Development of cationic solid lipid nanoparticles incorporating cholesteryl-9-carboxynonanoate (9CCN) for delivery of antagomiRs to macrophages.

Lipid-based nanoparticles are a useful tool for nucleic acids delivery and have been regarded as a promising approach for diverse diseases. However, off-targets effects are a matter of concern and some strategies to improve selectivity of solid lipid nanoparticles (SLNs) were reported. The goal of this study was to test formulations of SLNs incorporating lipid cholesteryl-9-carboxynonanoate (9CCN) as "eat-me" signal to target antagomiR oligonucleotides to macrophages. We formulate four SLNs, and those with a mean diameter of 200 nm and a Z-potential values between 25 and 40 mV, which allowed the antagomiR binding, were selected for in vitro studies. Cell viability, transfection efficiency and cellular uptake assays were performed within in vitro macrophages using flow cytometry and confocal imaging and the SLNs incorporating 25 mg of 9CCN proved to be the best formulation. Subsequently, we used a labeled antagomiR to study tissue distribution in in-vivo ApoE-/- model of atherosclerosis. Using the ApoE-/- model we demonstrated that SLNs with phagocytic signal 9-CCN target macrophages and release the antagomiR cargo in a selective way.

New and promising type of leukotriene B4 (LTB4) antagonists based on the 1,4-benzodioxine structure.

New leukotriene B4 (LTB4) antagonists have been synthesized that can be considered as potential anti-inflammatory drugs. Structures containing the dioxygenated nucleus of 1,4-benzodioxine constitute a potential group of leukotriene B4 (LTB4) antagonists. The objective of this study was to access efficient and selective LTB4 antagonists as a way to elucidate the role of LTB4 in inflammatory processes and therefore allow the development of new types of structures based on 1,4-benzodioxine. Forty-one new 1,4-benzodioxine molecules substituted at different positions of the heterocyclic nucleus were synthesized to determine the minimum structural requirements by studying structure-activity relationships. Eighteen of them were tested in vitro and in vivo for their anti-inflammatory activity related to the antagonist character of LTB4. Pharmacological tests have shown satisfactory in vitro activity for compounds 24b, 24c and 24e with IC50's of 288, 439, 477 nM respectively. The results of the in vivo tests, carried out with the compound that presented greater activity in the in vitro tests 24b, have shown significant anti-inflammatory properties.

Resveratrol derivatives: Synthesis and their biological activities.

Resveratrol, a natural compound known especially for its antioxidant properties and protective action, opens the door for both it and its structural derivatives to be considered not only as chemopreventive but also as cancer chemotherapeutic agents. Due to the pharmacokinetic problems of resveratrol that demonstrate its poor bioavailability, the study of new derivatives is of interest. Thus, in this work (E)-stilbenes derived directly from resveratrol and other cyclic analogues containing the benzofuran or indole nucleus have been synthesized. The synthesized compounds have been evaluated for their ability to affect tumor growth in vitro. Compounds 2, 3, 4 and 5 have shown cytotoxicity in human colon cancer (HT-29) and human pancreatic adenocarcinoma cells (MIA PaCa-2) higher than those of (E)-resveratrol. The indolic derivative 13, a cyclic analog of resveratrol, has shown in vitro cytotoxic activity 8 times higher than resveratrol against HT-29 cancer cells. The cyclic derivatives 8, 9 and 12 showed a high inhibition of cell growth in HCT-116 (KRas mutant) at 20 µM, while 13 shows moderate antiangiogenesis activity at 10 µM.

Melatonin in sleep disorders.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Decreased mortality among patients with catheter-related bloodstream infections at Catalan hospitals (2010-2019).

BACKGROUND: The incidence of catheter-related bloodstream infections (CRBSIs) has fallen over the last decade, especially in intensive care units (ICUs). AIM: To assess the existence of concomitant trends in outcomes and to analyse the current risk factors for mortality. METHODS: A multicentre retrospective cohort study was conducted at 24 Catalan hospitals participating in the Surveillance of healthcare-associated infections in Catalonia (VINCat). All hospital-acquired CRBSI episodes diagnosed from January 2010 to December 2019 were included. A common protocol including epidemiological, clinical, and microbiological data was prospectively completed. Mortality at 30 days after bacteraemia onset was analysed using the Cox regression model. FINDINGS: Over the study period, 4795 episodes of CRBSI were diagnosed. Among them, 75% were acquired in conventional wards and central venous catheters were the most frequently involved (61%). The 30-day mortality rate was 13.8%, presenting a significant downward trend over the study period: from 17.9% in 2010 to 10.6% in 2019 (hazard ratio (HR): 0.95; 95% confidence interval (CI): 0.92-0.98). The multivariate analysis identified age (HR: 1.03; 95% CI: 1.02-1.04), femoral catheter (1.78; 1.33-2.38), medical ward acquisition (2.07; 1.62-2.65), ICU acquisition (3.45; 2.7-4.41), S. aureus (1.59; 1.27-1.99) and Candida sp. (2.19; 1.64-2.94) as risk factors for mortality, whereas the mortality rate associated with episodes originating in peripheral catheters was significantly lower (0.69; 0.54-0.88). CONCLUSION: Mortality associated with CRBSI has fallen in recent years but remains high. Intervention programmes should focus especially on ICUs and medical wards, where incidence and mortality rates are highest.

Update on Chronic Prurigo. / Prurigo crónico: actualización.

Chronic prurigo is itself a common condition, but it can also occur secondary to a large number of diseases. Management is challenging as historically chronic prurigo has been poorly defined and very few treatments are available. Clinically, it presents as excoriated, hyperkeratotic lesions. When chronic prurigo is suspected, a comprehensive differential diagnosis is essential. New diagnostic criteria have appeared in recent years and new drugs have been developed. Although no truly effective treatment is yet available, patients will benefit from a greater understanding of this condition.

Spin Hall Magnetoresistance Effect from a Disordered Interface.

The spin Hall magnetoresistance (SMR) emerged as a reference tool to investigate the magnetic properties of materials with an all-electrical setup. Its sensitivity to the magnetization of thin films and surfaces may turn it into a valuable technique to characterize van der Waals magnetic materials, which support long-range magnetic order in atomically thin layers. However, realistic surfaces can be affected by defects and disorder, which may result in unexpected artifacts in the SMR, rather than the sole appearance of electrical noise. Here, we study the SMR response of heterostructures combining a platinum (Pt) thin film with the van der Waals antiferromagnet MnPSe3 and observe a robust SMR-like signal, which turns out to originate from the presence of strong interfacial disorder in the system. We use transmission electron microscopy (TEM) to characterize the interface between MnPSe3 and Pt, revealing the formation of a few nanometer-thick platinum-chalcogen amorphous layer. The analysis of the transport and TEM measurements suggests that the signal arises from a disordered magnetic system formed at the Pt/MnPSe3 interface, washing out the interaction between the spins of the Pt electrons and the MnPSe3 magnetic lattice. Our results show that the damaged interfaces can yield an important contribution to SMR, questioning a widespread assumption on the role of disorder in such measurements.

Calciphylaxis: Risk Factors and Histologic Findings in a Case Series From a Tertiary Care Referral Hospital. / Calcifilaxis: factores de riesgo y hallazgos histológicos en una serie de casos de un hospital terciario.

Recent years have seen important advances in our understanding of calciphylaxis, especially regarding newly identified risk factors and histologic findings that may aid diagnosis. This retrospective study of cases of calciphylaxis treated in our hospital in the last 13 years focuses on newly revealed aspects of this disease. We describe 16 patients (62.5% women; mean age, 67.9 years). In addition to advanced kidney disease (in 75% of our patients), other factors associated with the presence of calciphylaxis were a history of treatments related to phosphorus and calcium metabolism (75%) and anticoagulation (62.5%), usually with vitamin-K antagonists. Histology showed alterations in elastic fibers in only 25% of the biopsy specimens. Eleven of the patients died: sepsis was most often the cause.

Skin Biopsy in Chronic Urticaria: When and Where and What to Look for? / La biopsia cutánea en la urticaria crónica: cuándo realizarla, qué buscar y dónde hacerlo.

Chronic urticaria is a relatively common condition in dermatology and is usually diagnosed on clinical grounds. Skin biopsy, however, may be indicated in certain cases to confirm diagnosis and rule out other conditions that can cause hive-like rashes. We review histopathologic findings seen in both chronic urticaria and other entities in the differential diagnosis. We then propose an algorithm of indications for skin biopsy in patients with hive-like rashes and suggest possible diagnoses based on the histopathologic findings.

Aplicación forense de tecnología radiográfica dental portátil en Argentina: estado actual y perspectivas futuras / Forensic application of portable dental radiographic technology in Argentina: current status and future prospects

Objetivos: Mensurar los niveles de radiación de fuga y dispersión emanada a través de los blindajes y estructuras plomadas del tubo de rayos X de la unidad dental portátil NOMAD, controlando la retrodispersión con el uso del escudo protector de acrílico plomado adaptado en el extremo final del tubo localizador plomado. Se midieron las tasas de exposición dispersadas mediante un detector tipo Geiger-Müller y una cámara de ionización con respuesta en el rango de energías aportadas en diagnóstico por imágenes para la medición de la exposición directa y determinación posterior de las dosis. Se utilizó un fantomas diseñado para diagnóstico odontológico, sopesando la radiación en diferentes angulaciones de operación del equipo NOMAD, simulando los gestos posturales de odontólogos, radiólogos y sujetos a identificar. Se controlaron las tasas de exposición para determinar los valores de las dosis aportadas en las zonas significativas corporales más radiosensibles del operador del equipo. Se obtuvo como resultado que la retrodispersión en el cristalino del ojo del operador fue significativamente menor cuando el fantomas estaba acostado, mientras que a nivel de gónadas resultó más baja con el cuerpo sentado. La tasa de dosis máxima de radiación dispersa que impactó en los operadores fue de 350.8 micro Sieverts por hora (uSv/h) en la zona de gónadas, por cada radiografía tomada sin el uso del delantal de goma plomada, reduciéndose a 4.38 micro Sieverts por hora (uSv/h) al utilizarlo (AU)

[Sleep-related movement and behavioural disorders in adults]. / Trastornos del movimiento y de la conducta durante el sueño en el adulto.

Sleep-related movement and behaviour disorders may have an impact on sleep quality and lead to daytime symptoms. These groups of conditions include diseases such as restless legs syndrome, periodic leg movements, and REM and NREM parasomnias. The knowledge of their clinical features and management is of utmost importance for the neurologist and sleep specialist. Frequently, these patients are referred to such specialists and it is relevant to know that certain sleep disorders may be associated with other neurological conditions.

TITLE: Trastornos del movimiento y de la conducta durante el sueño en el adulto.Los trastornos del movimiento y de la conducta durante el sueño pueden tener un impacto en la calidad del sueño del paciente y dar lugar a síntomas diurnos. En estos grupos de enfermedades se incluyen entidades como el síndrome de piernas inquietas, los movimientos periódicos de las piernas y las parasomnias del sueño de movimientos oculares rápidos (REM) y no REM. El conocimiento de sus características clínicas y nociones sobre su manejo es de gran importancia para el neurólogo y especialista en sueño por su frecuencia e impacto en la calidad del sujeto. Con frecuencia, estos pacientes son referidos a dichos especialistas, y es relevante conocer que ciertos trastornos del sueño pueden asociarse a otras enfermedades neurológicas.

Circulating MicroRNA Profile Associated with Obstructive Sleep Apnea in Alzheimer's Disease.

The diagnosis of obstructive sleep apnea (OSA) in Alzheimer's disease (AD) by polysomnography (PSG) is challenging due to the required collaboration of the patients. In addition, screening questionnaires have demonstrated limited usefulness with this subpopulation. Considering this, we investigated the circulating microRNA (miRNA) profile associated with OSA in AD patients. This study included a carefully selected cohort of females with mild-moderate AD confirmed by biological evaluation (n = 29). The individuals were submitted to one-night PSG to diagnose OSA (apnea-hypopnea index ≥ 15/h) and the blood was collected in the following morning. The plasma miRNA profile was evaluated using RT-qPCR. The patients had a mean (SD) age of 75.8 (5.99) years old with a body mass index of 28.6 (3.83) kg m-2. We observed a subset of 15 miRNAs differentially expressed between OSA and non-OSA patients, of which 10 were significantly correlated with the severity of OSA. Based on this, we built a prediction model that generated an AUC (95% CI) of 0.95 (0.88-1.00) including 5 of the differentially expressed miRNAs that correlated with OSA severity: miR-26a-5p, miR-30a-3p, miR-374a-5p, miR-377-3p, and miR-545-3p. Our preliminary results suggest a plasma miRNA signature associated with the presence of OSA in AD patients. Further studies will be necessary to validate these findings.

Effectiveness of ustekinumab in patients with psoriatic arthritis in a real-world, multicenter study.

OBJECTIVE: To assess the effectiveness and survival of ustekinumab (UST) among patients with psoriatic arthritis (PsA) treated under routine clinical care. METHODS: Multicenter study. Epidemiological and clinical data was collected through electronic medical records of all patients with PsA who started UST in 15 hospitals of Spain. RESULTS: Two hundred and one patients were included, 130 (64.7%) with 45 mg and 71 (35.3%) with 90 mg. One hundred and thirty one patients (65.2%) had previously received another biological therapy. The median baseline DAS 28 ESR was 3.99, and Psoriasis Area and Severity Index (PASI) was 3. Overall, there was a significant decrease in DAS66/68 CRP, swollen joint count (SJC), tender joint count (TJC), and PASI in the first month of treatment, with earlier improvement in skin (PASI) than joints outcomes. Survival was numerically lower in patients with UST 45 mg (58.1%) than 90 mg (76.1%), although significant differences were not found (p = 0.147). When comparing naïve and < 1 TNF blocker versus > 2 TNF blocker-experienced patients, a significantly earlier response was seen in the former group regarding SJC (p = 0.029) at 1 month. Fifty-one patients (25.3%) stopped UST due to joint inefficacy and 4 patients due to adverse events (1.9%). Drug survival was significantly better in patients with fewer lines of previous biological agents (p = 0.003 for < 1 TNF blocker versus > 2 TNF blocker users). CONCLUSIONS: UST was effective in PsA patients in a routine clinical care setting. Patients with UST 90 mg and fewer lines of previous biologics achieved better and faster responses. Key Points • Largest cohort of patients with PsA in treatment with UST with specific rheumatological indication. • First cohort of patients with PsA comparing effectiveness of UST according to 45/90 mg dose.

Recommendations for the diagnosis and treatment of Clostridioides difficile infection: An official clinical practice guideline of the Spanish Society of Chemotherapy (SEQ), Spanish Society of Internal Medicine (SEMI) and the working group of Postoperative Infection of the Spanish Society of Anesthesia and Reanimation (SEDAR).

This document gathers the opinion of a multidisciplinary forum of experts on different aspects of the diagnosis and treatment of Clostridioides difficile infection (CDI) in Spain. It has been structured around a series of questions that the attendees considered relevant and in which a consensus opinion was reached. The main messages were as follows: CDI should be suspected in patients older than 2 years of age in the presence of diarrhea, paralytic ileus and unexplained leukocytosis, even in the absence of classical risk factors. With a few exceptions, a single stool sample is sufficient for diagnosis, which can be sent to the laboratory with or without transportation media for enteropathogenic bacteria. In the absence of diarrhoea, rectal swabs may be valid. The microbiology laboratory should include C. difficile among the pathogens routinely searched in patients with diarrhoea. Laboratory tests in different order and sequence schemes include GDH detection, presence of toxins, molecular tests and toxigenic culture. Immediate determination of sensitivity to drugs such as vancomycin, metronidazole or fidaxomycin is not required. The evolution of toxin persistence is not a suitable test for follow up. Laboratory diagnosis of CDI should be rapid and results reported and interpreted to clinicians immediately. In addition to the basic support of all diarrheic episodes, CDI treatment requires the suppression of antiperistaltic agents, proton pump inhibitors and antibiotics, where possible. Oral vancomycin and fidaxomycin are the antibacterials of choice in treatment, intravenous metronidazole being restricted for patients in whom the presence of the above drugs in the intestinal lumen cannot be assured. Fecal material transplantation is the treatment of choice for patients with multiple recurrences but uncertainties persist regarding its standardization and safety. Bezlotoxumab is a monoclonal antibody to C. difficile toxin B that should be administered to patients at high risk of recurrence. Surgery is becoming less and less necessary and prevention with vaccines is under research. Probiotics have so far not been shown to be therapeutically or preventively effective. The therapeutic strategy should be based, rather than on the number of episodes, on the severity of the episodes and on their potential to recur. Some data point to the efficacy of oral vancomycin prophylaxis in patients who reccur CDI when systemic antibiotics are required again.

Reasons for medication non-initiation: A qualitative exploration of the patients' perspective.

BACKGROUND: Non-initiation occurs when the doctor prescribes a new pharmacological treatment to a patient who does not fill the prescription. Non-initiation prevalence estimates range between 6% and 28% in Primary Care (PC) and it is associated with poorer clinical outcomes, more sick-leave days and higher costs. To date, the reasons for non-initiation have not been explored using a qualitative framework. OBJECTIVE: The aim of the present study was to identify reasons for medication non-initiation among PC patients with distinct treatment profiles (acute, chronic symptomatic and asymptomatic, and mental disorders). METHODS: An exploratory, explanatory qualitative study based on Grounded Theory. We conducted individual semi-structured interviews with 30 PC patients. A constant comparative method of analysis was performed. RESULTS: The results were similar for all therapeutic groups. The decision to initiate treatment is multifactorial. Users make a risk-benefit assessment which is influenced by their beliefs about the pathology and the medication, their emotional reaction, health literacy and cultural factors. The patients' context and relationship with the health system influence decision-making. CONCLUSIONS: The decision to initiate a treatment is strongly influenced by factors that health professionals can discuss with patients. Health professionals should explore patients' beliefs about benefits and risks to help them make informed decisions and promote shared decision-making. General practitioners should ensure that patients understand the benefits and risks of disease and treatment, while explaining alternative treatments, encouraging patients to ask questions and supporting their treatment decisions.