Assessment of disease activity in rheumatoid arthritis with (18)F-FDG PET.

The aim of this study was to assess synovitis by (18)F-FDG PET in an individual joint analysis and in a global analysis of rheumatoid arthritis (RA) disease activity and to compare (18)F-FDG PET parameters with clinical, biologic, and sonographic (US) rheumatoid parameters. METHODS: Three hundred fifty-six joints were assessed in 21 patients with active RA: the knees in all subjects and either wrists as well as metacarpophalangeal and proximal interphalangeal joints in 13 patients, or ankles and the first metatarsophalangeal joints in the remaining 8 patients. PET analysis consisted of a visual identification of (18)F-FDG uptake in the synovium and measurements of standardized uptake values (SUVs). Independent assessors performed the clinical and US examinations. RESULTS: PET positivity was found in 63% of joints, whereas 75%, 79%, and 56% were positive for swelling, tenderness, and US analysis, respectively. Both the rate of PET-positive joints and the SUV increased with the number of positive parameters present (swelling, tenderness, US positivity) and with the synovial thickness. The mean SUV was significantly higher in joints where a power Doppler signal was found. In a global PET analysis, the number of PET-positive joints and the cumulative SUV were significantly correlated with the swollen and tender joint counts, the patient and physician global assessments, the erythrocyte sedimentation rate and C-reactive protein serum levels, the disease activity score and the simplified disease activity index, the number of US-positive joints, and the cumulative synovial thickness. CONCLUSION: (18)F-FDG PET is a unique imaging technique that can assess the metabolic activity of synovitis and measure the disease activity in RA.     

Analysis of SAA1 gene polymorphisms in the Greek population: rheumatoid arthritis and FMF patients relative to normal controls. Homogeneous distribution and low incidence of AA amyloidosis.

OBJECTIVE: To address whether or not the rarity of amyloidosis in Greek patients with rheumatoid arthritis (RA) is related to specific alleles of single nucleotide polymorphisms (SNPs) in the 5'-flanking region and the exon 3 of the SSA1 gene. METHODS: The genotypes of the -13T/C SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 88 Greek patients with RA, 14 patients with familial Mediterranean fever (FMF) and 110 healthy controls. Linkage disequilibrium and haplotype frequencies involving -13T/C, 2995C/T and 3010C/T in these populations were tested and estimated, respectively. RESULTS: The genotypic distribution and allelic frequencies were similar in all groups tested. SNPs 2995 and 3010 were in linkage disequilibrium for all study populations (p < 0.05), whereas SNP -13 was not in linkage disequilibrium with either 2995 or 3010 (p > or = 0.05). Two major haplotypes presented in all patients with RA and FMF and controls: -13C; 2995T; 3010C (-13C; alpha) and -13C; 2995C; 3010T (-13C; beta). The -13T allele was linked with the gamma haplotype in Greek patients with RA and controls. The frequency of the -13T allele was found to be very rare in all groups tested. CONCLUSIONS: In conclusion, the rarity of the putative amyloidogenic -13T allele in Greek populations may be related to low prevalence of AA amyloidosis development in Greek RA patients.     

Tolerance in TCR/Cognate Antigen Double-Transgenic Mice Mediated by Incomplete Thymic Deletion and Peripheral Receptor Downregulation

Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed with transgenic mice expressing the cognate antigenic protein under the control of the H- 2K^b promoter. Double-transgenic mice show negative selection of thymocytes at the CD4⁺8⁺TCR¹⁰ to CD4⁺8⁺TCR^hi transition stage. A few CD8 T cells, however, escape clonal deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can develop low but detectable levels of antigen-specific cytotoxic function after stimulation in vitro in the presence of IL-2.     

Thymic selection and peptide-induced activation of T cell receptor-transgenic CD8 T cells in interleukin-2-deficient mice

The requirement for interleukin-2 (IL-2) in repertoire selection and peripheral activation of CD8 T cells was tested in mice rendered IL-2 deficient by gene targeting and expressing a transgenic T cell receptor (TcR) (F5) specific for influenza nucleoprotein (NP) 366-374 + H-2D^b. Positive selection of the transgenic F5 TcR into the CD8 compartment proceeded normally. Both in vivo and in vitro, the antigenic peptide induced depletion of immature thymocytes and proliferation of mature CD8 T cells regardless of the presence of an intact IL-2 gene. In contrast, cytotoxic T lymphocyte (CTL) activity was only generated by T cells from IL-2⁺ F5 transgenic mice. Exogenous IL-2 was able to fully restore the CTL response of IL-2^?/? responder cells in vitro. Thus, both in vivo and in vitro, clonal expansion of CD8 T cells can proceed in the absence of IL-2, whereas in peptide-immunized F5 transgenic mice, induction of cytotoxic effector function is IL-2 dependent.     

In vitro negative selection of αβ T cell receptor transgenic thymocytes by conditionally immortalized thymic cortical epithelial cell lines and dendritic cells

We have established conditionally immortalized thymic cortical epithelial cell lines from transgenic mice carrying a temperature-sensitive SV40 large Tantigen. One of these cell lines expresses cortical markers and produces IL-1α, IL-6, IL-7, and TGF-β1. These cells express class I major histocompatibility complex (MHC) constitutively and class II MHC upon induction with IFN-μ. The cells appear to have a normal class I antigen presenting pathway since messages for both peptide transporter genes (TAP1, TAP2) were detected. The ability of these cortical epithelial cells to present peptide antigen was compared to that of thymic dendritic cells. In suspension culture with αβ Tcell receptor (TcR) transgenic thymocytes, these epithelial cells and dendritic cells (pre-pulsed with peptide cognate for the transgenic TcR) caused down-regulation of CD4, CD8, and TcR in an antigen dose-dependent and MHC-restricted manner. CD4^dullCD8^dull cells were taken as evidence for negative selection because these cells contained apoptotic DNA. Concentration of peptide required for negative selection of thymocytes was similar between dendritic cells and cortical epithelial cells. In contrast, αβ transgenic spleen cells were activated only by dendritic cells but not by cortical epithelial cells.     

Preventable fatal injury during rally race: a multidisciplinary approach

International Journal of Legal Medicine - The motor vehicle crash (MVC) constitutes an important challenge for forensic pathology in order to identify the manner and cause of death. Our study...     

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (p_homogeneity = 0.42). This risk increased linearly with duration of use (p_trend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (p_homogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.     

Ag Surface and Bulk Segregations in Sputtered ZrCuAlNi Metallic Glass Thin Films

We report on the formation of Ag-containing ZrCuAlNi thin film metallic glass (nano)composites by a hybrid direct-current magnetron sputtering and high-power pulsed magnetron sputtering process. The effects of Ag content, substrate temperature and substrate bias potential on the phase formation and morphology of the nanocomposites were investigated. While applying a substrate bias potential did not strongly affect the morphological evolution of the films, the Ag content dictated the size and distribution of Ag surface segregations. The films deposited at low temperatures were characterized by strong surface segregations, formed by coalescence and Ostwald ripening, while the volume of the films remained featureless. At higher deposition temperature, elongated Ag segregations were observed in the bulk and a continuous Ag layer was formed at the surface as a result of thermally enhanced surface diffusion. While microstructural observations have allowed identifying both surface and bulk segregations, an indirect method for detecting the presence of Ag segregations is proposed, by measuring the electrical resistivity of the films.     

Results of the first international round robin for the quantification of urinary and plasma hepcidin assays: need for standardization

The recently discovered iron regulatory peptide hormone hepcidin holds promise as a novel biomarker in iron metabolism disorders. To date, various mass spectrometry and immunochemical methods have been developed for its quantification in plasma and urine. Differences in methodology and analytical performance hinder the comparability of data. As a first step towards method harmonization, several hepcidin assays were compared. Worldwide eight laboratories participated in a urinary and plasma round robin in which hepcidin was analyzed. For both urine and plasma: (i) the absolute hepcidin concentrations differed widely between methods, (ii) the between-sample variation and the analytical variation of the methods are similar. Importantly, the analytical variation as percentage of the total variance is low for all methods, indicating their suitability to distinguish hepcidin levels of different samples. Spearman correlations between methods were generally high. The round robin results inform the scientific and medical community on the status and agreement of the current hepcidin methods. Ongoing initiatives should facilitate standardization by exchanging calibrators and representative samples.     

Is polydipsia sometimes the cause of oxcarbazepine-induced hyponatremia?

Hyponatremia is a commonly encountered clinical problem with potentially severe complications. Among the underlying implicated etiologies are medications such as oxcarbazepine, which has been well documented and attributed to the syndrome of inappropriate antidiuretic hormones (SIADH). We report the case of a 28-year-old woman with a diagnosis of secondary antiphospholipid syndrome who presented with asymptomatic hyponatremia secondary to excessive water intake after oxcarbazepine ingestion, suggesting a new mechanism for oxcarbazepine-induced hyponatremia.