Associations between autistic-like traits and polymorphisms in NFKBIL1.

OBJECTIVE: The immune system has been suggested to be associated with neuropsychiatric disorders; for example, elevated levels of cytokines and the inflammation-related transcription factor nuclear factor kappa-B (NF-κB) have been reported in individuals with autism spectrum disorder (ASD). The aim of this study was to investigate possible associations between autistic-like traits (ALTs) and single nucleotide polymorphisms (SNPs) in NFKB1 (encoding a subunit of the NF-κB protein complex) and NF-κB inhibitor-like protein 1 (NFKBIL1). METHODS: The study was conducted in a cohort from the general population: The Child and Adolescent Twin Study in Sweden (CATSS, n = 12 319, 9-12 years old). The subjects were assessed by the Autism-Tics, ADHD, and Other Comorbidities Inventory. Five SNPs within the two genes were genotyped (NFKBIL1: rs2857605, rs2239707, rs2230365 and rs2071592; NFKB1: rs4648022). RESULTS: We found significant associations for two SNPs in NFKBIL1: rs2239707 showed a significant distribution of genotype frequencies in the case-control analysis both for all individuals combined and in boys only, and rs2230365 was significantly associated with the ALTs-module language impairment in boys only. Furthermore, we found nominal association in the case-control study for rs2230365, replicating earlier association between this SNP and ASD in an independent genome-wide association study. CONCLUSION: The shown associations between polymorphisms in NFKBIL1 and ALTs are supporting an influence of the immune system on neuropsychiatric symptoms.

S100B polymorphisms are associated with age of onset of Parkinson's disease.

BACKGROUND: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. METHODS: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. RESULTS: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. CONCLUSIONS: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.

CACNA1C polymorphism and altered phosphorylation of tau in bipolar disorder.

Several genome-wide association studies and case-control studies have associated the single nucleotide polymorphism (SNP) rs1006737, situated in CACNA1C encoding the alpha 1C subunit of the L-type voltage-gated calcium channel, with bipolar disorder and other psychiatric disorders. However, the causal pathway linking genetic variants in CACNA1C with increased risk for developing brain disorders remains unclear. Here, we explored the association between the rs1006737 SNP and cerebrospinal fluid (CSF) markers. We found a significant association between the risk allele in rs1006737 and a decreased CSF hyperphosphorylated tau/total tau ratio in patients with bipolar disorder, thus linking variation in the CACNA1C gene to a neurochemical marker of neuroaxonal plasticity in those with this disorder.

Is the Gly82Ser polymorphism in the RAGE gene relevant to schizophrenia and the personality trait psychoticism?

BACKGROUND: The receptor for advanced glycation end products (RAGE) is the main receptor for S100B, an astrogial proinflammatory mediator that has been suggested to be involved in the pathophysiology of schizophrenia. To further elucidate the possible relevance of inflammation for mental functions, we investigated a functional polymorphism in the gene coding for RAGE in relation to personality traits and susceptibility to schizophrenia. METHODS: We studied the Gly82Ser polymorphism (rs2070600, 244G>A) in 2 population-based cohorts of middle-aged participants assessed using the Karolinska Scales of Personality. In addition, we compared genotype frequencies between patients with schizophrenia and controls. RESULTS: The population-based cohorts included 270 women and 247 men, and the case-control study involved 138 patients with schizophrenia and 258 controls. In the population-based cohorts, 82Ser carriers were found to have significantly higher scores for the psychoticism personality trait comprising the detachment and suspicion subscales. The case-control study revealed that the 82Ser allele was significantly more frequent among patients than controls. LIMITATIONS: This study was limited by the modest sample size and the use of a self-report measure to assess personality traits. CONCLUSION: Our findings suggest that the proven relation between certain personality traits and schizophrenia can at least to some extent be explained on a genetic level. Also, the activated S100B-RAGE axis may be an underlying cause, not only a consequence, of the disease.

[What aspects do medical students find important during medical school to develop basic prescribing skills?] / Vad läkarstudenter anser viktigt på utbildningen för att kunna läkemedelsbehandla patienter.

The process of acquiring prescribing skills starts in medical school, and recent research highlights that educational efforts are needed to make students sufficiently prepared for this professional task. In this study, we explored and quantified aspects that medical students find important during medical school to develop basic prescribing skills. Written text from 75 final-year students (median age: 25 years, 59% female) formed the data. At the end of an anonymous and voluntary test in clinical pharmacology and therapeutics, the students provided (i) information regarding key elements in medical school that had prepared them for prescribing and (ii) suggestions for facilitating their learning of pharmacotherapy. In a manifest content analysis, five themes emerged: workplace-based learning under supervision and taking responsibility for patients; theoretical knowledge base for prescribing; writing prescriptions and helpful resources; varied teaching methods with specific examinations; and continuity, repetition, and progression. The quantitative analysis revealed that workplace-based learning was the most frequently recurring key element for the learning process, and case seminars a preferred pedagogic format. Most suggestions to facilitate learning concerned the category pharmacotherapeutics theory. Categories of the theme continuity, repetition, and progression, as opposed to other themes, encompassed no key elements but only suggestions to facilitate learning. These themes and categories, summarising aspects that medical students find important in the process of acquiring basic prescribing skills essential for their professional life, could form a basis for further developments of pharmacotherapy in medical school.

Influence of genetic variations in IL1B on brain region volumes in bipolar patients and controls.

Involvement of the immune system has been implicated in the etiology and pathophysiology of mood disorders, including bipolar disorder. Neuroimaging studies have reported structural brain pathology in bipolar disorder patients, and both levels of and genetic variants in cytokines have been associated with altered volumes of brain regions. The aim of this study was to investigate associations between single nucleotide polymorphisms in the gene coding for the pro-inflammatory cytokine interleukin-1 beta (IL1B) and whole brain grey matter volume, as well as volumes of several brain regions shown to be of importance in mood disorders. Structural magnetic resonance imaging and vertex-based morphometry were used to obtain volume of different brain regions in subjects with bipolar disorder (n=188) and healthy controls (n=54). Four IL1B polymorphisms were genotyped: rs1143623, rs1143627, and rs16944 in the promoter region together with the synonymous variant rs1143634 in the IL1B gene. The genotype distribution did not differ between bipolar subjects and controls. The T allele at rs16944 and the C allele at rs1143627 were associated with increased volumes of the putamen of the left hemisphere in patients and controls, which lends support to the role of this immune system mediator for brain structure.

Association between the AGTR1 polymorphism +1166A>C and serum levels of high-sensitivity C-reactive protein.

Genetic factors have been shown to influence high-sensitivity C-reactive protein (hsCRP) levels, however, which genes that are involved in this process remains to be clarified. The renin-angiotensin system (RAS) is of importance for the regulation of inflammation, and blockade of angiotensin II type 1 receptors (AGTR1) influences hsCRP levels. These findings prompted us to investigate whether a polymorphism in the AGTR1 gene may influence hsCRP levels. Additionally, a polymorphism in the CRP gene that has previously been shown to influence hsCRP levels was genotyped. Serum levels of hsCRP were measured in 270 42-year-old women recruited from the population registry. Two single nucleotide polymorphisms were analysed: +1166A>C and +1444C>T of the AGTR1 and CRP gene, respectively. The A allele of the AGTR1 polymorphism +1166A>C was dose-dependently associated with higher hsCRP levels (p=0.014, adjusted for confounding factors and multiple comparisons). hsCRP levels were not significantly influenced by the CRP +1444C>T genotype; however, an interaction between the two studied polymorphisms with respect to hsCRP levels was observed (p=0.018). The significant association between the AGTR1 polymorphism and hsCRP levels, which appears to be independent of anthropometric and metabolic traits, is yet another indication of a direct influence of RAS on inflammation.

[Preparing for the licence to prescribe in medical school - a questionnaire study on medical students professional confidence in the art of prescribing]. / Läkemedelsarbete behöver vara integrerat i klinisk utbildning - Att göra många läkemedelsgenomgångar ökar trygghet och reflektion över patientens behandling, visar enkätstudie.

A prerequisite for rational use of medicines is adequate prescribing skills; drug treatment is a complex task requiring diagnostic competence combined with pharmacologic knowledge and patient communication skills. Acquiring professional confidence in the art of prescribing is essential during medical training. The results of this questionnaire study, conducted in four medical schools in Sweden after the course in internal medicine (252 respondents; response rate: 74%; median age: 24 years, 61% female), show that 45% and 62% were confident in performing medication reviews and writing medication summary reports, respectively, i.e. the basics of prescribing. The confidence increased by the number of reviews and reports performed, i.e. the extent of practice (correlation coefficients: 0.41 and 0.38, respectively, both p<0.0001), as did the extent of the students' reflection on important aspects of drug treatment such as adherence, adverse reactions, renal function, dosing, and drug interactions. In multivariate regression analyses, major predictors for confidence in performing medication reviews were extent of practice and extent of clinical supervision. The results suggest that these factors are keys to acquiring professional confidence in the art of prescribing.

Association between serum levels of C-reactive protein and personality traits in women.

BACKGROUND: While low-grade inflammation has consistently been observed in subjects with depression, studies on the possible relationship between inflammation and other aspects of brain function are as yet sparse. In this study, we aimed to investigate the possible association between serum levels of the inflammation marker C-reactive protein (CRP) and personality traits. METHODS: In this study, serum levels of high-sensitivity CRP were determined by ELISA in a population of 270 42-year-old women recruited from the population registry who had been assessed using the Temperament and Character Inventory. Self-reported previous or ongoing depression was also recorded. Unpaired two-tailed t-tests were used for comparison between two groups and correlations were evaluated by the calculation of Pearson's r-coefficient. RESULTS: The temperament trait harm avoidance was positively (r = 0.227, p < 0.05) and the character trait self-directedness was negatively (r = -0.261, p < 0.01) associated with serum levels of CRP (p-values corrected for multiple comparisons). The correlations between the personality traits and CRP were observed also after exclusion of subjects reporting ongoing depression (n = 26). Whereas women reporting ongoing depression showed significantly increased levels of CRP as compared to non-depressed women (n = 155), women reporting a history of depression displayed no significant difference in CRP levels as compared to women that reported that they had never been depressed. CONCLUSION: Serum levels of CRP in women was found to be associated with the personality traits harm avoidance and self-directedness. In addition, moderately elevated levels may be a state dependent marker of depression.

Implant failure in young children with ectodermal dysplasia: a retrospective evaluation of use and outcome of dental implant treatment in children in Sweden.

PURPOSE: This study surveyed dental implant treatment in children up to age 16 years in Sweden between 1985 and 2005, with special reference to young children with ectodermal dysplasia (ED) and anodontia in the lower jaw. MATERIALS AND METHODS: A questionnaire was sent to Swedish specialist clinics in oral and maxillofacial surgery and prosthetic dentistry. Also, the teams who had treated children with ED were asked to submit their records for these children for a discussion on reasons for implant failure. RESULTS: Six out of 30 specialist centers (20%) in Sweden had treated 26 children with dental implants between 1985 and 2005. Twenty-one patients had received 33 implants to replace teeth missing from nonsyndromic agenesis or trauma at ages 14 or 15 years; 2 (6.1%) of these implants were lost. Five children with ED received 14 implants at 5 to 12 years of age; 9 (64.3%) of these implants were lost before loading. CONCLUSIONS: Dental implant placement has been a rarely used treatment modality in Swedish children less than 16 years old in the last 20 years. The failure rate in children treated because of tooth agenesis was only slightly higher than that reported for adult individuals, whereas in young children with ED and anodontia in the mandible, implants seemed to present special challenges, and the failure rate was very high. The small jaw size and peroperative conditions, rather than ED per se, were thought to be the main risk factors. Centralizing implant operations in young children with ED and monitoring outcomes in implant registers are strongly advocated.

Comparison of the effectiveness of fissure sealants in Finland, Sweden, and Greece.

OBJECTIVE: To evaluate the effectiveness of sealant treatment in preventing dental restorations due to caries in a practice-based research network in Finland, Sweden, and Greece. MATERIAL AND METHODS: Times of tooth emergence, sealing treatment, and dental caries were compiled from the dental charts of 4735 subjects born in 1970-72 in Finland and in 1980-82 in Finland, Sweden, and Greece. Survival time between tooth emergence and placement of first restoration was measured and estimated using survival analysis methodology. RESULTS: At the end of follow-up (7-10+ years), 30-40% of sealed molars and 60-80% of non-sealed molars were restored. Early sealant placement compared to late sealing did not result in significantly higher survival of 1st molars. The strategy of sealing the 1st molars only in high caries risk subjects was as effective as sealing all the molars and premolars routinely without caries risk determination. CONCLUSIONS: The sealing of all molar fissures proved to be no more effective than sealing risk fissures of subjects. Early sealing did not result in any better outcome than late sealing. The effectiveness of sealant treatment in preventing dental restorations is dependent on the caries risk of individuals and caries prevalence of the country.

Low density and high affinity of platelet [3H]paroxetine binding in women with bulimia nervosa.

Impaired serotonin transmission has been suggested to be implicated in the pathophysiology of bulimia nervosa. As an indirect measure of brain serotonergic activity, the binding of tritiated ligands to platelet serotonin transporters has been studied in bulimia nervosa as well as in other putatively serotonin-related psychiatric disorders. In this study, the density and affinity of platelet serotonin transporters were assessed in 20 women meeting the DSM-IV criteria for bulimia nervosa and in 14 controls without previous or ongoing eating disorder using [(3)H]paroxetine as a ligand. In comparison to controls, women with bulimia nervosa had a significantly reduced number of platelet binding sites (B(max) = 721 +/- 313 vs. 1145 +/- 293 fmol/mg protein) and an increase in the affinity for the ligand demonstrated by a lower dissociaton constant (K(d) = 33 +/- 10 vs. 44 +/- 10 pM). A significant correlation between B(max) and K(d) values was found in patients but not in controls. Our results support the notion that bulimia nervosa is associated with a reduction in platelet serotonin transporter density. In addition, our study is the first to report that this reduced transporter density in women with bulimia nervosa is accompanied by an increase in the affinity of the transporter for the ligand.

Investigation of transcription factor AP-2 beta genotype in women with premenstrual dysphoric disorder.

It has repeatedly been shown that the serotonergic system is involved in the symptomatology of premenstrual dysphoric disorder (PMDD). Women with PMDD are reported to differ from symptom-free controls with regard to serotonin-related biological markers. Evidence from family and twin studies suggests a genetic contribution to the aetiology of PMDD. The expression of human transcription factor AP-2beta in neural crest cell lineages and neuroectodermal cells suggests that this protein may be of importance for functional characteristics of neurons by regulating the expression of target genes. Within the monoaminergic systems, several genes have binding sites for AP-2beta in regulatory regions, suggesting an involvement of AP-2beta in these systems. The gene encoding AP-2beta is located on chromosome 6p12-p21.1 and includes a polymorphic region consisting of a variable number of [CAAA] repeats located in the second intron. We have earlier shown that AP-2beta genotype is associated with serotonergic phenotypes and that brainstem levels of AP-2beta correlate positively to serotonin metabolism in rat frontal cortex. The aim of this study was to investigate the relationship between PMDD and transcription factor AP-2beta genotype. The participants included 176 women with PMDD and 91 healthy controls. Genotyping was performed by polymerase chain reactions. We did not observe any differences in AP-2beta genotype frequencies between PMDD subjects and controls. Our results suggest that AP-2beta genotype is not a risk factor for PMDD. To our knowledge, this is the first study investigating transcription factor AP-2beta genotype in women with PMDD. Hence, these results should be considered preliminary until replicated.

Developments in oral health policy in the Nordic countries since 1990.

PURPOSE: There is a number of systems for the provision of oral health care, one of which is the Nordic model of centrally planned oral health care provision. This model has historically been firmly based on the concept of a welfare state in which there is universal entitlement to services and mutual responsibility and agreement to financing them. This study reports and analyses oral health care provision systems and developments in oral health policy in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) since 1990. MATERIAL AND METHODS: Descriptions of and data on the oral health care provision systems in the Nordic countries were obtained from the Chief Dental Officers of the five countries, and contemporary scientific literature was appraised using cross-case analyses to identify generalisable features. RESULTS: It was found that in many respects the system in Iceland did not follow the 'Nordic' pattern. In the other four countries, tax-financed public dental services employing salaried dentists were complemented by publicly subsidised private services. Additional, totally private services were also available to a variable extent. Recently, the availabilty of publicly subsidised oral health care has been extended to cover wider groups of the total population in Finland and Sweden and, to a smaller extent, in Denmark. Concepts from market-driven care models have been introduced. In all five countries, relative to the national populations and other parts of the world, there were high numbers of dentists, dental hygienists and technicians. Access to oral health care services was good and utilisation rates generally high. In spite of anticipated problems with increasing health care costs, more public funds have recently been invested in oral health care in three of the five countries. CONCLUSION: The essential principles of the Nordic model for the delivery of community services, including oral health care, i.e. universal availability, high quality, finance through taxation and public provision, were still adhered to in spite of attempts at privatisation during the 1990 s. It appeared that, in general, the populations of the Nordic countries still believed that there was a need for health and oral health care to be paid for from public funds.

Expression of inflammatory markers in a genetic rodent model of depression.

The complex bidirectional communication between the central nervous system and the peripheral immune system is of possible relevance for both normal brain functions and the development of psychiatric disorders. The aim of this investigation was to study central expression of inflammatory markers in a genetic rat model of depression (the Flinders sensitive line (FSL) and its control, the Flinders resistant line (FRL)). A peripheral immune activation was induced by lipopolysaccharide (LPS) in order to investigate possible differences in immune reactions between the two rat lines. To confirm behavioural differences between the rat lines the forced swim test was performed, a test to assess depressive-like behaviour. Expression of candidate inflammatory genes was measured in amygdala, hippocampus, hypothalamus, prefrontal cortex and striatum using quantitative real time PCR. Our results show, for the first time, significantly lower central expression of the glial-specific protein S100B and complement factor C3 in several brain regions of the FSL rats compared to controls, both at baseline and after peripheral immune stimulation. No significant differences in immune responses to LPS were observed between the rats lines. Both S100B and C3 have been suggested to be of relevance for brain development and plasticity as well as brain disorders. These proteins may be of importance for the behavioural differences between the FSL and FRL rats, and this model may be useful in studies exploring the influence of the immune system on brain functions.

Heart rate variability in premenstrual dysphoric disorder.

Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.

Timing and effect of fissure sealants on permanent molars: a study in Finland and Sweden.

Fissure sealants are frequently used in the Nordic countries for the prevention of caries in children. The aim here was to analyse their use and effect on dental health in children and adolescents in Finland and Sweden. A retrospective longitudinal population-based study was performed in northern Finland and Sweden, where different strategies have been adopted for sealing teeth. The timing of sealant and restoration placements up to 18 years was studied in representative samples of subjects born in the early 1980s in Kemi, Oulu, Raahe and Tornio in Finland (n = 908) and compared with a random sample of subjects from Norrbotten, Sweden (n = 634). A sensitive survival analysis method was applied to all the permanent molars separately (Virtanen et al. 1996). About 80-90% of molars had been sealed in the Finnish subjects, and approximately 30% in the Swedish cases, employing selective criteria. The filling increments were statistically significantly higher in Sweden than in Finland, although the differences were not of the same magnitude as the reduction in sealants. More than 30% of first molars and 50% of second molars had not been treated, i.e. were without sealants or fillings, by the end of the follow-up in Sweden, compared with 10% and 20%, respectively, in Finland. Fissure sealants were effective in preventing caries in molars in children and adolescents, and the use of selective criteria for targeting this treatment can yield savings in effort and costs in a low caries situation, although more research is needed to find the optimum cost-effective strategy.

Associations between avoidant focused coping strategies and polymorphisms in genes coding for brain-derived neurotrophic factor and vascular endothelial growth factor in suicide attempters: a preliminary study.

In this study we investigated whether single nucleotide polymorphisms (SNP) in the genes coding for BDNF (Val66Met) and VEGF (C2578A) may be associated with maladaptive strategies among suicide attempt patients. We found that BDNF Val66Met gene polymorphism probably affect avoidant coping strategies.

The +1444C>T polymorphism in the CRP gene: a study on personality traits and suicidal behaviour.

OBJECTIVES: Numerous studies have shown associations between an on-going depression and elevated serum levels of the acute-phase reactant C-reactive protein (CRP). Also, in suicidal behaviour, a proinflammatory state has been suggested to be of importance for the pathophysiology. There is a genetic susceptibility to suicidal behaviour, but studies with respect to genes related to inflammation are sparse. We have previously reported an association between a polymorphism located in the CRP gene, +1444C>T (rs1130864), and the personality trait impulsiveness in women assessed using the Karolinska Scales of Personality. The present study aims to replicate these results in suicide attempters and examine whether the polymorphism is associated with suicidal behaviour. MATERIALS AND METHODS: The +1444C>T polymorphism was genotyped in suicide attempters from two cohorts (a total of 106 patients) and healthy controls (n=517). RESULTS: We could replicate our previous finding, as the +1444T allele was associated with higher scores in the Karolinska Scales of Personality factor extraversion and its subscale impulsiveness in one of the patient cohorts. Furthermore, the +1444T allele was significantly more common among suicide attempters compared with the +1444C allele. CONCLUSION: The present results lend further support to the relevance of inflammation for suicidal behaviour. The association between the polymorphism and personality trait impulsiveness reinforces our hypothesis of the importance of immune-related genes also for normal mental functions such as personality traits. Given the fact that impulsiveness is a well-known risk factor for suicidal behaviour, we further hypothesize that the polymorphism studied may in part explain this relationship.