Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation.

DNA-protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such as replication, which is counteracted through proteolysis-mediated DPC removal by spartan (SPRTN) or the proteasome. However, whether DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here we show that DPCs severely impede RNA polymerase II-mediated transcription and are preferentially repaired in active genes by transcription-coupled DPC (TC-DPC) repair. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymerase II. CSA and CSB are indispensable for TC-DPC repair; however, the downstream TC-NER factors UVSSA and XPA are not, a result indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription.

Genome-wide RNA polymerase stalling shapes the transcriptome during aging.

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.

Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3.

Metastasis remains the leading cause of cancer mortality, and reactive oxygen species (ROS) signaling promotes the metastatic cascade. However, the molecular pathways that control ROS signaling relevant to metastasis are little studied. Here, we identify SIRT3, a mitochondrial deacetylase, as a regulator of cell migration via its control of ROS signaling. We find that, although mitochondria are present at the leading edge of migrating cells, SIRT3 expression is down-regulated during migration, resulting in elevated ROS levels. This SIRT3-mediated control of ROS represses Src oxidation and attenuates focal adhesion kinase (FAK) activation. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Finally, in human breast cancers, SIRT3 expression is inversely correlated with metastatic outcome and Src/FAK signaling. Our results reveal a role for SIRT3 in cell migration, with important implications for breast cancer progression.

Longitudinal training and assessing consultation competence, a role for self reflection on performance.

Medical consultation (patient-doctor encounter), consisting of history taking, physical examination and treatment, is the starting point of any contact between doctor and patient. Learning to conduct a consultation is a complex skill. Both communicative and medical contents need to be applied and integrated. Conducting an adequate consultation is a skill which is gradually learned and perfected during training and career. This article discusses the background and implementation of a longitudinal integrated consultation training programme in clerkships. In the programme, the student's reflection on the consultation plays an important role in education and assessment.

A minimally invasive vertebral hemangioma.

We describe a very unusual vertebral hemangioma presenting with a mixture of aggressive-like pattern (epidural extension, T1 hyposignal) and quiescent, inactive lesion (fatty infiltration), in association with a spiculated calcified epidural component.This paper emphasizes that CT and/or MR findings are accurate enough to make formal assessment of vertebral hemangioma, preventing patient's anguish and moreover unnecessary treatment. Furthermore this attractive case proposes a poorly known characteristic of vertebral hemangioma which is usually encountered and described only in skull hemangiomas.

Practice variability in the management of infrarenal arterial stenoses in seven Belgian hospitals.

This multicentre retrospective study describes the variation of therapeutic options, treatment outcomes and costs for treating infrarenal arterial stenoses as observed in daily practice in 1997-99 in seven Belgian hospitals. Data were obtained from clinical record review and from the sickness fund claims database, and included preoperative functional state, presence of acute ischaemia, diabetes and polyvascular disease, state of the lower-leg run-off arteries, anatomical site and type of lesion, type of treatment, result at 30 days and up to 4 years. A total of 442 episodes were studied, but most analyses dealt with a subgroup of 240 lesions in the common iliac up to the superficial femoral artery. The proportion of surgical treatments (as compared to an endovascular or mixed approach) varied from 15% to 81% between the hospitals. In univariate survival analysis, relapse or failure rates at 4 years ranged from 5% for the common iliac artery to 35% for the superficial femoral artery. Polyvascular disease, a poor run-off, multiple stenoses and chronic occlusion were significant risk factors; age and diabetes were not. In the multivariate (stratified Cox regression) analysis, only a location in the superficial femoral artery and a poor preoperative clinical stage were significant risk factors, but type of therapeutic approach was not. The total average cost of treatment was 5300 Euro, of which 15% was contributed by the patient. Surgery was associated with longer stays (median at 12 days) than endovascular treatments (median 2 d), and was 1.9 times more expensive. In conclusion, the results of the present study suggest that a multidisciplinary approach, orienting the patient to the most appropriate therapeutic pathway could increase both the quality and the cost-effectiveness of the care. In many clinical situations, the endovascular approach appears to offer similar long-term results as surgery, but at a substantially lower cost, both for the patient and for society, especially when performed in a (semi-)ambulatory radiology setting.

Practice variability in the management of subrenal arterial stenoses in seven Belgian hospitals.

This multicentre retrospective study describes the variation of therapeutic options, treatment outcomes and costs for treating subrenal arterial stenoses as observed in daily practice in 1997-99 in seven Belgian hospitals. Data were obtained from clinical record review and from the sickness fund claims database, and included preoperative functional state, presence of acute ischaemia, diabetes and polyvascular disease, state of the lower-leg run-off arteries, anatomical site and type of lesion, type of treatment, result at 30 days and up to 4 years. A total of 442 episodes were studied, but most analyses dealt with a subgroup of 240 lesions in the common iliac up to the superficial femoral artery. The proportion of surgical treatments (as compared to an endovascular or mixed approach) varied from 15% to 81% between the hospitals. In univariate patency analysis, relapse or failure rates at 4 years ranged from 5% for the common iliac artery to 35% for the superficial femoral artery. Polyvascular disease, a poor run-off, multiple stenoses and chronic occlusion were significant risk factors; age and diabetes were not. In the multivariate (stratified Cox regression) analysis, only a location in the superficial femoral artery and a poor preoperative clinical stage were significant risk factors, but type of therapeutic approach was not. The total average cost of treatment was 5,300 Euros, of which 15% was contributed by the patient. Surgery was associated with longer stays (median at 12 days) than endovascular treatments (median 2 days), and was 1.9 times more expensive. In conclusion, the results of the present study suggest that a multidisciplinary approach, orienting the patient to the most appropriate therapeutic pathway, could increase both the quality and the cost-effectiveness of the care.

Acute renal failure requiring haemodialysis after high doses percutaneous acetic acid injection for hepatocellular carcinoma.

Recently, ultrasound-guided percutaneous acetic acid injection has been proposed in the treatment of hepatocellular carcinoma as an alternative to percutaneous ethanol injection. We report the case of severe renal failure requiring haemodialysis which occurred in a patient with 4 cm hepatocellular carcinoma treated adequately by high dose percutaneous acetic acid injection. The risk of such a serious side effect, likely related to a direct toxic effect of acetic acid, should be of concern when considering percutaneous treatment of hepatocellular carcinoma. Acute renal failure has been reported as a complication of acetic acid poisoning, but to our knowledge, we report here the first case of acute renal failure following high dose percutaneous acetic acid injection.

[Late diagnosis of a traumatic pseudo-aneurysm of the subclavian artery]. / Diagnostic tardif d'un pseudoanévrysme traumatique de l'artère sous-clavière.

The authors report a rare case of subclavian pseudoaneurysm diagnosed six months after a left clavicular fracture. The leading symptoms were pain and claudication in the left arm related to peripheral embolization. The essential diagnosis was made by selective arteriography followed by arterio-CT. Peripheral embolization or brachial nerve compression are the most common presentations of subclavian pseudoaneurysms. To avoid such late complications, the authors emphasize the importance of the initial vascular examination of the shoulder after blunt trauma with or without clavicular fracture. Surgery is imperative and the use of autologous vein graft is the method of choice.

[2 cases of giant aneurysm of the splenic artery: contribution of Doppler echography]. / Deux cas d'anévrisme géant de l'artère splénique: apports de l'écho-Doppler.

Excluding the extremely uncommon cases of completely thrombosed aneurysm, color Doppler US plays a leading part in establishing the diagnosis of splenic artery aneurysm. The color Doppler US patterns are typical, as illustrated in the two reported cases of splenic artery aneurysm larger than 5.0 cm.

[Infected urachal cyst]. / Kyste de l'ouraque surinfecté.

There is a wide variety of pathologies associated with the presence of urachal remnants. We describe a case of infected urachal cyst in a young adult male, with classical symptoms of dysuria, lower abdominal pain, and fever. Ultrasound, cystography and CT are described, ultrasound being often the modality of choice. Differential diagnosis of acute abdominal and pelvic pain or a midline lower abdominal mass at this age should include infection of an urachal remnant.

[Adventitial cyst of the common femoral artery: computerized tomography demonstration of the articular origin of this disorder]. / Le kyste adventiciel de l'artère fémorale commune: démonstration tomodensitométrique de l'origine articulaire de cette pathologie.

Cystic adventitial disease is very rarely described in the common femoral artery, the usual location being the popliteal artery. CT in this patient shows the extension of an enlarged bursa of the psoas muscle reaching the cyst in the arterial wall.

[Wegener's granulomatosis: breast localization]. / Granulomatose de Wegener: localisation mammaire.

The case of a 37-year-old patient with a history of Wegener's granulomatosis presenting with a right painless breast mass is reported. Breast mammography and sonography were poorly contributive and the inflammatory nature of the lesion was established by fine needle biopsy.

[Endobronchial lipoma: a potential CT diagnosis]. / Lipome endobronchique: diagnostic TDM possible.

Bronchial lipomas are rare and benign neoplasms. Computed tomography can provide a powerful adjunct to conventional modalities in determining the nature of an endobronchial lesion. The reflex vasoconstriction can also be nicely depicted.