Gene expression rearrangements denoting changes in the biological state

In many situations, the gene expression signature is a unique marker of the biological state. We study the modification of the gene expression distribution function when the biological state of a system experiences a change. This change may be the result of a selective pressure, as in the Long Term Evolution Experiment with E. Coli populations, or the progression to Alzheimer disease in aged brains, or the progression from a normal tissue to the cancer state. The first two cases seem to belong to a class of transitions, where the initial and final states are relatively close to each other, and the distribution function for the differential expressions is short ranged, with a tail of only a few dozens of strongly varying genes. In the latter case, cancer, the initial and final states are far apart and separated by a low-fitness barrier. The distribution function shows a very heavy tail, with thousands of silenced and over-expressed genes. We characterize the biological states by means of their principal component representations, and the expression distribution functions by their maximal and minimal differential expression values and the exponents of the Pareto laws describing the tails

TLS- and inventory-based Magnitude – Frequency relationship for rockfall in Montserrat and Castellfollit de la Roca

Hazard scenarios are defined by a representative event of a certain magnitude, which corresponds to a frequency of occurrence or annual probability. In rockfall, scenario magnitude is identified by the total volume detached. Therefore, in diffuse hazard assessment it is crucial to fit this relationship magnitude/frequency, called McF, where cumulated frequency is quoted in spatial & temporal terms. Inventories are the classical source of data to deal with this objective. Last decade, TLS or digital photogrammetry monitoring came to offer a complementary approach. The samples obtained by the two methods have a specific coverage and each has its own lack of information that can be compensated together.Peer ReviewedPostprint (published version

In Vitro Antibacterial Activity of Silver Nanoparticles Conjugated with Amikacin and Combined with Hyperthermia against Drug-Resistant and Biofilm-Producing Strains

Antibacterial activity; Biofilms; Silver nanoparticlesActividad antibacteriana; Biopelículas; Nanopartículas de plataActivitat antibacteriana; Biopel·lícules; Nanopartícules de plataIn view of the current increase and spread of antimicrobial resistance (AMR), there is an urgent need to find new strategies to combat it. This study had two aims. First, we synthesized highly monodispersed silver nanoparticles (AgNPs) of approximately 17 nm, and we functionalized them with mercaptopoly(ethylene glycol) carboxylic acid (mPEG-COOH) and amikacin (AK). Second, we evaluated the antibacterial activity of this treatment (AgNPs_mPEG_AK) alone and in combination with hyperthermia against planktonic and biofilm-growing strains. AgNPs, AgNPs_mPEG, and AgNPs_mPEG_AK were characterized using a suite of spectroscopy and microscopy methods. Susceptibility to these treatments and AK was determined after 24 h and over time against 12 clinical multidrug-resistant (MDR)/extensively drug-resistant (XDR) isolates of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The efficacy of the treatments alone and in combination with hyperthermia (1, 2, and 3 pulses at 41°C to 42°C for 15 min) was tested against the same planktonic strains using quantitative culture and against one P. aeruginosa strain growing on silicone disks using confocal laser scanning microscopy. The susceptibility studies showed that AgNPs_mPEG_AK was 10-fold more effective than AK alone, and bactericidal efficacy after 4, 8, 24, or 48 h was observed against 100% of the tested strains. The combination of AgNPs_mPEG_AK and hyperthermia eradicated 75% of the planktonic strains and exhibited significant reductions in biofilm formation by P. aeruginosa in comparison with the other treatments tested, except for AgNPs_mPEG_AK without hyperthermia. In conclusion, the combination of AgNPs_mPEG_AK and hyperthermia may be a promising therapy against MDR/XDR and biofilm-producing strains. IMPORTANCE Antimicrobial resistance (AMR) is one of the greatest public health challenges, accounting for 1.27 million deaths worldwide in 2019. Biofilms, a complex microbial community, directly contribute to increased AMR. Therefore, new strategies are urgently required to combat infections caused by AMR and biofilm-producing strains. Silver nanoparticles (AgNPs) exhibit antimicrobial activity and can be functionalized with antibiotics. Although AgNPs are very promising, their effectiveness in complex biological environments still falls below the concentrations at which AgNPs are stable in terms of aggregation. Thus, improving the antibacterial effectiveness of AgNPs by functionalizing them with antibiotics may be a significant change to consolidate AgNPs as an alternative to antibiotics. It has been reported that hyperthermia has a large effect on the growth of planktonic and biofilm-producing strains. Therefore, we propose a new strategy based on AgNPs functionalized with amikacin and combined with hyperthermia (41°C to 42°C) to treat AMR and biofilm-related infections.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162); la Marató TV3 (472/U/2018); the CaixaImpulse Program (Fundació LaCaixa); and the Spanish Network for Research in Infectious Diseases (REIPI RD19/0016)

Insulinoma : a Rare Cause of Hypoglycemia in Childhood

Rare disease. Insulinomas are pancreatic neuroendocrine tumors that cause non-ketotic hypoglycemia due to hyperinsulinism; they are extremely rare, especially in children. We present a case of a sporadic insulinoma in an 11-year-old boy who had episodes of self-limited drowsiness and behavior changes over a 3-month period, thought to be caused by psychological issues. Non-ketotic hypoglycemia was confirmed at our center. A fasting blood test found inappropriately elevated insulin levels during hypoglycemia, undetectable β-hydroxybutyrate, and increased C-peptide levels in line with insulin levels. Anti-insulin antibodies were negative and antidiabetic drugs untraceable. The glucagon-stimulation test was positive. Growth hormone, adrenocorticotropin hormone, and phosphorus and calcium metabolism were normal. Dual-phase computed tomography detected a lesion compatible with an insulinoma. Endoscopic ultrasound showed a homogenous lesion at the junction of the body and tail of the pancreas. Histologic analysis of a fine-needle aspiration biopsy was compatible with neuroendocrine neoplasia. Preoperatively, a fractional diet avoiding fast-absorbing carbohydrates maintained normal glucose blood levels. Enucleation was not possible, so the lesion was resected along with portions of the body and tail of the pancreas. The well-differentiated tumor measured 15×13 mm. Postoperative blood glucose levels were correct, allowing a normal diet. In children with unspecific symptoms compatible with hypoglycemia, blood glucose must be evaluated to confirm low blood glucose levels. Determining blood ketone levels is important for the differential diagnosis. The diagnostic approach to pediatric insulinoma represents a challenge for multidisciplinary teamwork

Una propuesta de normalización de la escritura celtibérica

Presentamos una propuesta de normalización de la identificación de los signos paleohispánicos empleados en la escritura celtibérica que facilite su taxonomía y posterior estudio. Partiendo de la revisión de los trabajos de clasificación de las inscripciones ibéricas nororientales y celtibéricas realizados por Untermann, que son la referencia aún vigente, hemos procedido a seleccionar la representación básica de cada uno de dichos signos a la vez que hemos expuesto los criterios en los que nos hemos basado para ello así como para la eliminación de los que hemos considerado como sus microvariantes.El conjunto resultante de signos paleohispánicos canónicos y de sus correspondientes variantes aporta una base más científica para el estudio de la epigrafía o paleografía paleohispánica que los métodos con los que ésta se ha venido realizando hasta ahora. Conjunto que está pendiente de que se revisen y completen cada uno de sus signos como consecuencia de que se contraste su utilización en todas y cada una de las inscripciones conocidas. Por lo que esperamos que con la continuación de esta línea de trabajo también se puedan obtener datos y conocimientos acerca de estas lenguas y sistemas de escritura, así como de quienes las usaron. Información que podrá complementarse con la procedente del correspondiente estudio lingüístico de los textos analizados que, a su vez y de forma recursiva, también complementará y será completada por el conocimiento arqueológico e histórico de las inscripcione

Cognitive impairment in multiple sclerosis: diagnosis and monitoring

Multiple sclerosis; Neurophysiological monitoring; Neuropsychological testsEsclerosi múltiple; Monitorització neurofisiològica; Proves neuropsicològiquesEsclerosis múltiple; Monitoreo neurofisiológico; Pruebas neuropsicológicasIntroduction Cognitive impairment (CI) has a prevalence of 45–70% in people with multiple sclerosis (MS), producing a negative impact on their quality of life, personal life, and work. Early detection of CI has become an important aspect to be considered for an adequate follow-up, to optimize social adaptation and to implement specific cognitive rehabilitation strategies. The aim of this work is to propose a suitable cognitive evaluation of patients with MS based on available and efficient tools for diagnosis and monitoring purposes well supported by literature review and clinical experience. Methods A multidisciplinary panel of professionals from the field of neurology, neuropsychology, and neuroimaging performed a literature review of the topic of cognitive impairment assessment. This was combined and completed with their clinical experience to produce a set of recommendations. Results Some limitations to cognitive evaluation are described: shortage of time and resources during the neurology consultation, scarceness or absence of specialized professionals’ availability, importance of tests adaptation, and doubts about its use to define therapeutic efficiency. We recommend a baseline and annual screening evaluation, and we suggest a baseline and periodic neuropsychological assessment. The latter ought to change to a recommendation with the presence of either positive screening test, or subjective to cognitive complaints, screening-test results and patient or family report mismatch, or in specific social/work situations. Conclusions Cognitive evaluation should be performed on all patients diagnosed with MS and throughout follow-up. It is necessary to support the creation of multidisciplinary MS teams to optimize the evaluation and follow-up of MS patients

Hyperthermia Prevents In Vitro and In Vivo Biofilm Formation on Endotracheal Tubes

Animal model; Biofilm; HyperthermiaModel animal; Biofilm; HipertèrmiaModelo animal; Biofilm; HipertermiaThere is currently an urgent need to find new strategies to tackle antimicrobial resistance and biofilm-related infections. This study has two aims. First, we evaluated the in vitro efficacy of hyperthermia in preventing biofilm formation on the surfaces of polyvinyl chloride discs. Second, we assessed the in vivo efficacy of hyperthermia in preventing biofilm formation in endotracheal tubes (ETTs) of a rabbit model. For the in vitro studies, nine clinical extensively drug-resistant/multidrug-resistant Gram-negative isolates of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa and three clinical methicillin-resistant Staphylococcus aureus strains were studied. For biofilm formation, an adhesion step of 30 or 90 min followed by a growth step of 24 h were performed with application of one, two, and three pulses at 42°C for 15 min each pulse after the adhesion step. For the in vivo studies, New Zealand rabbits were intubated with ETTs previously colonized with K. pneumoniae or P. aeruginosa strains, and three pulses at 42°C for 15 min were applied after the adhesion step. The application of three pulses at 42°C for 15 min each pulse was needed to achieve the prevention of the in vitro biofilm formation of 100% of the tested strains. The application of heat pulses in a rabbit intubation model led to biofilm prevention of 85% against two K. pneumoniae strains and 80% against two P. aeruginosa strains compared to the control group. Hyperthermia application through pulses at 42°C could be a new nonantibiotic strategy to prevent biofilm formation in ETTs. IMPORTANCE Biofilm-producing microorganisms are considered medically crucial since they cause 80% of the infections that occur in the human body. Medical devices such as endotracheal tubes (ETTs) can act as a reservoir for pathogens providing the surface to which microorganisms can adhere and cause biofilm-associated infections in critically ill patients. This biofilm has been related with the development of ventilator-associated pneumonia (VAP), with an incidence of 8 to 28%, a mortality rate up to 17% and its associated high extra costs. Although some VAP-preventive measures have been reported, they have not demonstrated a significant reduction of VAP incidence. Therefore, we present a new nonantibiotic strategy based on hyperthermia application to prevent biofilm formation inside ETTs. This technology could reduce VAP incidence, intubation duration, hospital and intensive care unit (ICU) length stays, and mortality rates. Consequently, this could decrease the antibiotics administered and influence the impact of antibiotic resistance in the ICU.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162), la Marató TV3 (472/U/2018), the CaixaImpulse Program (Fundació “LaCaixa”), the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE 3932-21), and the Spanish Network for the Research in Infectious Diseases (REIPI RD19/0016)

In Vitro and In Vivo Antimicrobial Activity of Hypochlorous Acid against Drug-Resistant and Biofilm-Producing Strains

Antibiotic lock technique; Biofilms; Catheter-related infectionTécnica de bloqueo antibiótico; Biopelículas; Infección relacionada con el catéterTècnica de bloqueig antibiòtic; Biofilms; Infecció relacionada amb el catèterThe aims of this study were as follows. First, we determined the antimicrobial efficacy of hypochlorous acid (HClO) against bacterial, fungal, and yeast strains growing planktonically and growing in biofilms. Second, we sought to compare the activity of the combination of daptomycin and HClO versus those of the antimicrobial agents alone for the treatment of experimental catheter-related Staphylococcus epidermidis infection (CRI) using the antibiotic lock technique (ALT) in a rabbit model. HClO was generated through direct electric current (DC) shots at determined amperages and times. For planktonic susceptibility studies, 1 to 3 DC shots of 2, 5, and 10 mA from 0 to 300 s were applied. A DC shot of 20 mA from 0 to 20 min was applied to biofilm-producing strains. Central venous catheters were inserted into New Zealand White rabbits, inoculated with an S. epidermidis strain, and treated with saline solution or ALT using daptomycin (50 mg/mL), HClO (20 mA for 45 min), or daptomycin plus HClO. One hundred percent of the planktonic bacterial, fungal, and yeast strains were killed by applying one DC shot of 2, 5, and 10 mA, respectively. One DC shot of 20 mA for 20 min was sufficient to eradicate 100% of the tested biofilm-producing strains. Daptomycin plus HClO lock therapy showed the highest activity for experimental CRI with S. epidermidis. HClO could be an effective strategy for treating infections caused by extensively drug-resistant or multidrug-resistant and biofilm-producing strains in medical devices and chronic wounds. The results of the ALT using daptomycin plus HClO may be promising. IMPORTANCE Currently, drug-resistant infections are increasing and there are fewer antibiotics available to treat them. Therefore, there is an urgent need to find new antibiotics and nonantimicrobial strategies to treat these infections. We present a new nonantibiotic strategy based on hypochlorous acid generation to treat long-term catheter-related and chronic wounds infections.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162), la Marató TV3 (472/U/2018), and CaixaImpulse Program (Fundació “LaCaixa”) and the Spanish Network for the Research in Infectious Diseases (REIPI RD19/0016)

Rockfall Magnitude-Frequency Relationship Based on Multi-Source Data from Monitoring and Inventory

Quantitative hazard analysis of rockfalls is a fundamental tool for sustainable risk management, even more so in places where the preservation of natural heritage and people's safety must find the right balance. The first step consists in determining the magnitude-frequency relationship, which corresponds to the apparently simple question: how big and how often will a rockfall be detached from anywhere in the cliff? However, there is usually only scarce data on past activity from which to derive a quantitative answer. Methods are proposed to optimize the exploitation of multi-source inventories, introducing sampling extent as a main attribute for the analysis. This work explores the maximum possible synergy between data sources as different as traditional inventories of observed events and current remote sensing techniques. Both information sources may converge, providing complementary results in the magnitude-frequency relationship, taking advantage of each strength that overcomes the correspondent weakness. Results allow characterizing rockfall detachment hazardous conditions and reveal many of the underlying conditioning factors, which are analyzed in this paper. High variability of the hazard over time and space has been found, with strong dependencies on influential external factors. Therefore, it will be necessary to give the appropriate reading to the magnitude-frequency scenarios, depending on the application of risk management tools (e.g., hazard zoning, quantitative risk analysis, or actions that bring us closer to its forecast). In this sense, some criteria and proxies for hazard assessment are proposed in the paper