Longterm survey (7 years) in a population at risk for Lyme borreliosis: what happens to the seropositive individuals?

In 1986, a 26% seroprevalence of IgG- anti-Borrelia burgdorferi antibodies was observed among 950 orienteers and the incidence of new clinical infections was 0.8%. In 1993, a total of 305 seropositive orienteers were reexamined. During that time, 15 cases (4.9%) of definite/probable Lyme disease occurred in this seropositive group (12 skin manifestations and 3 monoarticular joint manifestations). Among the 12 definite cases, 9 showed new clinical infections (7 EM, 1 acrodermatitis chronica atrophicans, 1 arthritis), and 3 were recurrent (2 EM, 1 arthritis). The annual incidence (0.8%) in this seropositive group was identical to the incidence observed among the whole population in 1986. The individual antibody titer decreased slightly but the seroreversion rate was low (7%). Serology was not very helpful in identifying clinical cases and evolutions, and it can be stated, that a positive serology is much more frequent in this risk group than clinical disease

Longitudinal study of Lyme borreliosis in a high risk population in Switzerland

Orienteers from all parts of Switzerland (n = 416) were included in a longitudinal study for Lyme borreliosis. In spring 1986, the seroprevalence was 28.1 %. At the beginning of the study, 84.3 % of orienteers reported a history of tick bite, and 3.8 % reported a past history of Lyme borreliosis. During the first (spring 1986-autumn 1986), second (autumn 1986-spring 1987) and third (spring 1987-autumn 1987) period, rates of seroconversion were 0.6 %, 2.7 % and 2.1 % respectively. During the first and second period, clinical incidence were 1.0 % and 0.25 % respectively. No active Lyme borreliosis was detected during the third period. Among orienteers who seroconverted during the study (n = 16), only two developed clinical symptoms. Hence, Borrelia burgdorferi infection is often asymptomatic

Construction and Performance of a Micro-Pattern Stereo Detector with Two Gas Electron Multipliers

The construction of a micro-pattern gas detector of dimensions 40x10 cm**2 is described. Two gas electron multiplier foils (GEM) provide the internal amplification stages. A two-layer readout structure was used, manufactured in the same technology as the GEM foils. The strips of each layer cross at an effective crossing angle of 6.7 degrees and have a 406 um pitch. The performance of the detector has been evaluated in a muon beam at CERN using a silicon telescope as reference system. The position resolutions of two orthogonal coordinates are measured to be 50 um and 1 mm, respectively. The muon detection efficiency for two-dimensional space points reaches 96%.Comment: 21 pages, 17 figure

The Prevalence and Incidence of Clinical and Asymptomatic Lyme Borreliosis in a Population at Risk

A past history of clinical Lyme borreliosis and the 6-month incidence of clinical and asymptomatic Lyme borreliosis was studied prospectively in a high-risk population. In the spring, blood samples were drawn from 950 Swiss orienteers, who also answered a questionnaire. IgG anti-Borrelia burgdorferi antibodies were detected by ELISA. Positive IgG antibodies were seen in 248 (26.1%), in contrast to 3.9%-6.0% in two groups of controls (n = 101). Of the orienteers, 1.9%-3.1% had a past history of definite or probable clinical Lyme borreliosis. Six months later a second blood sample was obtained from 755 participants, 558 (73.9%) of whom were seronegative initially; 45 (8.1%) had sero converted from negative to positive. Only 1 (2.2%) developed clinical Lyme borreliosis, Among all participants, the 6-month incidence of clinical Lyme borreliosis was 0.8% (6/755) but was much higher (8.1%) for asymptomatic seroconversion (45/558). In conclusion, positive Lyme serology was common in Swiss orienteers, but clinical disease occurred infrequentl

Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

BACKGROUND T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain RESULTS Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. CONCLUSION The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.This work was supported by grants from the NHMRC and the Juvenile Diabetes Research Foundation

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS (DISH) OF THE ELBOW: A CAUSE OF ELBOW PAIN? A CONTROLLED STUDY

Elbow pain is a common complaint and elbow hyperostosis a frequent radiological condition. However, little is known about the association between the clinical and radiological findings. To evaluate the relationship between spinal and extraspinal hyperostotic features and the clinical relevance of elbow hyperostosis we have performed the first controlled, double-blinded study of 85 hospitalized probands, 33 with and 52 without thoracospinal hyperostosis on lateral chest X-ray. Elbow and shoulder hyperostosis were graded on bilateral standard radiographs. Elbow pain was assessed by an interviewer using a standardized questionnaire and extraskeletal causes of elbow pain were recorded. The prevalence of elbow hyperostosis was increased in cases with thoracospinal hyperostosis compared to controls (82% versus 58%, X2 = 5.32, P<0.025, n = 85, odds ratio (OR) 3.30 (95% Cl 1.16-9.35)). Similarly, the prevalence of elbow hyperostosis was increased in cases with shoulder hyperostosis compared to controls (83% versus 60%, x2 = 4.51, P<0.05, n = 84, OR = 3.20 (95% CI 1.06-9.66)), emphasizing the multifocal nature of hyperostotic features. Elbow pain was only slightly more prevalent in cases with elbow hyperostosis compared to controls (21% versus l3%, x2 = 0.75, NS, OR = 1.84 (95% CI 0.46-7.44)). We conclude that elbow hyperostosis is a radiological finding of doubtful clinical relevanc

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy

Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to beta-particle emitter Lutetium-177 labeled somatostatin analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of H2AX-foci formation and its downstream effects. To determine relative biological effectiveness (RBE) between the two isotopes somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks were quantified after immunofluorescence staining of H2AX. Cell cycle was analyzed by flow cytometry. In vivo, uptake of both radiolabeled somatostatin-analogues into subcutaneous AR42J tumors and number of cells displaying H2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities translated from in vitro cytotoxicity. Ac-225-DOTATOC was synthesized with specific activities between 0.2-0.4 MBq/µg and radiochemical purity of > 90%. ED50 values were 30 kBq/ml after 24 h and 14 kBq/ml after 48 h. Lu-177-DOTATOC displayed radiochemical purity of >95% and ED50 values of 10 MBq/ml after 48 h. Number of DNA double strand breaks increased with increasing concentration of Ac 225 DOTATOC and Lu-177-DOTATOC similarly, if a factor of approximately 700 of Lu-177 activities over Ac-225 activities was applied. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical with 7.5 %ID/g, though overall number of cells with H2AX-foci was higher for tumors treated with 48 kBq Actinium-225-DOTATOC than tumors treated with 30 MBq Lutetium-177-DOTATOC (35% vs. 21%). Tumors with a mean volume of 0.34 ml reached exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC), after 21 days (34 MBq Lu-177-DOTATOC) and after 5 days (control). Thus H2AX-foci displayed the key parameter after irradiation with similar downstream effects for beta and alpha irradiation.JRC.E.5-Nuclear chemistr

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O 6 -methylguanine in vivo

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. N-nitroso compounds are alkylating agents, which are widespread in our diet and the environment. They induce DNA alkylation adducts such as O 6 -methylguanine (O 6 -MeG), which is repaired by O 6 -methylguanine-DNA methyltransferase (MGMT). Persistent O 6 -MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O 6 -MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to monitor O 6 -MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adduct-specific antibody, allowed for the semi-quantitative, dose-dependent assessment of O 6 -MeG in CRC cells. Using the highly sensitive and specific UPLC–MS/MS, TMZ-induced O 6 -MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O 6 -MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC–MS/MS measurements and dose–response modeling revealed a non-linear formation of hepatic and colonic O 6 -MeG adducts in WT, whereas linear O 6 -MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC–MS/MS analysis is highly sensitive and specific for O 6 -MeG, thereby allowing for the first time for the determination of a genotoxic threshold upon exposure to O 6 -methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures