DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

“Medically unexplained” symptoms and symptom disorders in primary care: prognosis-based recognition and classification

Background: Many patients consult their GP because they experience bodily symptoms. In a substantial proportion of cases, the clinical picture does not meet the existing diagnostic criteria for diseases or disorders. This may be because symptoms are recent and evolving or because symptoms are persistent but, either by their character or the negative results of clinical investigation cannot be attributed to disease: so-called “medically unexplained symptoms” (MUS). MUS are inconsistently recognised, diagnosed and managed in primary care. The specialist classification systems for MUS pose several problems in a primary care setting. The systems generally require great certainty about presence or absence of physical disease, they tend to be mind-body dualistic, and they view symptoms from a narrow specialty determined perspective. We need a new classification of MUS in primary care; a classification that better supports clinical decision-making, creates clearer communication and provides scientific underpinning of research to ensure effective interventions. Discussion: We propose a classification of symptoms that places greater emphasis on prognostic factors. Prognosis-based classification aims to categorise the patient’s risk of ongoing symptoms, complications, increased healthcare use or disability because of the symptoms. Current evidence suggests several factors which may be used: symptom characteristics such as: number, multi-system pattern, frequency, severity. Other factors are: concurrent mental disorders, psychological features and demographic data. We discuss how these characteristics may be used to classify symptoms into three groups: self-limiting symptoms, recurrent and persistent symptoms, and symptom disorders. The middle group is especially relevant in primary care; as these patients generally have reduced quality of life but often go unrecognised and are at risk of iatrogenic harm. The presented characteristics do not contain immediately obvious cut-points, and the assessment of prognosis depends on a combination of several factors. Conclusion: Three criteria (multiple symptoms, multiple systems, multiple times) may support the classification into good, intermediate and poor prognosis when dealing with symptoms in primary care. The proposed new classification specifically targets the patient population in primary care and may provide a rational framework for decision-making in clinical practice and for epidemiologic and clinical research of symptoms

Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force

BackgroundNeuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma.MethodsThe International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force.ResultsGuidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation.ConclusionsMetaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy

Surface runoff and accelerated erosion in a peri‑urban wellhead area in southeastern Brazil

Degradation of hydrological conditions can adversely impact water resource quality and quantity. This degradation can generate social and economic losses, including losses for users outside the basin area. Therefore, studies focusing on surface runof and accelerated erosion processes are needed to enable interventions that address degradation-induced challenges. In the present study, the surface runof and accelerated erosion potential of the Feijão River basin were presented in charts at a 1:50,000 scale. The Feijão River basin has an area of 243.16 km2 and is used as the main water source for the city of São Carlos, Brazil. Geoenvironmental attributes, such as substrate, climate, relief, soil, water bodies and land cover and use, were integrated and assessed in a GIS environment, using a multicriteria analysis and weighted sum tool. The results show that a large part of the area (86.12% of the basin) exhibits a low surface runof potential and a moderate accelerated erosion potential. Accelerated erosive processes are triggered by changes in soil cover and have a direct relationship with the removal of existing vegetation and implementation of anthropogenic activities. In this case, as well as for most of the areas in southeastern Brazil, extensive grazing followed by sugar cane cultivation was the main driving force of erosion, acting as trigger for accelerated erosive processes at the water source area

Low-energy control of electrical turbulence in the heart

abstract: ©2011 Macmillan Publishers Limited. All rights reserve

The impact of frailty on ICU and 30-day mortality and the level of care in very elderly patients (≥ 80 years).

PURPOSE: Very old critical ill patients are a rapid expanding group in the ICU. Indications for admission, triage criteria and level of care are frequently discussed for such patients. However, most relevant outcome studies in this group frequently find an increased mortality and a reduced quality of life in survivors. The main objective was to study the impact of frailty compared with other variables with regards to short-term outcome in the very old ICU population. METHODS: A transnational prospective cohort study from October 2016 to May 2017 with 30 days follow-up was set up by the European Society of Intensive Care Medicine. In total 311 ICUs from 21 European countries participated. The ICUs included the first consecutive 20 very old (≥ 80 years) patients admitted to the ICU within a 3-month inclusion period. Frailty, SOFA score and therapeutic procedures were registered, in addition to limitations of care. For measurement of frailty the Clinical Frailty Scale was used at ICU admission. The main outcomes were ICU and 30-day mortality and survival at 30 days. RESULTS: A total of 5021 patients with a median age of 84 years (IQR 81-86 years) were included in the final analysis, 2404 (47.9%) were women. Admission was classified as acute in 4215 (83.9%) of the patients. Overall ICU and 30-day mortality rates were 22.1% and 32.6%. During ICU stay 23.8% of the patients did not receive specific ICU procedures: ventilation, vasoactive drugs or renal replacement therapy. Frailty (values ≥ 5) was found in 43.1% and was independently related to 30-day survival (HR 1.54; 95% CI 1.38-1.73) for frail versus non-frail. CONCLUSIONS: Among very old patients (≥ 80 years) admitted to the ICU, the consecutive classes in Clinical Frailty Scale were inversely associated with short-term survival. The scale had a very low number of missing data. These findings provide support to add frailty to the clinical assessment in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03134807).This study was endorsed by the ESICM. Free support for running the electronic database and eCRF was granted from the Department of Epidemiology, University of Aarhus, Denmark