A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis.

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis.

Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

Late stage cathepsin C, CXCL13 and Ki-67 overexpression correlate with regional neuropathology in a BSE transgenic murine model.

A DNA microarray-based gene expression analysis study was performed with bovine spongiform encephalopathy (BSE) transgenic mice. Several genes were found to be overexpressed including the lysosomal enzyme cathepsin C, the chemokine CXCL13 and a number of genes related to cellular proliferation. The brains from terminal stage, BSE inoculated, 'bovinized', transgenic mice were subjected to immunohistochemistry with antibodies against these two proteins and Ki-67, a cell proliferation marker, to assess the biological relevance of the gene expression changes. Differential expression of cathepsin C and CXCL13 proteins and increased expression of Ki-67 was observed. These changes were localized to areas of deposition of PrP(res) and spongiform change and to areas showing an astroglial and microglial response. These findings suggest that these proteins are involved in the mechanisms leading to the establishment of transmissible spongiform encephalopathy.

131I activity in urine to the sewer system due to thyroidal treatments.

In nuclear medicine, estimating the radioactivity contained in the urine of patients treated with I and discharged to the environment could prevent the exposure of a population to radioactive effluents and the pollution of the aquatic environment with ionizing radiation. This can be a regulatory requirement (as in Spain) or requested by the sewer authority. Seventy-nine differentiated thyroid cancer cases (undergone as inpatients) and 187 hyperthyroidism cases (undergone as outpatients) were treated in our hospital with I throughout the year 2009. In hyperthyroidism treatments, the effective elimination constant was used to calculate the corresponding discharged activity in the urine, giving an activity level always below 0.7 GBq. In differentiated thyroid cancer treatments, patient's urine was collected in storage tanks during the hospitalization. Measurements of external exposure at 1 m made every day were used to calculate the activity contained in the urine. The tank activity was always below 15 GBq, but always higher than 2 GBq. Obtained results show that effective doses to sewage workers, received from liquid discharges, can only be reduced to less than 10 µSv if storage tanks are installed. Without tanks, 157 µSv can be reached, above the constrain dose used in nuclear installations (100 µSv). Our calculations may be helpful to the regulatory authority to review the clinical radiation waste normative, especially in countries where the discharges are released directly into public sewage plants.

Biological and physical methods for risk estimation in interventional radiology: a detrimental effect approach.

Interventional radiologists and staff members are frequently exposed to the effects of direct and scattered radiation, which undergo in deterministic effects (radiodermitis, aged skin, cataracts, telangiectasia in nasal region, vasocellular epitelioms, hands depilation) and/or stochastic ones (cancer incidence). A methodology has been proposed for estimating the radiation risk or detriment from a group of six exposed interventional radiologists of the Hospital Universitario La Fe (Valencia, Spain), which had developed general exposition symptoms attributable to deterministic effects of ionizing radiation. Equivalent doses have been periodically registered using termoluminiscence dosimeters (TLD's) and wrist dosimeters, H(p)(10) and H(p)(0.07), respectively, and estimated through the observation of translocations in lymphocytes of peripheral blood (biological methods), by extrapolating the yield of translocations to their respective dose-effect curves. The software RADRISK has been applied for estimating radiation risks in these occupational radiation exposures. The minimum and maximum average excess ratio for skin cancer has been, using wrist physical doses, of [1.03 × 10(-3), 5.06 × 10(-2)], concluding that there is not an increased risk of skin cancer incidence. The minimum and maximum average excess ratio for leukemia has been, using TLD physical doses, of [7.84 × 10(-2), 3.36 × 10(-1)], and using biological doses, of [1.40 × 10(-1), 1.51], which is considerably higher than incidence rates, showing an excess radio-induced risk of leukemia in the group under study. Finally, the maximum radiological detriment in the group, evaluated as the total number of radio-induced cancers using physical dosimetry, has been of 2.18 per 1000 person-year (skin and leukemia), and using biological dosimetry of 9.20 per 1000 PY (leukemia). As a conclusion, this study has provided an assessment of the non-deterministic effects (rate of radio-induced cancer incidence) attributable to the group under study due to their professional activity.

A comprehensive study of the Gafchromic EBT2 radiochromic film. A comparison with EBT.

PURPOSE: Radiochromic film has become an important tool to assess complex dose distributions. In particular, EBT was accepted by the scientific community as a reference two-dimensional detector. Recently, Gafchromic EBT2 has replaced old film, providing new improvements in both accuracy and handling. METHODS: This work presents a dosimetric study of the new Gafchromic EBT2 using an Epson 10000XL flatbed scanner, also comparing the results with EBT film as reference when necessary. The most important film characteristics have been studied, such as ambient light sensitivity, different possibilities of the three RGB color channels, postirradiation development, high dose behavior, exposition at temperatures similar to the human body, and dependence on orientation during the scanning process. RESULTS: The results obtained confirm a considerably lower sensitivity to ambient light of EBT2, as well as a fast stabilization of the film within 2 h. It has also been found that the green channel has a better behavior at high dose levels up to 35 Gy, in addition to good behavior of the red channel at doses below 10 Gy. Other features, such as temperature independence and scanning orientation dependence, have also been shown. CONCLUSIONS: Gafchromic EBT2 can be used for clinical practice in the same way as the old EBT film. However, a much easier handling as the result of all new enhancements improves film behavior, expanding in this way the potential applications of radiochromic film dosimetry.

Radiation effects analysis in a group of interventional radiologists using biological and physical dosimetry methods.

Interventional radiologists and staff members are frequently exposed to protracted and fractionated low doses of ionizing radiation, which extend during all their professional activities. These exposures can derive, due to the effects of direct and scattered radiation, in deterministic effects (radiodermitis, aged skin, cataracts, telangiectasia in nasal region, vasocellular epitelioms, hands depilation) and/or stochastic ones (cancer incidence). A methodology has been proposed for estimating the radiation risk or detriment from a group of six exposed interventional radiologists of the Hospital Universitario La Fe (Valencia, Spain), which had developed general exposition symptoms attributable to deterministic effects of ionizing radiation. Equivalent doses have been periodically registered using TLD's and wrist dosimeters, H(p)(10) and H(p)(0.07), respectively, and estimated through the observation of translocations in lymphocytes of peripheral blood (biological methods), by extrapolating the yield of translocations to their respective dose-effect curves. The software RADRISK has been applied for estimating radiation risks in these occupational radiation exposures. This software is based on transport models from epidemiological studies of population exposed to external sources of ionizing radiation, such as Hiroshima and Nagasaki atomic bomb survivors [UNSCEAR, Sources and effects of ionizing radiation: 2006 report to the general assembly, with scientific annexes. New York: United Nations; 2006]. The minimum and maximum average excess ratio for skin cancer has been, using wrist physical doses, of [1.03x10(-3), 5.06x10(-2)], concluding that there is not an increased risk of skin cancer incidence. The minimum and maximum average excess ratio for leukemia has been, using TLD physical doses, of [7.84x10(-2), 3.36x10(-1)], and using biological doses, of [1.40x10(-1), 1.51], which is considerably higher than incidence rates, showing an excess radio-induced risk of leukemia in the group under study. Finally, the maximum radiological detriment in the group, evaluated as the total number of radio-induced cancers using physical dosimetry, has been of 2.18/1000 person-year (skin and leukemia), and using biological dosimetry of 9.20/1000 PY (leukemia). As a conclusion, this study has provided an assessment of the non-deterministic effects (rate of radio-induced cancer incidence) attributable to the group under study due to their professional activity.

Analysis of the radiological detriment for premenopausal women in a breast early detection program during 2008.

The Valencian Breast Cancer Early Detection Program (VBCEDP) started in the Valencian Community (Spain) in 1992. Up to now, 24 mammographic units have been installed all over the region. Mammography is used to aid in the diagnosis of breast cancer diseases in women. There is a health risk in the studied women due to ionising radiation that has to be estimated and controlled. A methodology to calculate approximately the radiological detriment in the VBCEDP has been developed based on Monte Carlo techniques. It has been used, as qualitative parameter, the average mean glandular dose from representative sample populations undergoing screening mammography (digital or screenfilm) from each of the twenty-four units in operation. The American College of Radiology Imaging Network reached to conclusion that digital mammography performed significantly better than film for pre and perimenopausal women younger than 50. Women who are undergoing the program are between 45 and 69. This fact allows us to study premenopausic women. Our group uses the software SCREENRISK to estimate induction and mortality rates in order to corroborate American conclusions in an European region. The obtained results confirm the American results about the application of digital mammography in pre and perimenopausal women younger than 50 years.

Analysis of CR dose reduction in pediatric patients, based on computer-simulated noise addition.

This paper validates a technique to add statistical noise to a Computed Radiography (CR) in order to simulate accurately how the same image would appear if taken at a reduced tube current. To that, a noise addition software has been developed to create lower dose CR using existing pediatric radiographies based on the selection of lower X-ray tube current. The effect of different milliAmpere-seconds (mAs) setting on image quality has been evaluated using the CDMAM 3.4 phantom and the obtained results show good agreements between the simulated and real images in terms of noise measurement. The new CR images allow medical researchers to study how lower dose affects the patient diagnosis.

Lack of PrP(sc) immunostaining in intracranial ectopic lymphoid follicles in a sheep with concomitant non-suppurative encephalitis and Nor98-like atypical scrapie: a case report.

During active surveillance for transmissible spongiform encephalopathies (TSEs) in sheep, an initial reactor was detected using a rapid test on a brain sample. Immunohistochemistry confirmed an atypical TSE presentation that closely resembled the previously described Nor98 cases. Sequencing of the prnp gene confirmed the ARQ/AHQ genotype with the L141F mutation at codon 141 associated with this phenotype. The head, including the brain and cranial lymphoid tissues, was sampled and examined thoroughly. Non-purulent encephalitis, with ectopic lymphoid follicle formation within the brain, was diagnosed concomitant to the TSE. When scrapie-associated prion protein (PrP(sc)) deposition was studied by immunohistochemistry there was a noticeable lack of lymphotropism. The distribution of PrP(sc) in the brain differed considerably from that of classical scrapie cases. Astrogliosis and microgliosis were demonstrated by histochemical procedures.

Molecular profiling and comparison of field transmissible spongiform encephalopathy cases diagnosed in Catalunya.

Molecular profiling of the proteinase K resistant prion protein (PrP(res)) is a technique that has been applied to the characterisation of transmissible spongiform encephalopathy (TSE) strains. An interesting example of the application of this technique is the ability to differentiate, at the experimental level, between bovine spongiform encephalopathy (BSE) and scrapie infection in sheep, and to distinguish between classical and atypical BSE and scrapie cases. Twenty-six BSE cases and two scrapie cases from an active TSE surveillance program and diagnosed at the PRIOCAT, TSE Reference Laboratory (Centre de Recerca en Sanitat Animal, Universitat Autònoma de Barcelona, Catalunya, Spain) were examined by Western blotting. Molecular profiling was achieved by comparing the glycosylation profile, deglycosylated PrP molecular weight and 6H4/P4 monoclonal antibody binding ratio. The results obtained during the characterisation of these field cases indicated an absence of atypical BSE cases in Catalunya.

Immunohistochemical approach to the pathogenesis of bovine spongiform encephalopathy in its early stages.

An immunohistochemical and histochemical study was carried out on the brains of nine cases of BSE-diagnosed cattle as part of the surveillance plan in Catalonia, Spain. The animals had no clinical symptoms reported and were thus at early stages of the disease. The first part of the study consisted of a characterization of PrP(BSE) deposits throughout the encephalon. The behaviour of the different immuno-labelling patterns was analysed and tropism of some patterns towards certain brain areas was described. This tropism is principally directed to the brain stem region; however, an association of the stellate pattern was found with areas where PrP(BSE) is deposited less abundantly, such as the cerebral cortex. Secondly, distinct pathogenesis mechanisms that take place in the early stages of BSE, which would include these cases were investigated. This study describes the glial response to the presence of PrP(BSE) (using antibodies against astrocytic glial fibrillary acidic protein and lectin from Griffonia simplicifolia to identify microglia), the presence of mild oxidative stress phenomena (antibodies against metallothioneins I and II and against nitrated aminoacidic residues: nitrotyrosine), the apparent absence of apoptotic cellular death (cleaved caspase 3) and the preservation of synaptic proteins synaptophysin and small synaptosome-associated 25 kDa protein immuno-labelling. Finally, no alteration of the extra-cellular matrix was detected with the use of Wisteria floribunda agglutinin, a marker for perineuronal nets.

Endoscopic release of the carpal tunnel: a randomized prospective multicenter study.

A 10-center randomized prospective multicenter study of endoscopic release of the carpal tunnel was carried out. Surgery was performed with a new device for transecting the transverse carpal ligament while control hands were treated with conventional open surgery. There were 122 patients in the study; 25 had carpal tunnel surgery on both hands and 97 had surgery on one hand. Of the surgical procedures, 65 were in the control group and 82 were in the device group. The endoscopic device was coupled to a fiberoptic light and a video camera. A trigger-activated blade was used to incise the transverse carpal ligament. After surgery, the best predictors of return to work and to activities of daily living were strength and tenderness variables. For patients in the device group with one affected hand, the median time for return to work was 21 1/2 days less than that for the control group. Two patients treated with the endoscopic device required reoperation by open surgical decompression; only one of these had incomplete release with the device. Two patients in the device group experienced transient ulnar neurapraxia.

Treatment of painful hand neuromas by their transfer into bone.

Painful neuromas in the hand are not only very disabling for the patient, but difficult to treat. We present the results of 20 painful neuromas treated by burying the neuroma in the bone. Eighteen of the 20 neuromas operated on had acceptable results, according to the criteria of Herndon et al. We present our technique and compare our results with other treatments in the literature.