Stochastic Modeling of Expression Kinetics Identifies Messenger Half-Lives and Reveals Sequential Waves of Co-ordinated Transcription and Decay

The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli. Citation: Cacace F, Paci P, Cusimano V, Germani A, Farina L (2012) Stochastic Modeling of Expression Kinetics Identifies Messenger Half-Lives and Reveals Sequential Waves of Co-ordinated Transcription and Decay. PLoS Comput Biol 8(11): e1002772. doi:10.1371/journal.pcbi.100277

Mortalidad y causas de muerte en pacientes con lupus eritematoso sistémico

Introduction: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by chronic systemic inflammation. Causes of death in SLE have a bimodal pattern: during the first 5 years, infections and disease activity prevail, whereas beyond 5 years cardiovascular complications and accumulated organ damage are the main causes. Objective: To determine causes of death in adult patients diagnosed with SLE admitted to the Department of internal Medicine of the National Hospital from January 2010 to December 2018. Materials and methods: Retrospective, observational, descriptive, cross sectional study of adult patients admitted to the Department of internal Medicine and the Emergency Depart- ment of the National Hospital of Itauguá, from 2010 to 2018. Out of 585 patients with SLE admitted during this period, 63 died. 25 patients were included and 38 were excluded due to incomplete studies. SLE diagnosis was made according to SLiCC criteria. The variables analyzed were demographic, clinical, laboratory, causes of death, mortality. Data was analyzed with descriptive statistics. Frequencies and proportions were used for qualitative variables, means and standard deviation for continuous variables. Results: 25 patients were included, 18 were women (72%) and 7 were men (28%). Mean age was 30±15.5 (18-77). 40% (n=10) came from Central Department and 60% (n=15) were from the countryside. 70.8% of the patients had a disease duration between 2 and 5 years (n=18). 92% had been previously diagnosed with SLE. Regarding disease activity, patients presented with nephritis (76%), alveolar hemorrhage (12%), pneumonitis (4%), neurolupus (4%) and CNS vasculitis (4%). On the subject of infections, the following were found: nosocomial pneumonia (45%), community acquired pneumonia (8%), strongyloides hyperinfection (4%), disseminated cryptococcosis (4%). The main causes of death were infections (44%), followed by disease activity (36%) and causes not related to SLE (20%; severe mitral and aortic insufficiency, acute pulmonary edema secondary to chronic kidney disease as complication of lupus nephritis, hemorrhagic stroke). 100% received corticosteroids and 60% immunosuppressants. Conclusion: Mortality was 10.8%, the main causes of death were infections followed by disease activity.Introducción: El Lupus Eritematoso Sistémico (LES), es una enfermedad autoinmune caracterizada por una inflamación sistémica crónica. Las principales causas de muerte son las infecciones y la actividad de la enfermedad en los primeros 5 años y a los 5 a 10 años son las complicaciones cardiovasculares y la acumulación de daño de órgano. Objetivo: Determinar la mortalidad y las causas de muerte en pacientes adultos con diagnóstico de LES internados en el Departamento de Medicina interna del Hospital Nacional en el periodo enero 2010-diciembre 2018. Material y Métodos: Estudio observacional retrospectivo de corte trasverso de pacientes adultos internados en el Departamento de Medicina interna y urgencias del Hospital Nacional de Itauguá, en el periodo 2010-2018. De 585 pacientes adultos con LES internados, fallecieron 63 pacientes, fueron excluidos 38 pacientes por presentar estudios incompletos. Para la descripción de la cohorte fueron incluidos 25 pacientes. El diagnóstico de LES fue realizado según los criterios del SLICC. Las variables analizadas fueron las demográficas, clínicas, laboratoriales y las causas de mortalidad. Los datos fueron analizados con estadística descriptiva; se utilizaron frecuencias y proporciones para las variables cualitativas, medias y desvió estándar para las continuas. Resultados: De los 25 pacientes analizados, 18 eran mujeres el 72% y 7 eran varones (28%). La edad media fue de 30 ±15,5 (18-77) años. Eran procedentes del Departamento Central el 40% (n=10) y el 60% (n=15) eran del interior del país. El 70,8% (n=18) de los pacientes tenían una duración de la enfermedad entre 2 y 5 años. Eran pacientes conocidos con el diagnóstico de LES en seguimiento el 92% de los pacientes. En relación a las manifestaciones clínicas, el 76% presentaba nefritis lúpica, seguida por hemorragia alveolar (12%), neumonitis lúpica (4%), neurolupus (4%), vasculitis del SNC (4%). Entre los procesos infecciosos registrados se constató neumonía nosocomial (45%), neumonía de la comunidad (8%), hiperinfeccion por estrongiloides (4%), criptococosis diseminada (4%). tuberculosis miliar (4%). Las causas principales de muerte fueron las causas infecciosas (44%), seguida por actividad de la enfermedad (36%) y por otras causas no relacionadas con el lupus (20%) (i.e. Insuficiencia mitral y aortica severa, edema agudo de pulmón secundaria a una enfermedad renal crónica como complicación de una nefritis lúpica, 2 pacientes con ictus hemorrágico). Recibieron corticoides (100%) e inmunosupresores (60%). Conclusión: La mortalidad fue del 10,8%, las principales causas de muerte fueron las infecciones seguida de la actividad de la enfermedad

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

La Volontà e la Scienza. Relazione di cura e disposizioni anticipate di trattamento.

Quest’opera collettanea nasce dalla profonda convinzione che la storia della relazione fra medico e paziente non possa che raccontarsi con il linguaggio, con lo sguardo e con la sensibilità di diverse discipline e professioni, innanzitutto per non perdere l’autenticità stessa della materia trattata. In questa direzione, ai contributi d’impronta più propriamente giuridica (Diritti e Regole: la disciplina della relazione e le situazioni giuridiche soggettive configurantisi, alla lente del diritto pubblico e del diritto privato) si succedono quelli di natura medicale (Scienza e Medicina: con le voci di specialisti diversi ad interrogarsi sulle rispettive peculiarità del rapporto con i propri pazienti) ed, infine, i saggi a carattere latamente filosofico/bioetico/psicologico (Volontà e Relazioni: perché l’esperienza della malattia e della morte richiama, in maniera dirompente, l’umanità di tutti i soggetti coinvolti, anche dello stesso operatore sanitario). L’occasione è l’emanazione della legge n. 219/2017, la quale compone Volontà e Scienza disciplinando la relazione terapeutica nel quadro dei princìpi etici dell’autonomia e della beneficità, ove il medico attua il mandato di cura realizzando il best interest del paziente nel rispetto della sua dignità e della sua autodeterminazione

Advance care directives: Citizens, patients, doctors, institutions

Italian Law no. 219/2017 established the advance care directives (“Disposizioni anticipate di trattamento” – DAT), a legal document specifying the person’s wishes in relation to health, drawn up in case of the possible future incapacity to make informed decisions. DAT are an important instrument of empowerment for a person who is not necessarily a “patient” and enable the dialogue between healthcare providers and patient to continue when the latter is no longer able to take part consciously. DAT can only be implemented by guaranteeing the fundamental rights of the person, i.e. by ensuring the “non-complicated” use of this instrument and easy access to the DAT whenever it may be necessary. Furthermore, on the one hand, the requirement of adequate prior medical information has to contend with the fact that the wishes expressed in the document may have been formed outside of the therapeutic relationship; on the other hand, institutions must ensure that DAT are collected and recorded in such a way as to ensure their availability whenever and wherever necessar

Modeling and Optimal Control of an Octopus Tentacle

We present a control model for an octopus tentacle based on the dynamics of an inextensible string with curvature constraints and curvature controls. We derive the equations of motion together with an appropriate set of boundary conditions, and we characterize the corresponding equilibria. The model results in a system of fourth-order evolutive nonlinear controlled PDEs, generalizing the classic Euler's dynamic elastica equation, that we approximate and solve numerically by introducing a finite difference scheme. We proceed by investigating a reachability optimal control problem associated to our tentacle model. We first focus on the stationary case, establishing a relation with the celebrated Dubins car problem. Moreover, we propose an augmented Lagrangian method for its numerical solution. Finally, we address the evolutive case obtaining first order optimality conditions, then we numerically solve the optimality system by means of an adjoint-based gradient descent method