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OBJECTIVES: Preoperative medication errors can be prevented by screening patients through a preoperative pharmaceutical care consultation. The aim of this study was to analyse the cost-effectiveness of implementing such a consultation and to determine which patients would benefit most. METHODS: A retrospective study was conducted that included all patients who underwent a preoperative pharmacy consultation between 2016 and 2020. During this consultation, two part-time pharmacists reviewed patients' appropriate preoperative chronic medication management. All prevented errors were collected and classified by therapeutic group and type of error. A team of pharmacists and anaesthetists assigned to each prevented medication error a probability of causing an adverse event 'p', following the methodology of Nesbit et al by establishing five different 'p' values: 0, 0.01, 0.1, 0.4, and 0.6. 'p' = 1 was not considered. The cost of an adverse event was determined to be between 4124 and 6946 according to current literature, and a sensitivity analysis was performed by increasing the interval by 20% above and below. The cost of employing two part-time specialist pharmacists was estimated to be 59 142. Savings per medication error prevented were calculated as (4124 OR 6946) × 'p'. Total savings were the sum of all costs associated with prevented medication errors. Patients on chronic medications who were in therapeutic groups with a 0.6 probability of an adverse event or who were in therapeutic groups responsible for 50% of the prevented adverse events were considered prioritisable. RESULTS: 3105 patients attended the consultation and 1179 medication errors were prevented, corresponding to 300 adverse events. 42.2% of the errors had a 'p' of 0.4. The costs avoided by this consultation ranged from 1 237 200 to 2 083 800, while the cost of its implementation was 295 710. The cost-effectiveness ratio was between 4.2 and 7.0 saved per euro invested. In the sensitivity analysis, the ratios ranged from 3.3 to 8.5 per euro invested. Fifteen different therapeutic groups accounted for 90% of the medication errors prevented. The therapeutic groups 'Agents acting on the renin-angiotensin system', 'Antidiabetics, non-insulin (excluding SGLT2)' and 'Antithrombotics: low molecular weight heparins' were responsible for 56% of the prevented adverse events. The therapeutic groups 'Antidiabetics: rapid-acting insulin' and 'Antithrombotic agents: vitamin K antagonists, low-molecular-weight heparins, or direct oral anticoagulants' had a 'p' of 0.6. Therefore, patients in six therapeutic groups should be prioritised for preoperative pharmacy counselling. CONCLUSIONS: The implementation of preoperative pharmaceutical care consultations in Spain has proven to be cost-effective. Incorporating the probability of a medication error causing an adverse event allowed the prioritisation of patients for these consultations. Patients taking anticoagulants, oral antidiabetics, rapid-acting insulins, and agents acting on the renin-angiotensin system benefited the most. This study could serve as a basis for implementing such consultations in other hospitals, as they are effective in reducing the cost of medication errors in surgical patients.
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OBJECTIVES: Perform radiologic measurements and analysis of normal brain computed tomography (CT) scans; delineate a new ventricular entry point from cutaneous landmarks, highlighting the potential surgical implications of these findings. METHODS: Six radiologic distances (AR; BR; AL; BL, C, and D) were measured in normal brain CT scans using Horos software. Statistical analysis of the measurements was performed with minitab18 software based on age, sex, and side. RESULTS: 132 brain CT scans were analyzed, yielding the following mean results: AR distance: 2.1 cm; BR distance: 7 cm; AL distance: 2.1 cm; BL distance: 7.1 cm; C distance: 12.4 cm; D distance: 7 cm; new ventricular entry point: 12.4 cm posterior to the nasion, and 2.1 cm lateral to the midline. CONCLUSIONS: The freehand technique for accessing the lateral ventricles is a common neurosurgical procedure but is often accompanied by complications. To address this, we suggest a novel entry point for ventricular access, determined by cutaneous reference points. This point is situated 12.4 cm posterior to the nasion along the midline and 2.1 cm lateral to the midline. Although our findings may play a role in presurgical planning for ventricular pathologies, future prospective studies are warranted.
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Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Adulto Joven , Adolescente , Ventrículos Cerebrales/cirugía , Ventrículos Cerebrales/diagnóstico por imagen , Anciano de 80 o más Años , Puntos Anatómicos de Referencia , Piel/diagnóstico por imagen , Ventriculostomía/métodos , Ventrículos Laterales/cirugía , Ventrículos Laterales/diagnóstico por imagenRESUMEN
Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Current therapies are only symptomatic and are not able to stop or delay its progression. In order to search for new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds that are able to improve locomotor ability in DJ-1ß mutant flies (a Drosophila model of familial PD) and reduce oxidative stress (OS)-induced lethality in DJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability, and reduced OS levels in DJ-1-deficient human cells. In addition, our results show that VIN might be exerting its beneficial role, at least partially, by the inhibition of voltage-gated sodium channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD and that VIN represents a potential therapeutic treatment for the disease.
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Proteínas de Drosophila , Neuroblastoma , Enfermedad de Parkinson , Vincamina , Animales , Humanos , Suplementos Dietéticos , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas del Tejido Nervioso/genética , Estrés Oxidativo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Proteína Desglicasa DJ-1/genética , Proteína Desglicasa DJ-1/farmacología , Proteína Desglicasa DJ-1/uso terapéutico , Vincamina/farmacología , Vincamina/uso terapéuticoRESUMEN
Diabetes mellitus (DM) is a chronic metabolic disease characterized by high blood glucose levels, resulting from insulin dysregulation. Parkinson's disease (PD) is the most common neurodegenerative motor disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. DM and PD are both age-associated diseases that are turning into epidemics worldwide. Previous studies have indicated that type 2 DM might be a risk factor of developing PD. However, scarce information about the link between type 1 DM (T1DM) and PD does exist. In this work, we have generated a Drosophila model of T1DM based on insulin deficiency to evaluate if T1DM could be a risk factor to trigger PD onset. As expected, model flies exhibited T1DM-related phenotypes such as insulin deficiency, increased content of carbohydrates and glycogen, and reduced activity of insulin signaling. Interestingly, our results also demonstrated that T1DM model flies presented locomotor defects as well as reduced levels of tyrosine hydroxylase (a marker of DA neurons) in brains, which are typical PD-related phenotypes. In addition, T1DM model flies showed elevated oxidative stress levels, which could be causative of DA neurodegeneration. Therefore, our results indicate that T1DM might be a risk factor of developing PD, and encourage further studies to shed light into the exact link between both diseases.
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Diabetes Mellitus Tipo 1 , Insulinas , Enfermedad de Parkinson , Animales , Enfermedad de Parkinson/etiología , Drosophila , Diabetes Mellitus Tipo 1/complicaciones , Factores de RiesgoRESUMEN
In 2022, mpox, an orthopoxvirus first isolated in 1958 in cynomolgus monkeys, became a global public health threat. While the virus can be communicated through skin-to-skin contact from any infected person to non-infected person, most cases in the United States have been in gay and bisexual men. Consequently, early public health and community-based efforts concentrated on reducing infections in this population. This article explores current mpox case count epidemiologic data and trends. In addition, vaccination indications, contraindications, adverse events, and national administration data are provided along with directions for nurses and other clinicians moving forward in the outbreak.
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Mpox , Minorías Sexuales y de Género , Humanos , Masculino , Estados Unidos/epidemiología , Enfermería en Salud Pública , Brotes de Enfermedades , Salud PúblicaRESUMEN
Introduction: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. Methods: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. Results: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.735.2]), hospitalization in the past 12 months (OR 3.7 [1.59.2]), and bronchiectasis (OR 3.2 [1.47.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. Conclusions: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy. (AU)
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Infecciones Comunitarias Adquiridas , Neumonía/epidemiología , Antibacterianos/uso terapéutico , Pseudomonas , Factores de RiesgoRESUMEN
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. METHODS: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. RESULTS: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. CONCLUSIONS: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.
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Infecciones Comunitarias Adquiridas , Neumonía , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Antibacterianos/uso terapéutico , Neumonía/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/epidemiología , Streptococcus pneumoniae , Pseudomonas aeruginosaAsunto(s)
Humanos , Masculino , Femenino , Mortalidad , Angioplastia , Mortalidad Hospitalaria , Resultado del Tratamiento , Infarto del Miocardio , Cardiología , Cardiopatías , EspañaRESUMEN
Although long-term smoking has been associated with chronic kidney disease, its effect on kidney function in early stages has not been clarified. Therefore, the proposed objectives were: (1) to identify subclinical kidney damage in smokers, through a panel of biomarkers; (2) to evaluate the progression of subclinical kidney damage after two years of consumption in these patients; and (3) study whether quitting smoking reduces kidney damage. A prospective study was carried out (patients recruited from a primary care centre and a clinical smoking unit). Kidney function was assessed using a panel of biomarkers and compared between smokers and non-smokers, taking into account potential risk factors for kidney damage. These results show, for the first time in the literature, the relationship between smoking and early (subclinical) kidney damage and provide a panel of biomarkers capable of detecting this condition (Neutrophil gelatinase-associated lipocalin, Kidney injury molecule-1, N-acetyl-beta-D-glucosaminidase, transferrin, and ganglioside-activating protein GM2). This study also indicates that subclinical damage is maintained when use continues, but can be reversed if patients stop smoking. The use of these biomarkers as diagnostic tools can be a preventive measure in the development of chronic kidney disease associated with smoking and in the prevention of acute events associated with potentially nephrotoxic pharmacological treatment in smokers. Trial registration number: NCT03850756.
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Parkinson's disease (PD) is the second most common neurodegenerative disease. Diabetes mellitus (DM) is a metabolic disease characterized by high levels of glucose in blood. Recent epidemiological studies have highlighted the link between both diseases; it is even considered that DM might be a risk factor for PD. To further investigate the likely relation of these diseases, we have used a Drosophila PD model based on inactivation of the DJ-1ß gene (ortholog of human DJ-1), and diet-induced Drosophila and mouse type 2 DM (T2DM) models, together with human neuron-like cells. T2DM models were obtained by feeding flies with a high sugar-containing medium, and mice with a high fat diet. Our results showed that both fly models exhibit common phenotypes such as alterations in carbohydrate homeostasis, mitochondrial dysfunction or motor defects, among others. In addition, we demonstrated that T2DM might be a risk factor of developing PD since our diet-induced fly and mouse T2DM models present DA neuron dysfunction, a hallmark of PD. We also confirmed that neurodegeneration is caused by increased glucose levels, which has detrimental effects in human neuron-like cells by triggering apoptosis and leading to cell death. Besides, the observed phenotypes were exacerbated in DJ-1ß mutants cultured in the high sugar medium, indicating that DJ-1 might have a role in carbohydrate homeostasis. Finally, we have confirmed that metformin, an antidiabetic drug, is a potential candidate for PD treatment and that it could prevent PD onset in T2DM model flies. This result supports antidiabetic compounds as promising PD therapeutics.
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Diabetes Mellitus Tipo 2 , Proteínas de Drosophila , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Carbohidratos , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Glucosa/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo , Enfermedad de Parkinson/metabolismo , Proteína Desglicasa DJ-1/metabolismo , AzúcaresRESUMEN
Neurodegenerative diseases (NDs) constitute a global challenge to human health and an important social and economic burden worldwide, mainly due to their growing prevalence in an aging population and to their associated disabilities. Despite their differences at the clinical level, NDs share fundamental pathological mechanisms such as abnormal protein deposition, intracellular Ca2+ overload, mitochondrial dysfunction, redox homeostasis imbalance and neuroinflammation. Although important progress is being made in deciphering the mechanisms underlying NDs, the availability of effective therapies is still scarce. Carnosine is a natural endogenous molecule that has been extensively studied during the last years due to its promising beneficial effects for human health. It presents multimodal mechanisms of action, being able to exert antioxidant, anti-inflammatory and anti-aggregate activities, among others. Interestingly, most NDs exhibit oxidative and nitrosative stress, protein aggregation and inflammation as molecular hallmarks. In this review, we discuss the neuroprotective functions of carnosine and its implications as a therapeutic strategy in different NDs. We summarize the existing works that study alterations in carnosine metabolism in Alzheimer's disease and Parkinson's disease, the two most common NDs. In addition, we review the beneficial effect that carnosine supplementation presents in models of such diseases as well as in aging-related neurodegeneration.
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Parkinson's disease (PD) is the second-most common neurodegenerative disorder, whose physiopathology is still unclear. Moreover, there is an urgent need to discover new biomarkers and therapeutic targets to facilitate its diagnosis and treatment. Previous studies performed in PD models and samples from PD patients already demonstrated that metabolic alterations are associated with this disease. In this context, the aim of this study is to provide a better understanding of metabolic disturbances underlying PD pathogenesis. To achieve this goal, we used a Drosophila PD model based on inactivation of the DJ-1ß gene (ortholog of human DJ-1). Metabolomic analyses were performed in 1-day-old and 15-day-old DJ-1ß mutants and control flies using 1H nuclear magnetic resonance spectroscopy, combined with expression and enzymatic activity assays of proteins implicated in altered pathways. Our results showed that the PD model flies exhibited protein metabolism alterations, a shift fromthe tricarboxylic acid cycle to glycolytic pathway to obtain ATP, together with an increase in the expression of some urea cycle enzymes. Thus, these metabolic changes could contribute to PD pathogenesis and might constitute possible therapeutic targets and/or biomarkers for this disease.
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Proteínas de Drosophila , Enfermedad de Parkinson , Proteína Desglicasa DJ-1 , Animales , Modelos Animales de Enfermedad , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/metabolismo , Proteína Desglicasa DJ-1/genética , Proteína Desglicasa DJ-1/metabolismoRESUMEN
OBJECTIVES: Nonagenarians are a fast-growing age group among cardiovascular patients, but data about their management and prognosis after an acute coronary syndrome (ACS) is scarce. This study aimed to analyze characteristics of nonagenarian patients with ACS and to compare in-hospital and 1-year clinical outcomes between those treated with medical treatment (MT) alone and those receiving percutaneous coronary intervention (PCI). DESIGN: Multicenter observational study. SETTING AND PARTICIPANTS: We included consecutive nonagenarian patients with ACS admitted at 4 academic centers between 2005 and 2018. Only patients with type 1 myocardial infarction were included. METHODS: Standardized definitions of all patient-related variables, clinical diagnoses, and hospital complications and outcomes were used. The primary endpoint was 1-year all-cause mortality. Long-term survival was compared between patients undergoing PCI and those managed with MT alone. Given differences in baseline characteristics could substantially interfere in outcomes, 3 sensitivity analyses were performed to adjust for confounders. RESULTS: A total of 680 nonagenarians were included (59% females). Of them, 373 (55%) patients presented with non-ST-segment elevation ACS (NSTE-ACS) and 307 (45%) with ST-segment elevation myocardial infarction (STEMI). A coronary angiogram was performed in 115 (31%) of NSTE-ACS and in 182 (60%) of STEMI patients with subsequent PCI in 81 (22%) and 156 (51%), respectively. Overall mortality rates were 17% in-hospital and 39% at 1-year follow-up. PCI was independently associated with a decreased risk of 1-year all-cause death [hazard ratio (HR) 0.57, 95% confidence interval (CI) 0.35, 0.95; P < .05], mainly observed in those patients without disability (HR 0.59, 95% CI 0.37, 0.94; P < .01) and lower Killip class (HR 0.50, 95% CI 0.28, 0.89; P < .001). CONCLUSIONS AND IMPLICATIONS: The prognosis of nonagenarians after an ACS was associated with comorbidities and the therapeutic approach. Although PCI appeared to be a safe and effective strategy, it is still necessary to refine the decision-making process in this high-risk population group.
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Síndrome Coronario Agudo , Infarto del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Síndrome Coronario Agudo/terapia , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Nonagenarios , Factores de Riesgo , Resultado del TratamientoRESUMEN
Dopamine replacement represents the standard therapy for Parkinson's disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood-brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1ß is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1ß exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1ß mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials.
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Enfermedad de Parkinson , Animales , Drosophila/genética , Drosophila/metabolismo , Estrés Oxidativo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteína Desglicasa DJ-1/genética , Proteína Desglicasa DJ-1/metabolismo , Purinonas/metabolismo , Purinonas/farmacología , Purinonas/uso terapéuticoRESUMEN
Mapping of Event-Related Potentials (ERP) associated with auditory and visual odd-ball paradigms has shown consistent differences between healthy controls and schizophrenia patients. It may be hypothesized that higher task attentional/cognitive demand will result in larger differences in these paradigms, which may help understanding the substrates of cognitive deficits in this syndrome. To this aim, we performed an EEG study comparing the effects of increasing the attentional/cognitive load of an auditory N-back task on the Event-Related Potential in 50 subjects with schizophrenia (11 first episodes) and 35 healthy controls. We considered a post-target window of 1000 ms to explore possible between groups differences in N100, P300, and Late Slow Wave (LSW), and compared these components between 0-back ('lower attentional/cognitive load) and 1-back ('higher attentional/cognitive load') conditions. Our results showed that N100 and LSW amplitude increase from 0- to 1-back condition was significantly larger in healthy controls compared to schizophrenia patients. Furthermore, LSW amplitude difference between 0- and 1-back conditions positively correlated with performance in the behavioral cognitive assessment. Taken together, these results support that higher task attentional/cognitive load (0-back vs. 1-back condition) increase N100 amplitude differences and reveal new findings related to the LSW component in schizophrenia.
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Atención/fisiología , Disfunción Cognitiva/fisiopatología , Potenciales Relacionados con Evento P300/fisiología , Potenciales Evocados Auditivos/fisiología , Esquizofrenia/fisiopatología , Análisis y Desempeño de Tareas , Adulto , Electroencefalografía , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricosRESUMEN
DJ-1 is a causative gene for familial Parkinson's disease (PD) with different functions, standing out its role against oxidative stress (OS). Accordingly, PD model flies harboring a mutation in the DJ-1ß gene (the Drosophila ortholog of human DJ-1) show high levels of OS markers like protein carbonylation, a common post-translational modification that may alter protein function. To increase our understanding of PD pathogenesis as well as to discover potential therapeutic targets for pharmacological intervention, we performed a redox proteomic assay in DJ-1ß mutant flies. Among the proteins that showed increased carbonylation levels in PD model flies, we found SERCA, an endoplasmic reticulum Ca2+ channel that plays an important role in Ca2+ homeostasis. Interestingly, several studies have supported the involvement of Ca2+ dyshomeostasis in PD. Thus, we decided to study the relation between SERCA activity and PD physiopathology. Our results showed that SERCA enzymatic activity is significantly reduced in DJ-1ß mutant flies, probably as a consequence of OS-induced carbonylation, as well as in a human cell PD model based on DJ-1-deficiency. Indeed, higher carbonylation levels of SERCA were also observed in DJ-1-deficient cells compared to controls. In addition, the specific activator of SERCA, CDN1163, was also able to restore PD-related phenotypes in both familial PD models by increasing SERCA activity. Taken together, our results indicate that impaired SERCA activity due to oxidative modification may play a role in PD physiopathology. Furthermore, we demonstrate that therapeutic strategies addressing SERCA activation could be beneficial to treat this disease as shown for CDN1163.
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Modelos Animales de Enfermedad , Neuroblastoma/patología , Estrés Oxidativo , Enfermedad de Parkinson/patología , Carbonilación Proteica , Proteína Desglicasa DJ-1/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Animales Modificados Genéticamente , Calcio/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Humanos , Mutación , Neuroblastoma/genética , Neuroblastoma/metabolismo , Oxidación-Reducción , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Fenotipo , Proteína Desglicasa DJ-1/genética , Proteoma/análisis , Proteoma/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genéticaRESUMEN
BACKGROUND: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. RESEARCH QUESTION: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? STUDY DESIGN AND METHODS: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. RESULTS: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P = .021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P < .001) when compared with patients with severe CAP/AspRF+ and severe CAP/AspRF-, respectively. Most patients (>50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. INTERPRETATION: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.