Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising ...strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 4-2-(4-chlorophenyl)ethyl-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.
•SA-57 inhibits fatty acid amide hydrolase and monoacylglycerol lipase.•SA-57 reverses allodynia in mouse neuropathic and inflammatory pain models.•CB1 and CB2 receptors mediate the antinociceptive effects of SA-57 in the carrageenan model of inflammatory pain.•SA-57 enhances morphine-induced antinociception.•SA-57 reduces heroin self-administration.
Root rot affecting holm oak is a cause of high ecological and economic losses in the Iberian Peninsula, highlighting the relevance of developing disease control methods. The aim of this work was to ...assess the effect of a biological treatment composed of beneficial organisms (Trichoderma complex, T-complex) on holm oak seedlings infected by Phytophthora cinnamomi in two contrasted holm oak ecotypes, one considered highly susceptible (HU) and another considered tolerant to the pathogen (GR). For this purpose, a complete multifactorial test was carried out in a greenhouse, and seedlings were monitored for survival analysis and morphological and physiological attribute evaluation. Mortality began earlier in the susceptible (HU) than in the tolerant (GR) ecotype, and survival showed different trends due to the inoculation with beneficial microorganisms depending on the ecotype of the plants. The tolerant ecotype showed a high survival rate and better response to the treatment with beneficial microorganisms. GLM showed that the main reason for differences between treatments was ecotype, followed by T-complex and irrigation, and a weak interaction between ecotype and P. cinnamomi was found. The linear relationship between photosynthesis (A) and transpiration (Tr) showed an increase in the A/Tr rates for infected and inoculated plants under drought conditions for the GR ecotype. The tolerant ecotype was benefited more by the beneficial microorganism treatment. The understanding of the genetic diversity of Q. ilex and water stress influence on the efficacy of biological treatments against root rot provides useful information to develop environmentally friendly disease control methods to address the holm oak decline.
Pseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve ...suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia.
We ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers.
The median (25-75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75-5.69), 0.72 (0.12-3.35), and 0.90 (0-4.55) log
CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas.
In a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.
Animal models of acute respiratory distress syndrome (ARDS) do not completely resemble human ARDS, struggling translational research. We aimed to characterize a porcine model of ARDS induced by ...pneumonia-the most common risk factor in humans-and analyze the additional effect of ventilator-induced lung injury (VILI).
Bronchoscopy-guided instillation of a multidrug-resistant Pseudomonas aeruginosa strain was performed in ten healthy pigs. In six animals (pneumonia-with-VILI group), pulmonary damage was further increased by VILI applied 3 h before instillation and until ARDS was diagnosed by PaO
/FiO
< 150 mmHg. Four animals (pneumonia-without-VILI group) were protectively ventilated 3 h before inoculum and thereafter. Gas exchange, respiratory mechanics, hemodynamics, microbiological studies and inflammatory markers were analyzed during the 96-h experiment. During necropsy, lobar samples were also analyzed.
All animals from pneumonia-with-VILI group reached Berlin criteria for ARDS diagnosis until the end of experiment. The mean duration under ARDS diagnosis was 46.8 ± 7.7 h; the lowest PaO
/FiO
was 83 ± 5.45 mmHg. The group of pigs that were not subjected to VILI did not meet ARDS criteria, even when presenting with bilateral pneumonia. Animals developing ARDS presented hemodynamic instability as well as severe hypercapnia despite high-minute ventilation. Unlike the pneumonia-without-VILI group, the ARDS animals presented lower static compliance (p = 0.011) and increased pulmonary permeability (p = 0.013). The highest burden of P. aeruginosa was found at pneumonia diagnosis in all animals, as well as a high inflammatory response shown by a release of interleukin (IL)-6 and IL-8. At histological examination, only animals comprising the pneumonia-with-VILI group presented signs consistent with diffuse alveolar damage.
In conclusion, we established an accurate pulmonary sepsis-induced ARDS model.
To evaluate the expression dynamics of biofilm genes in methicillin-resistant
(MRSA) retrieved from endotracheal tubes (ETT) and to determine how gene regulation is attenuated in vitro where ...host-environmental factors are no longer present.
Biofilm was grown (24 h) in tryptic broth soy plus 0.25% glucose for a clinical MRSA isolate in planktonic state and after sessile growth named ETT-MRSA (S2, S3, S4, S5, S6, S7). Gene expression of five biofilm-related genes (
,
,
,
, and
) was assessed consecutively from day 1 to day 4 after ETT growth through real-time PCR. 16S rRNA was used as a control.
The MRSA isolates retrieved from ETT were capable of producing biofilms dependent on
. The gene expression dynamics of ETT-MRSA changed progressively compared to planktonic MRSA gene expression under both ambient air (
< 0.001) and ambient air with 5% CO2 (
< 0.001). Dynamic assessment of
expression in both atmospheric conditions showed progressive downregulation in vitro compared to in vivo ETT biofilms. The expression patterns of
and
genes were similar to
In contrast, the expression of the
gene showed progressive upregulation from day 1 to day 4 (
< 0.001).
MRSA loses its biofilm gene expression in vitro, by adaptive features across multiple generations, as evidenced by the progressive downregulation of
and upregulation of
. These findings underscore the significance of host-environment dependence in regulating bacterial biofilm genes, highlighting its importance in diagnostics. Bacterial strains lose their host-specific characteristics as they are cultured in vitro.
Among all cases of nosocomial pneumonia, Staphylococcus aureus is the second most prevalent pathogen (17.8%). In Europe, 29.9% of the isolates are oxacillin-resistant. The changing epidemiology of ...methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infections and the decreasing susceptibility to first-line antibiotics leave clinicians with few therapeutic options. The objective of our study was to determine the antimicrobial susceptibility, the associated molecular mechanisms of resistance and the epidemiological relatedness of MRSA strains isolated from the endotracheal tubes (ETT) of intubated critically ill patients in the intensive care unit (ICU) with nosocomial pneumonia caused by Staphylococcus aureus.
The antimicrobial susceptibility to vancomycin, linezolid, ciprofloxacin, clindamycin, erythromycin, chloramphenicol, fusidic acid, gentamicin, quinupristin-dalfopristin, rifampicin, sulfamethoxazole/trimethoprim, and tetracycline were measured. Resistance mechanisms were then analyzed by polymerase chain reaction and sequencing. Molecular epidemiology was carried out by multi-locus sequence typing.
S. aureus isolates were resistant to ciprofloxacin, erythromycin, gentamicin, tetracycline, clindamycin, and fusidic acid. The most frequent mutations in quinolone-resistant S. aureus strains were S84L in the gyrA gene, V511A in the gyrB gene, S144P in the grlA gene, and K401R/E in the grlB gene. Strains resistant to erythromycin carried the ermC, ermA, and msrA genes; the same ermC and ermA genes were detected in strains resistant to clindamycin. The aac(6')-aph(2″) gene was related to gentamicin resistance, while resistance to tetracycline was related to tetK (efflux pump). The fusB gene was detected in the strain resistant to fusidic acid. The most frequent sequence types were ST22, ST8, and ST217, which were distributed in four clonal complexes (CC5, CC22, CC45, and CC59).
High levels of resistance to second-line antimicrobials threatens the treatment of nosocomial respiratory infections due to methicillin-resistant S. aureus with decreased susceptibility to linezolid and vancomycin. The wide genotypic diversity found reinforces the central role of ICU infection control in preventing nosocomial transmission.
Biofilm production is an important yet currently overlooked aspect of diagnostic microbiology that has implications for antimicrobial stewardship. In this study, we aimed to validate and identify ...additional applications of the BioFilm Ring Test® (BRT) for Pseudomonas aeruginosa (PA) isolates from patients with bronchiectasis (BE).
Sputa were collected from BE patients who had at least one PA positive culture in the previous year. We processed the sputa to isolate both mucoid and non-mucoid PA, and determined their susceptibility pattern, mucA gene status, and presence of ciprofloxacin mutations in QRDR genes. The Biofilm production index (BPI) was obtained at 5 and 24 hours. Biofilms were imaged using Gram staining.
We collected 69 PA isolates, including 33 mucoid and 36 non-mucoid. A BPI value below 14.75 at 5 hours predicted the mucoid PA phenotype with 64% sensitivity and 72% specificity.
Overall, our findings suggest that the fitness-cost associated with the mucoid phenotype or ciprofloxacin resistance is shown through a time-dependent BPI profile. The BRT has the potential to reveal biofilm features with clinical implications.
Ubicación de empresas del sector comercio en Bogotá en 2015 Diego Rafael Roberto Cabrera-Moya, Ph.D.; Germán Alfonso Prieto-Rodríguez, Ph.D. (c)
Cuadernos Latinoamericanos de Administraciâon (En linea),
04/2021, Volume:
17, Issue:
32
Journal Article
Peer reviewed
Open access
El texto se basa en la tesis doctoral adelantada por uno de los autores en el marco del Doctorado en Ciencias de la Dirección de la Universidad del Rosario en Bogotá, Colombia. En la investigación se ...estudió la relación entre el desarrollo del sistema de transporte BRT de la ciudad y las decisiones de localización que toman las empresas en Bogotá. Allí se comprueba la dinámica evolutiva de la ubicación de las empresas y la morfología urbana de la ciudad durante los años 2005, 2010 y 2015. En este artículo se presentan los resultados de la evaluación del índice I de Moran como evidencia de la tipología de distribución para las empresas del sector comercial en el año 2015. Esta evaluación analizada en conjunto con resultados obtenidos mediante el uso de otros indicadores de distribución espacial permite afirmar que, la figura de distribución urbana que en la década de los años 70´s del siglo XX correspondía a la categoría de monocentrismo y que al inicio de los años 2000 correspondía a la categoría de policentrismo, en al año 2015 se había transformado respondiendo a los principios de la categoría que en la literatura se conoce como policentrismo especializado. Esta categoría se considera como un indicador de presencia de dinámicas de aglomeración empresarial en la ciudad. Como conclusión se destaca que los resultados el estudio demuestran la hipótesis cuya verificación se anuncia en el título y que a su vez se convierte en el planteamiento del problema: la ciudad de Bogotá y en particular las empresas del sector comercio evidencia la presencia de dinámicas de aglomeración, respondiendo a los principales postulados de esta teoría.
Social stress in adulthood enhances cocaine self‐administration, an effect that has been related with an increase in extracellular signal‐regulated kinase and p38α mitogen‐activated protein kinase ...phosphorylation. A detrimental effect of cocaine on blood–brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self‐administration, conditioned place preference and quantitative analysis of claudin‐5, laminin, collagen‐IV and IgG immunoreactivity took place 3 weeks after RSD. Mice socially defeated during adolescence developed conditioned place preference and exhibited reinstated preference with a non‐effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine self‐administration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin‐5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen‐IV expression) in the nucleus accumbens and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen‐IV expression in the hippocampus was more pronounced in RSD mice. In summary, our findings suggest that stress and cocaine can increase the long‐term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB.
The current study shows for the first time that mice exposed to RSD undergo significant changes in BBB structure. RSD during adolescence induces a marked reduction in expression of the tight junction protein claudin‐5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen‐IV expression) in the NAc in adulthood. Concomitantly, there is an increase in IgG extravasation, indicating that social defeat increases BBB permeability, probably through alterations in structural proteins.
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