Immunoglobulin G1 Antibodies Against Phosphorylcholine Are Associated With Protection in Systemic Lupus Erythematosus and Atherosclerosis: Potential Underlying Mechanisms.

OBJECTIVE: Immunoglobulin M antibodies against phosphorylcholine (anti-PCs) may be protective in atherosclerosis, cardiovascular disease (CVD), and systemic lupus erythematosus (SLE). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti-PCs, with a focus on atherosclerosis and SLE. METHODS: We determined anti-PCs by using the enzyme-linked immunosorbent assay in 116 patients with SLE and 110 age- and sex-matched controls. For functional studies, we used three in-house-generated, fully human monoclonal IgG1 anti-PCs (A01, D05, and E01). Apoptosis was induced in Jurkat T cells and preincubated with A01, D05, E01, or IgG1 isotype control, and effects on efferocytosis by human macrophages were studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach. RESULTS: IgG1, but not IgG2, anti-PC levels were higher among patients with SLE (P = 0.02). IgG1 anti-PCs were negatively associated with Systemic Lupus International Collaborating Clinics (SLICC) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (odds ratio [OR]: 2.978 [confidence interval (CI): 0.876-10.098] and OR: 5.108 [CI 1.3-20.067], respectively) and negatively associated with CVD, atherosclerotic plaques, and echolucent plaques (potentially vulnerable plaques), but the association for the two former was not significant after controlling for confounders. D05 had a maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC-associated neoepitopes. A peptide analysis showed a difference in the complementarity-determining region 3 of the three IgG1 anti-PC clones that are crucial for recognition of PC on apoptotic cell surfaces and other neoepitopes. CONCLUSION: IgG1 anti-PCs are negatively associated with disease activity and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.

Subthreshold and threshold attention deficit hyperactivity disorder symptoms in childhood: psychosocial outcomes in adolescence in boys and girls.

OBJECTIVE: To examine the association between different levels of childhood attention deficit hyperactivity disorder (ADHD) symptoms and sex differences in psychosocial outcomes during adolescence. METHOD: Swedish children (n = 4635) were screened for neuropsychiatric symptoms at age 9 or 12. ADHD symptoms were divided into three levels: screen-negative, screen-intermediate, and screen-positive. At follow-up (age 15), parents and teenagers filled out questionnaires regarding (i) hyperactivity/inattention, (ii) peer problems, (iii) school problems, (iv) internalizing problems, (v) antisocial behaviour, (vi) alcohol misuse, and (vii) drug misuse. All outcomes were controlled for symptoms of diagnostic categories other than ADHD. RESULTS: Increasing levels of ADHD symptoms in childhood were associated with higher proportions of adolescents who displayed negative psychosocial outcomes. More girls than boys reported internalizing problems (all levels) and risky drug use (screen-intermediate and screen-positive only). More boys reported antisocial behaviour at the screen-negative and screen-intermediate levels, but at the screen-positive level, similar proportions of girls and boys displayed antisocial behaviour. CONCLUSION: The findings support the view that ADHD symptoms, as well as their negative outcomes, are dimensionally distributed in the population and that adolescent girls and boys display different risk profiles. The findings confirm that ADHD symptoms are associated with higher risk of drug misuse in girls.

Preschool to School in Autism: Neuropsychiatric Problems 8 Years After Diagnosis at 3 Years of Age.

The study presents neuropsychiatric profiles of children aged 11 with autism spectrum disorder, assessed before 4.5 years, and after interventions. The original group comprised a community sample of 208 children with ASD. Parents of 128 participated-34 with average intellectual function, 36 with borderline intellectual function and 58 with intellectual disability. They were interviewed using the Autism-Tics, AD/HD and other Comorbidities interview. Criteria for a clinical/subclinical proxy of ASD were met by 71, 89 and 95 %, respectively. Criteria for at least one of ASD, AD/HD, Learning disorder or Developmental Coordination Disorder were met by 82, 94 and 97 %. More than 90 % of children with a preschool diagnosis of ASD have remaining neuropsychiatric problems at 11, despite early intervention.

Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples.

The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires-Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)-designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 × 10(-7) in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 × 10(-5). Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one potential target in the treatment of aggressive antisocial behavior.

Renal function and symptoms/adverse effects in opioid-treated patients with cancer.

BACKGROUND: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an under-investigated issue. This study aimed at analysing if symptoms/adverse effects in opioid-treated patients with cancer were associated with renal function. METHODS: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005-2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. RESULTS: Mild to severe low GFR was observed among 40-54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. CONCLUSION: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.

Language and mathematical problems as precursors of psychotic-like experiences and juvenile mania symptoms.

BACKGROUND: Psychotic-like experiences (PLEs) and juvenile mania in adolescence index risk for severe psychopathology in adulthood. The importance of childhood problems with communication, reading, speech and mathematics for the development of PLEs and juvenile mania is not well understood. METHOD: Through the Child and Adolescent Twin Study in Sweden, we identified 5812 children. The parents were interviewed about their children's development at age 9 or 12 years. At age 15 or 18 years, children and parents completed questionnaires targeting current PLEs and juvenile mania symptoms. Logistic regressions were used to assess associations between problems with communication, reading, speech and mathematics and PLEs/juvenile mania symptoms. To evaluate the relative importance of genes and environment in these associations, we used bivariate twin analyses based on structural equation models. RESULTS: Children with parent-endorsed childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations and parental-reported juvenile mania symptoms in adolescence. The most consistent finding was that children with childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations [for example, the risk for self-reported auditory hallucinations at age 15 was increased by 96% for children with communication problems: OR (odds ratio) 1.96, 95% confidence interval (CI) 1.33-2.88]. The twin analyses showed that genetic effects accounted for the increased risk of PLEs and juvenile mania symptoms among children with communication problems. CONCLUSIONS: Childhood problems with communication, reading and mathematics predict PLEs and juvenile mania symptoms in adolescence. Similar to the case for schizophrenia and bipolar disorder, PLEs and juvenile mania may share genetic aetiological factors.

Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.

Autistic-like traits and their association with mental health problems in two nationwide twin cohorts of children and adults.

BACKGROUND: Autistic-like traits (ALTs), that is restrictions in intuitive social interaction, communication and flexibility of interests and behaviors, were studied in two population-based Swedish twin studies, one in children and one in adults: (1) to examine whether the variability in ALTs is a meaningful risk factor for concomitant attention deficit hyperactivity disorder (ADHD), anxiety, conduct problems, depression and substance abuse, and (2) to assess whether common genetic and environmental susceptibilities can help to explain co-existence of ALTs and traits associated with such concomitant problems. METHOD: Two nationwide twin cohorts from Sweden (consisting of 11 222 children and 18 349 adults) were assessed by DSM-based symptom algorithms for autism. The twins were divided into six groups based on their degree of ALTs and the risk for concomitant mental health problems was calculated for each group. Genetic and environmental susceptibilities common to ALTs and the other problem types were examined using bivariate twin modeling. RESULTS: In both cohorts, even the lowest degree of ALTs increased the risk for all other types of mental health problems, and these risk estimates increased monotonically with the number of ALTs. For all conditions, common genetic and environmental factors could be discerned. Overall, the phenotypic correlation between ALTs and the traits examined were less pronounced in adulthood than in childhood and less affected by genetic compared with environmental factors. CONCLUSIONS: Even low-grade ALTs are relevant to clinical psychiatry as they increase the risk for several heterotypical mental health problems. The association is influenced partly by common genetic and environmental susceptibilities. Attention to co-existing ALTs is warranted in research on a wide range of mental disorders.

The existential impact of starting corticosteroid treatment as symptom control in advanced metastatic cancer.

Treatment with corticosteroids often results in increased appetite, reduced nausea and improved well-being in patients with advanced metastatic cancer. Therefore, we have studied the existential impact of starting corticosteroid treatment as symptom control in this patient group using qualitative content analysis with both a descriptive and an interpretative focus. Ten patients were interviewed before and after 1 week of treatment with 4 mg betamethasone. Prior to treatment, patients reported distressing symptoms, deterioration and diminished autonomy, symbolising threat and death. Corticosteroid treatment produced symptom relief in the majority of the patients. They reported enhanced physical abilities and experienced feelings of a more normalized life and strengthened autonomy, symbolising health and hope. This transfer from threat to hope has important existential consequences in end-of-life care and should be addressed when communicating goals of treatment and care with the patient and family.

Aspects of delayed chemotherapy-induced nausea. Dexamethasone and adrenal response patterns in patients and healthy volunteers.

Delayed chemotherapy-induced nausea is still a clinical problem, and the underlying mechanisms are poorly understood. Previous studies have suggested that corticosteroids are involved, although the mechanisms by which corticosteroids exert their antiemetic effect are largely unknown. We have previously found impaired control of delayed nausea after injection of dexamethasone. The possibility of differences in the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after injection of dexamethasone was investigated in patients (n = 5) with gynaecological cancer being treated with platinum-based chemotherapy and in healthy female volunteers (n = 10). Urinary free cortisol was used to assess the levels of endogenous cortisol. Results showed that in both patients and controls injections of dexamethasone led to a significant decline in endogenous cortisol levels in 24 h and a subsequent significant recovery in the next 24 h. We conclude that the recovery of the HPA axis is rapid after a single dose of dexamethasone in patients and controls. The absence of an abnormal response pattern in patients makes it probable that the suppression and recovery of the HPA axis after injection of dexamethasone does not influence the corticosteroid-induced rebound effect on delayed platinum-induced nausea.

Concurrent video filming and measuring for visualization of exposure.

A method has been developed for simultaneous video filming and exposure measurement with a presentation of the current exposure level mixed into the picture. With the aid of special equipment, the video camera and the instruments are coupled together in such a way that the outgoing video signal will give a picture carrying superimposed information as to the current level of the exposure. It is intended to serve as an aid in the evaluation of various measures for reducing the exposure and in connection with the training of personnel performing work involving exposure. The method has been tried out for air pollutants in seven different cases where exposure to organic solvents, carbon monoxide, wood dust and fume from welding occurred. The result, in the form of a film, showed with great clarity what working operations were critical with regard to the current exposure. In one plant where the method was used in connection with spray-painting, a study was undertaken in order to see how the exposure could be reduced by simple measures. The results showed that the exposure was reduced drastically. The method is usable for air pollutants and also for other measurable environmental factors. The method is ready for use, but there are many ways in which the system could be improved. Further evaluation is also necessary.

Hydrocarbon exposure and glomerulonephritis: evidence from patients' occupations.

The occupations, as given in the national public census 1975, of 124 adult patients with non-systemic glomerulonephritis were compared with those of the general population in the catchment area of the hospital. Occupations assumed to be linked with exposure to organic solvents or fuels were commoner among patients than in the general population. The finding supports the idea that such exposure is causal in glomerulonephritis.