Co-delivery of free vancomycin and transcription factor decoy-nanostructured lipid carriers can enhance inhibition of methicillin resistant Staphylococcus aureus (MRSA)

Bacterial resistance to antibiotics is widely regarded as a major public health concern with last resort MRSA treatments like vancomycin now encountering resistant strains. TFDs (Transcription Factor Decoys) are oligonucleotide copies of the DNA-binding sites for transcription factors. They bind to and sequester the targeted transcription factor, thus inhibiting transcription of many genes. By developing TFDs with sequences aimed at inhibiting transcription factors controlling the expression of highly conserved bacterial cell wall proteins, TFDs present as a potential method for inhibiting microbial growth without encountering typical resistance mechanisms. However, the efficient protection and delivery of the TFDs inside the bacterial cells is a critical step for the success of this technology. Therefore, in our study, specific TFDs against S. aureus were complexed with two different types of nanocarriers: cationic nanostructured lipid carriers (cNLCs) and chitosan-based nanoparticles (CS-NCs). These TFD-carrier nanocomplexes were characterized for size, zeta potential and TFD complexation or loading efficiency in a variety of buffers. In vitro activity of the nanocomplexes was examined alone and in combination with vancomycin, first in methicillin susceptible strains of S. aureus with the lead candidate advancing to tests against MRSA cultures. Results found that both cNLCs and chitosan-based carriers were adept at complexing and protecting TFDs in a range of physiological and microbiological buffers up to 72 hours. From initial testing, chitosan-TFD particles demonstrated no visible improvements in effect when co-administered with vancomycin. However, co-delivery of cNLC-TFD with vancomycin reduced the MIC of vancomycin by over 50% in MSSA and resulted in significant decreases in viability compared with vancomycin alone in MRSA cultures. Furthermore, these TFD-loaded particles demonstrated very low levels of cytotoxicity and haemolysis in vitro. To our knowledge, this is the first attempt at a combined antibiotic/oligonucleotide-TFD approach to combatting MRSA and, as such, highlights a new avenue of MRSA treatment combining traditional small molecules drugs and bacterial gene inhibition

Related Factors of Anemia in Critically Ill Patients: A Prospective Multicenter Study

Anemia; Blood; Practice managementAnemia; Sangre; Gestión prácticaAnèmia; Sang; Gestió pràcticaAnemia is common in critically ill patients; almost 95% of patients admitted to intensive care units (ICUs) have hemoglobin levels below normal. Several causes may explain this phenomenon as well as the tendency to transfuse patients without adequate cause: due to a lack of adherence to protocols, lack of supervision, incomplete transfusion request forms, or a lack of knowledge about the indications, risks, and costs of transfusions. Daily sampling to monitor the coagulation parameters and the acid–base balance can aggravate anemia as the main iatrogenic factor in its production. We studied the association and importance of iatrogenic blood loss and other factors in the incidence of anemia in ICUs. We performed a prospective, observational, multicenter study in five Spanish hospitals. A total of 142 patients with a median age of 58 years (IQI: 48–69), 71.83% male and 28.17% female, were admitted to ICUs without a diagnosis of iatrogenic anemia. During their ICU stay, anemia appeared in 66.90% of the sample, 95 patients, (95% CI: 58.51–74.56%). Risk factors associated with the occurrence of iatrogenic anemia were arterial catheter insertion (72.63% vs. 46.81%, p-value = 0.003), venous catheter insertion (87.37% vs. 72.34%, p-value = 0.023), drainages (33.68% vs. 12. 77%, p-value = 0.038), and ICU stay, where the longer the stay, the higher the rate of iatrogenic anemia (p-value < 0.001). We concluded that there was a statistical significance in the production of iatrogenic anemia due to the daily sampling for laboratory monitoring and critical procedures in intensive care units. The implementation of patient blood management programs could address these issues

Identification of a Twelve-microRNA Signature with Prognostic Value in Stage II Microsatellite Stable Colon Cancer

Simple Summary Colorectal cancer (CRC) is one of the most prevalent cancers, and approximately a quarter of patients diagnosed at stage II exhibit a significant risk of recurrence. In this study, we successfully identified a microRNA (miRNA) signature allowing the recognition of patients at high recurrence risk. The validity of these findings has been confirmed through an entirely separate group of patients diagnosed with stage II microsatellite stability (MSS) colon adenocarcinoma (COAD). Most of the miRNAs present in the signature have demonstrated prognostic relevance in various other cancer types. Upon examining their gene targets, we discovered that some of these miRNAs are intricately involved in pivotal pathways of cancer progression. We aimed to identify and validate a set of miRNAs that could serve as a prognostic signature useful to determine the recurrence risk for patients with COAD. Small RNAs from tumors of 100 stage II, untreated, MSS colon cancer patients were sequenced for the discovery step. For this purpose, we built an miRNA score using an elastic net Cox regression model based on the disease-free survival status. Patients were grouped into high or low recurrence risk categories based on the median value of the score. We then validated these results in an independent sample of stage II microsatellite stable tumor tissues, with a hazard ratio of 3.24, (CI95% = 1.05-10.0) and a 10-year area under the receiver operating characteristic curve of 0.67. Functional analysis of the miRNAs present in the signature identified key pathways in cancer progression. In conclusion, the proposed signature of 12 miRNAs can contribute to improving the prediction of disease relapse in patients with stage II MSS colorectal cancer, and might be useful in deciding which patients may benefit from adjuvant chemotherapy

“COAGULATION”: a mnemonic device for treating coagulation disorders following traumatic brain injury—a narrative-based method in the intensive care unit

IntroductionCoagulopathy associated with isolated traumatic brain injury (C-iTBI) is a frequent complication associated with poor outcomes, primarily due to its role in the development or progression of haemorrhagic brain lesions. The independent risk factors for its onset are age, severity of traumatic brain injury (TBI), volume of fluids administered during resuscitation, and pre-injury use of antithrombotic drugs. Although the pathophysiology of C-iTBI has not been fully elucidated, two distinct stages have been identified: an initial hypocoagulable phase that begins within the first 24 h, dominated by platelet dysfunction and hyperfibrinolysis, followed by a hypercoagulable state that generally starts 72 h after the trauma. The aim of this study was to design an acronym as a mnemonic device to provide clinicians with an auxiliary tool in the treatment of this complication.MethodsA narrative analysis was performed in which intensive care physicians were asked to list the key factors related to C-iTBI. The initial sample was comprised of 33 respondents. Respondents who were not physicians, not currently working in or with experience in coagulopathy were excluded. Interviews were conducted for a month until the sample was saturated. Each participant was asked a single question: Can you identify a factor associated with coagulopathy in patients with TBI? Factors identified by respondents were then submitted to a quality check based on published studies and proven evidence. Because all the factors identified had strong support in the literature, none was eliminated. An acronym was then developed to create the mnemonic device.Results and conclusionEleven factors were identified: cerebral computed tomography, oral anticoagulant &amp; antiplatelet use, arterial blood pressure (Hypotension), goal-directed haemostatic therapy, use fluids cautiously, low calcium levels, anaemia-transfusion, temperature, international normalised ratio (INR), oral antithrombotic reversal, normal acid–base status, forming the acronym “Coagulation.” This acronym is a simple mnemonic device, easy to apply for anyone facing the challenge of treating patients of moderate or severe TBI on a daily basis

Role of the satiety factor oleoylethanolamide in alcoholism

Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism

Related Factors of Anemia in Critically Ill Patients : A Prospective Multicenter Study

Anemia is common in critically ill patients; almost 95% of patients admitted to intensive care units (ICUs) have hemoglobin levels below normal. Several causes may explain this phenomenon as well as the tendency to transfuse patients without adequate cause: due to a lack of adherence to protocols, lack of supervision, incomplete transfusion request forms, or a lack of knowledge about the indications, risks, and costs of transfusions. Daily sampling to monitor the coagulation parameters and the acid-base balance can aggravate anemia as the main iatrogenic factor in its production. We studied the association and importance of iatrogenic blood loss and other factors in the incidence of anemia in ICUs. We performed a prospective, observational, multicenter study in five Spanish hospitals. A total of 142 patients with a median age of 58 years (IQI: 48-69), 71.83% male and 28.17% female, were admitted to ICUs without a diagnosis of iatrogenic anemia. During their ICU stay, anemia appeared in 66.90% of the sample, 95 patients, (95% CI: 58.51-74.56%). Risk factors associated with the occurrence of iatrogenic anemia were arterial catheter insertion (72.63% vs. 46.81%, p -value = 0.003), venous catheter insertion (87.37% vs. 72.34%, p -value = 0.023), drainages (33.68% vs. 12. 77%, p -value = 0.038), and ICU stay, where the longer the stay, the higher the rate of iatrogenic anemia (p -value < 0.001). We concluded that there was a statistical significance in the production of iatrogenic anemia due to the daily sampling for laboratory monitoring and critical procedures in intensive care units. The implementation of patient blood management programs could address these issue