferon alone for previously untreated patients with chronic HCV infection in Sweden. Clinical praxis and quality adjustments were based on expert estimates and costs were gathered from different health care providers in Sweden. RESULTS: Combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 0.5 to 1.1 years at marginal cost-effectiveness ratios of US$ 1,400 to US$ 6,000 per DQALY (discounted quality-adjusted life-year) for patients with genotype 1. In genotype 1, 48 weeks compared to 24 weeks of combination therapy prolonged quality adjusted life expectancy by 0.6 years at a marginal cost-effectiveness ratio of $US 9,800 per DQALY. For patients with genotype non-1, combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 2.3 years, with combination therapy for 24 weeks being money-saving. The results were robust in sensitivity analyses. CONCLUSION: Combination therapy with interferon and ribavirin increased quality-adjusted life expectancy and was cost-effective for patients with chronic hepatitis C.

Direct and indirect costs of dental trauma in Sweden: a 2-year prospective study of children and adolescents.

OBJECTIVES: To study total costs, including direct costs (health care service, loss of personal property, medicine and transport) and indirect costs (loss of production or leisure) of dental trauma to children and adolescents with special reference to predictors. METHODS: The study was based on a random sample of 192 children and adolescents with a dental trauma reported to an insurance company and prospectively followed up by telephone interviews over a period of 2 years. RESULTS: On average, health care service costs represented 2,955 SEK (SD=3,818) and total costs 4,569 SEK (SD=3,053) for dental trauma to permanent teeth, and 837 SEK (SD=898) and 1,746 SEK (SD=1,183) for trauma to primary teeth. The most extensive type of indirect cost was loss of production or leisure, which averaged 1,286 SEK (SD=1,830) for injuries to permanent teeth and 699 SEK (SD=1,239) for injuries to primary teeth. Multiple regression analysis of demographic and dental injury variables showed that complicated trauma was of special importance to costs for permanent and primary teeth injuries. The average relative increase in total costs to patients and companions for complicated injury to permanent teeth was 140% (95% confidence interval [CI], 66-248%) for patients and 132% (95% CI, 54-249%) for companions. Lack of access to a dental clinic near the place of residence could increase the average total costs of injuries to permanent teeth by 91% for companions (95% CI, 20-204%) and for primary teeth by 134% (95% CI, 38-296%). CONCLUSIONS: Dental traumas result in both direct and indirect costs, with a predominance of direct costs. The direct costs primarily depend on degree of severity, while indirect costs are mostly due to compromised access to health care service. Traumas to permanent teeth are especially costly and, due to additional maintenance, the care may continue for several years. This study has drawn attention to the significant implications of dental trauma to patient and companion, a new area where further studies are warranted.

Short-term effects of severe hypoglycaemia in children and adolescents with type 1 diabetes. A cost-of-illness study.

UNLABELLED: The aim of this study was to describe costs and other short-term effects of severe hypoglycaemia in children and adolescents with type 1 diabetes. The study comprised a geographic population of 129 patients <19 y of age with families prospectively registering detailed data after self-reported severe hypoglycaemia. In the period Jan.-Dec. 1998, 16 events were reported with unconsciousness and 95 events without unconsciousness but needing the assistance of another person. Of all events, 20-30% had effects requiring the assistance of people other than parents, school absence, parents' absence from work, extra transport and/or telephone calls. Patient (family) activities were cancelled after 10% (5%) of events. Increased worry for parents was reported after 8% and poor sleep after 7% of events. Hospital visits took place at 5% and hospitalizations at 3% of all events. Patients with severe hypoglycaemia indicated lower global quality of life (p=0.0114). The average socio-economic burden for events of severe hypoglycaemia was estimated at EURO 17,400 yearly per 100 type 1 diabetes patients. Average cost was estimated at EURO 239 per event of severe hypoglycaemia with unconsciousness or EURO 478 yearly per patient with unconsciousness, and EURO 63 per event of severe hypoglycaemia without unconsciousness but needing assistance from another person or EURO 307 yearly per patient in this category. These are conservative estimates and do not include unpaid time and other intangibles, possible road traffic accidents, disabling or premature deaths. CONCLUSIONS: The results suggest the potential for socio-economic savings and increased quality of life for patients and families from severe hypoglycaemia prevention programs.

Socioeconomic costs of rheumatic diseases. Implications for technology assessment.

OBJECTIVES: To study the socioeconomic impact of rheumatic illness in Sweden and to discuss the consequences for technology assessment studies. METHODS: A cost-of-illness study based on data from official statistics and treatment studies. RESULTS: The total socioeconomic cost was 52 billion Swedish kronor (SEK) in 1994. The imbalance between direct (10% of total) and indirect costs (90 effectiveness of the healthcare sector, the need for new treatment methods, appropriate information systems, and technology assessment studies as well as the institutional arrangements for rehabilitation and basic medical research. CONCLUSIONS: A discussion of solutions for financial cooperation between county councils and regional social insurance offices should be considered. The new biotechnological pharmaceuticals will increase the cost for drugs in health care about 20 times, but the total socioeconomic cost for society may remain at the same level due to a decrease of inpatient costs and indirect costs for loss of production as well as a decrease of transfer payments from social insurance. It is unavoidable that the new pharmaceuticals require priority discussions and active resource allocation in health care and in other sectors of society.

Job control, job demands and social support at work in relation to cardiovascular risk factors in MONICA 1995, Göteborg.

BACKGROUND: Job control and work environment are related to risk of coronary heart disease (CHD), but there is limited understanding of the independent risks associated with these factors. OBJECTIVE: To investigate the association between psychosocial work characteristics and biological risk factors for both sexes for a random population sample in Göteborg, Sweden. DESIGN: A cross-sectional study. METHODS: We used an age-stratified random sample of men and women aged 25-64 years comprising 1200 men and 1412 women, from which 746 men and 872 women responded to the invitation for screening, which included questionnaires and physical/laboratory investigations in 1995. RESULTS: Women had lower job control than did men (P=0.00001); job demands were equal and social support at work slightly higher among women (P=0.04). Job control was positively related to education and social group. Smoking women had low job control and high job demands. Women with high grades of psychological stress had low job control and low social support at work (P=0.001 and P=0.01). For both sexes job demands were high (P=0.0001) among those who reported high psychological stress. Men with high job control and high social support at work were more physically active during leisure time. Subjects with job strain had low social support (P=0.01). Job-stress factors were not related to biological coronary risk factors. CONCLUSIONS: Women had lower job control than did men. Job control was positively related to education, social class and physical activity. Psychosocial factors were not related to biological coronary risk factors.

Cost-effectiveness of clozapine treatment in therapy-refractory schizophrenia.

The costs and effects of clozapine treatment of refractory schizophrenic patients have been discussed recently. This study shows that 18 months of clozapine treatment results in an improvement of symptoms and social functioning in approximately 70% of treatment-refractory schizophrenic patients, compared with treatment with conventional neuroleptics during a similar period of time. Treatment with clozapine reduces the cost of inpatient care but places increased demands on active rehabilitation resources in outpatient care. This leads to increased total costs in a short-term perspective, but clozapine treatment is cost-saving for annual maintenance therapy. These costs must be weighed against the positive effects on psychotic symptoms and social functioning.