Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE-and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.
Background Appropriate three-dimensional imaging of the hip joint is a substantial prerequisite for planning and performing surgical correction of deformities. Although surgeons still use computed tomography (CT), modern and fast acquisition techniques of volumetric imaging using magnetic resonance imaging (MRI) for pelvic measurements enable similar resolution. Purpose This study was designed to determine if already described measures of acetabular morphology are comparable in both techniques and if assessment can be performed with equal intra-observer and inter-observer reliability. Material and Methods Thirty-two hips (16 patients) were examined with a pelvic CT and a MRI with 3-T. Pelvic orientation was standardized by each observer in coronal, axial, and sagittal planes. Acetabular version as well as seven acetabular sector angles were measured by two observers twice with a minimum of four weeks between sessions. Results Inter-rater reliability showed excellent results for intra- and inter-rater reliability for CT (0.977-0.999) and MRI (0.969-0.998) measuring acetabular version and sector angles. Evaluating the reliability of CT and MRI for each observer revealed excellent results (0.972-0.998). Evaluating the Bland-Altman plots for intra-observer reliability showed an equal distribution of angles, within acceptable 95% limits of agreement. The same results were observed for inter-observer reliability evaluating CT and MRI as well as inter-method reliability. Conclusion Modern MRI scans are equally applicable to assess the bony pelvis as CT scans. In addition, MRI would enable the examination of soft tissues such as chondrolabral structures and muscle in the same examination. Since hip-preserving surgery is mostly conducted in younger patients, the reduction of radiation exposure is a benefit.
Background Pancreatic cancer is a devastating disease with a 5-year survival rate of 20–25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [ 18 F]2-fluoro-2-deoxy- d -glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy. Methods Patients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen. Results A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUV max ) during therapy ( p < 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7–38 months). Conclusion Based on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results. Electronic supplementary material The online version of this article (10.1007/s00066-020-01654-4) contains supplementary material, which is available to authorized users.
Background Periacetabular osteotomy is a successful treatment for hip dysplasia. The results are influenced, however, by optimal positioning of the acetabular fragment, femoral head morphology and maybe even femoral version as well as combined anteversion have an impact. In order to obtain better insight on fragment placement, postoperative acetabular orientation and femoral morphology were evaluated in a midterm follow-up in regard to functional outcome and osteoarthritis progression. Methods A follow-up examination with 49 prospectively documented patients (66 hips) after periacetabular osteotomy (PAO) was performed after 62.2 ± 18.6 months. Mean age of patients undergoing surgery was 26.7 ± 9.6 years, 40 (82%) of these patients were female. All patients were evaluated with an a.p. pelvic x-ray and an isotropic MRI in order to assess acetabular version, femoral head cover, alpha angle, femoral torsion and combined anteversion. The acetabular version was measured at the femoral head center as well as 0.5 cm below and 0.5 and 1 cm above the femoral head center and in addition seven modified acetabular sector angles were determined. Femoral torsion was assessed in an oblique view of the femoral neck. The combined acetabular and femoral version was calculated as well. To evaluate the clinical outcome the pre- and postoperative WOMAC score as well as postoperative Oxford Hip Score and Global Treatment Outcome were analyzed. Results After PAO acetabular version at the femoral head center (31.4 ± 9.6°) was increased, the anterior cover at the 15 o’clock position (34.7 ± 15.4°) was reduced and both correlated significantly with progression of osteoarthritis, although not with the functional outcome. Combined acetabular and femoral torsion had no influence on the progression of osteoarthritis or outcome scores. Conclusion Long-term results after PAO are dependent on good positioning of the acetabular fragment in all 3 planes. Next to a good lateral coverage a balanced horizontal alignment without iatrogenic pincer impingement due to acetabular retroversion, or insufficient coverage of the anterior femoral head is important.
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