Complex PTSD symptoms mediate the association between childhood trauma and physical health problems

The ICD-11 reconceptualized Posttraumatic Stress Disorder (PTSD) as a narrowly defined fear-based disorder, and introduced Complex PTSD (CPTSD) as a new diagnosis comprised of PTSD symptoms and symptoms of ‘Disturbances in Self-Organization’ (DSO) that are more reflective of general dysphoria. Previous research suggests that PTSD symptoms mediate the association between childhood trauma and physical health problems, including cardiovascular disease. No study has yet assessed how posttraumatic stress symptoms, as outlined in the ICD-11, influence the association between childhood trauma and somatic problems in adulthood.ObjectiveThis cross-sectional descriptive study examined whether PTSD and DSO symptoms mediated the associations between childhood physical and sexual abuse and childhood emotional abuse and neglect and somatic problems and cardiovascular diseases (CVD) load in adulthood.MethodsGeneral adult population samples from Ireland (N = 1020) and the United Kingdom (N = 1051) completed self-report questionnaires online.ResultsStructural equation modelling results indicated that PTSD and DSO symptoms fully mediated the association between both forms of childhood trauma and somatic problems, and that PTSD symptoms but not DSO symptoms fully mediated the association between childhood trauma and CVD load.ConclusionPsychological interventions that effectively treat CPTSD symptoms may have the added benefit of reducing risk of physical health problems

PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) ≥ 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis. Conclusions The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic

Road traffic noise and children's inattention

BACKGROUND: An increasing number of children are exposed to road traffic noise levels that may lead to adverse effects on health and daily functioning. Childhood is a period of intense growth and brain maturation, and children may therefore be especially vulnerable to road traffic noise. The objective of the present study was to examine whether road traffic noise was associated with reported inattention symptoms in children, and whether this association was mediated by sleep duration. METHODS: This study was based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Parental reports of children's inattention at age 8 were linked to modelled levels of residential road traffic noise. We investigated the association between inattention and noise exposure during pregnancy (n = 1934), noise exposure averaged over 5 years (age 3 to 8 years; n = 1384) and noise exposure at age 8 years (n = 1384), using fractional logit response models. The participants were children from Oslo, Norway. RESULTS: An association with inattention at age 8 years was found for road traffic noise exposure at age 8 years (coef = .0083, CI = [.0012, .0154]; 1.2% point increase in inattention score per 10 dB increase in noise level), road traffic noise exposure average for the last 5 years (coef = .0090, CI = [.0016, .0164]; 1.3% point increase/10 dB), and for pregnancy road traffic noise exposure for boys (coef = .0091, CI = [.0010, .0171]), but not girls (coef = -.0021, CI = [-.0094, .0053]). Criteria for doing mediation analyses were not fulfilled. CONCLUSION: Results indicate that road traffic noise has a negative impact on children's inattention. We found no mediation by sleep duration

MS

thesisAutoimmune pathologies result from an immune response against autologous antigens. In myasthenia gravis autoantibodies are directed toward acetylcholine receptors (AChR) causing a disruption in neuromuscular transmission. Although testing is available for measurement of a heterogeneous binding autoantibody population, recent evidence suggests that specific modulating and blocking antibodies correlate more closely with disease status. General AChR binding antibodies are measured with 125I-bungarotoxin (125I-aButx) and solubilized human AChR in an immunoprecipitation RIA. Specific blocking and modulating antibodies are measured with a sequential RIA using rhabdomyosarcoma (RD) cells. The anchorage dependent cells are grown in vitro, enzymatically released and used as a "free" suspension. Expression of receptor was measured as was equivalence of RD-AChR to other sources. Performance of the specific systems was evaluated. Over 100 samples submitted for binding were also tested for blocking and modulating antibody. HPLC of endocytosed 125I1Vutx and AChR binding ability was measured. Binding antibody was also measured in autoimmune thyroid receptor antibody (TRAB) sample. Approximately 2.2 x 10(6) RD cells were used per test at a ratio of 10 mL patient sera/million cells. Maximum radiolabel binding to cells was observed in approximately 4 hours with a Kd of 5.3 x 10-(10)M. Within-assay imprecision was less than 14% and 18% for blocking and modulating assays respectively. Of the 107 samples tested, 57 were negative for all three antibodies and 31 testes positive. Using the binding assay only, 32% of the population were classified positive. When specific antibody tests were included 46% were positive. Endocytosed radiolabel lost 80% of receptor binding capacity and may be altered in size TRAB samples appeared to have higher AChR-binding than controls. The AChR binding assays is not capable of measuring all relevant antoantibodies. The RD assays proved added capability. However, there remain autoantibodies not measured by any of these assays. Future studies with clinically defined samples are necessary

Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

According to the quality of response they mediate, autoreactive T cells recognizing islet β cell peptides could represent both disease effectors in the development of type 1 diabetes (T1DM) and directors of tolerance in nondiabetic individuals or those undergoing preventative immunotherapy. A combination of the rarity of these cells, inadequate technology, and poorly defined epitopes, however, has hampered examination of this paradigm. We have identified a panel of naturally processed islet epitopes by direct elution from APCs bearing HLA-DR4. Employing these epitopes in a sensitive, novel cytokine enzyme-linked immunosorbent spot assay, we show that the quality of autoreactive T cells in patients with T1DM exhibits extreme polarization toward a proinflammatory Th1 phenotype. Furthermore, we demonstrate that rather than being unresponsive, the majority of nondiabetic, HLA-matched control subjects also manifest a response against islet peptides, but one that shows extreme T regulatory cell (Treg, IL-10–secreting) bias. We conclude that development of T1DM depends on the balance of autoreactive Th1 and Treg cells, which may be open to favorable manipulation by immune intervention

Oestrogen hormone receptors in focal nodular hyperplasia

BackgroundThe role of hormones in focal nodular hyperplasia (FNH) has been investigated with conflicting results.ObjectiveThe aim of this study was to evaluate oestrogen and progesterone receptor immunohistochemical expression in FNH and surrounding normal liver (control material).MethodsBiopsy materials from FNH and control tissue were investigated using an immunostainer. Receptor expression was graded as the proportion score (percentage of nuclear staining) and oestrogen receptor intensity score.ResultsStudy material included tissue from 11 resected FNH lesions and two core biopsies in 13 patients (two male). Twelve samples showed oestrogen receptor expression. The percentage of nuclear oestrogen receptor staining was 67% in both core biopsies. The better staining in core biopsies relates to limitations of the staining technique imposed by the fibrous nature of larger resected FNH. Control samples from surrounding tissue were available for nine of the resected specimens and all showed oestrogen receptor expression. Progesterone receptor expression was negligible in FNH and control samples.ConclusionsBy contrast with previous studies, the majority of FNH and surrounding liver in this cohort demonstrated oestrogen receptor nuclear staining. The implications of this for continued oral contraceptive use in women of reproductive age with FNH remain uncertain given the lack of consistent reported growth response to oestrogen stimulation or withdrawal