Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation

Abstract Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life –sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array

Assessment of the capacity to consent to treatment in patients admitted to acute medical wards

BACKGROUND: Assessment of capacity to consent to treatment is an important legal and ethical issue in daily medical practice. In this study we carefully evaluated the capacity to consent to treatment in patients admitted to an acute medical ward using an assessment by members of the medical team, the specific Silberfeld's score, the MMSE and an assessment by a senior psychiatrist. METHODS: Over a 3 month period, 195 consecutive patients of an internal medicine ward in a university hospital were included and their capacity to consent was evaluated within 72 hours of admission. RESULTS: Among the 195 patients, 38 were incapable of consenting to treatment (unconscious patients or severe cognitive impairment) and 14 were considered as incapable of consenting by the psychiatrist (prevalence of incapacity to consent of 26.7%). Agreement between the psychiatrist's evaluation and the Silberfeld questionnaire was poor (sensitivity 35.7%, specificity 91.6%). Experienced clinicians showed a higher agreement (sensitivity 57.1%, specificity 96.5%). A decision shared by residents, chief residents and nurses was the best predictor for agreement with the psychiatric assessment (sensitivity 78.6%, specificity 94.3%). CONCLUSION: Prevalence of incapacity to consent to treatment in patients admitted to an acute internal medicine ward is high. While the standardized Silberfeld questionnaire and the MMSE are not appropriate for the evaluation of the capacity to consent in this setting, an assessment by the multidisciplinary medical team concurs with the evaluation by a senior psychiatrist

In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography

Development of hypoxia-targeted therapies has stimulated the search for clinically applicable noninvasive markers of tumour hypoxia. Here, we describe the validation of [18F]fluoroetanidazole ([18F]FETA) as a tumour hypoxia marker by positron emission tomography (PET). Cellular transport and retention of [18F]FETA were determined in vitro under air vs nitrogen. Biodistribution and metabolism of the radiotracer were determined in mice bearing MCF-7, RIF-1, EMT6, HT1080/26.6, and HT1080/1-3C xenografts. Dynamic PET imaging was performed on a dedicated small animal scanner. [18F]FETA, with an octanol–water partition coefficient of 0.16±0.01, was selectively retained by RIF-1 cells under hypoxia compared to air (3.4- to 4.3-fold at 60–120 min). The radiotracer was stable in the plasma and distributed well to all the tissues studied. The 60-min tumour/muscle ratios positively correlated with the percentage of pO2 values <5 mmHg (r=0.805, P=0.027) and carbogen breathing decreased [18F]FETA-derived radioactivity levels (P=0.028). In contrast, nitroreductase activity did not influence accumulation. Tumours were sufficiently visualised by PET imaging within 30–60 min. Higher fractional retention of [18F]FETA in HT1080/1-3C vs HT1080/26.6 tumours determined by dynamic PET imaging (P=0.05) reflected higher percentage of pO2 values <1 mmHg (P=0.023), lower vessel density (P=0.026), and higher radiobiological hypoxic fraction (P=0.008) of the HT1080/1-3C tumours. In conclusion, [18F]FETA shows hypoxia-dependent tumour retention and is, thus, a promising PET marker that warrants clinical evaluation

Effects of secretory products of breast cancer cells on osteoblast-like cells

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Hemorragia maciça do intestino grosso: o que está ao nosso alcance? Massive large bowel bleeding: what is within our reach?

A forma de avaliar e lidar com a hemorragia aguda digestiva baixa tem sido modificado com os recentes desenvolvimentos de novas técnicas e aparelhos. O nosso objetivo, por esse manuscrito, é demonstrar com simplicidade uma forma de condução dos pacientes com hemorragia digestiva baixa aguda, sobretudo para os sangramentos que parecem mais graves, principalmente quando nos faltam os recursos das avançadas tecnologias atuais. Doenças localizadas no intestino grosso respondem por ¼ dos casos de hemorragias digestivas que são motivos para admissão hospitalar e têm como principais agentes etiológicos os divertículos, na moléstia diverticular, e as alterações vasculares, nas angiodisplasias. Na grande maioria das vezes o sangramento que pode parecer abundante cessa espontaneamente. Os distúrbios circulatórios graves não são comuns e os sinais mais frequentes são a queda do valor da hemoglobina observada na metade dos pacientes, e algumas alterações hemodinâmicas como a variação pressórica postural que pode ser vista em até 30% dos casos; a síncope em 10% e alguma forma de colapso circulatório, em 9%. Contudo, a faixa etária em que ocorre, as condições da senilidade, as doenças eventualmente associadas e a falta de recursos materiais e humanos para lidar com esse tipo de problema são os motivos que mais causam preocupação. A abordagem clínica simples com uma história bem elaborada; o exame físico com atenção e objetividade, a inclusão do exame proctológico, a obrigatória disponibilidade de aparelho para a coloscopia e os conhecimentos básicos sobre o evento formam o conjunto necessário e, na maioria das vezes, suficiente para o correto desempenho profissional na elaboração dos cuidados que devem ser dados a esses pacientes.<br>The evaluation and management of the acute lower digestive hemorrhage has been modified with the recent development of new techniques and devices. The aim of this manuscript was to demonstrate with simplicity how to treat the patients with acute lower intestinal hemorrhage. Diseases of the large bowel account for the ¼ of the cases of digestive hemorrhages on the hospital admission and have as main etiological agents the diverticula, in the diverticular disease, and small vascular malformation, in the angiodysplasias. Sometime, it can be seen as a life-threatening condition, however, most of the times, the hemorrhage stops spontaneously. The serious circulatory disturbances are not common; the most frequent signs are the decrease in hemoglobin occurring on about one half of patients and some form of circulatory disturbance as orthostatic changes in 30%; as syncope in 10% and as cardiovascular collapse in 9%. However, the age group, the conditions of the senility, the eventually associated diseases and the lack of material and human resources to handle with that kind of problem are the reasons for concern. The simple clinical approach with a well elaborated history; the physical examination released with attention and objectivity, the inclusion of the proctologic exam, the obligatory readiness for an endoscope for colonoscopy, the basic knowledge on the event are necessary and, in most of the times, enough for the good professional acting in the elaboration of the cares that it should be given to those patient ones