Cristina Estrada

Inflammation in Parkinson’s disease: role of glucocorticoids

Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD). Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules e.g., TNF-α, iNOS, IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Recent genetic studies point to the role of immune system in the etiology of PD, thus in combination with environmental factors, both peripheral and CNS-mediated immune responses could play important roles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are known to mediate chronic inflammation, the roles of other immune-competent cells are less well understood. Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis. Glucocorticoids (GCs) released from adrenal glands upon stimulation of HPA axis, in response to either cell injury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both through direct transcriptional action on target genes and by indirectly inhibiting transcriptional activities of transcriptional factors such as NF-κB, AP-1 or interferon regulatory factors. In PD patients, the HPA axis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GR function in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucial effect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover, GCs are also known to regulate human brain vasculature as well as blood brain barrier (BBB) permeability, any dysfunction in their actions may influence infiltration of cytotoxic molecules resulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor actions is likely important in dopamine neuron degeneration through establishment of chronic inflammation.

Near-infrared spectroscopy in the critical setting.

Near-infrared spectroscopy is a noninvasive means of determining real-time changes in regional oxygen saturation of cerebral and somatic tissues. Hypoxic neurologic injuries not only involve devastating effects on patients and their families but also increase health care costs to the society. At present, monitors of cerebral function such as electroencephalograms, transcranial Doppler, jugular bulb mixed venous oximetry, and brain tissue oxygenation monitoring involve an invasive procedure, are operator-dependent, and/or lack the sensitivity required to identify patients at risk for cerebral hypoxia. Although 20th century advances in the understanding and management of resuscitation of critically ill and injured children have focused on global parameters (ie, pulse oximetry, capnography, base deficit, lactate, etc), a growing body of evidence now points to regional disturbances in microcirculation that will lead us in a new direction of adjunctive tissue monitoring and response to resuscitation. In the coming years, near-infrared spectroscopy will be accepted as a way for clinicians to more quickly and noninvasively identify patients with altered levels of cerebral and/or somatic tissue oxygenation and, in conjunction with global physiologic parameters, guide efficient and effective resuscitation to improve outcomes for critically ill and injured pediatric patients.

Procalcitonin as a marker of severe bacterial infection in children in the emergency department.

Procalcitonin, the prohormone of calcitonin, is a relatively new and innovative marker of bacterial infection that has multiple potential applications in the pediatric emergency department. In healthy individuals, circulating levels of procalcitonin are generally very low (<0.05 ng/mL), but in the setting of severe bacterial infection and sepsis, levels can increase by hundreds to thousands of fold within 4 to 6 hours. Although the exact physiologic function of procalcitonin has not been determined, the consistent response and rapid rise of this protein in the setting of severe bacterial infection make procalcitonin a very useful biomarker for invasive bacterial disease. In Europe, serum procalcitonin measurements are frequently used in the diagnosis and the management of patients in a variety of clinical settings. To date, the use of procalcitonin has been limited in the United States, but this valuable biomarker has many potential applications in both the pediatric emergency department and the intensive care unit. The intent of this article is to review the history of procalcitonin, describe the kinetics of the molecule in response to bacterial infection, describe the laboratory methods available for measuring procalcitonin, examine the main causes of procalcitonin elevation, and evaluate the potential applications of procalcitonin measurements in pediatric patients.

Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure

BACKGROUND Ketamine is widely used for procedural sedation, but there is limited knowledge on whether ketamine use is associated with elevated intraocular pressure (IOP). OBJECTIVE The aim of this study was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation. METHODS We prospectively enrolled children without ocular abnormalities undergoing procedural sedation that included ketamine for nonperiorbital injuries. We measured IOP for each eye before and at 1, 3, 5, 15, and 30 minutes after initial intravenous ketamine administration. We performed Bland-Altman plots to determine if IOP measurements in both eyes were in agreement. Linear regression was used to model the mean IOP of both eyes as a function of time, dose, and age, with a robust sandwich estimator to account for repeated measures. RESULTS Among 25 participants, median (interquartile range) age was 11 (9-12) years, and 18 (72%) were male. Median ketamine dose was 1.88 mg/kg (interquartile range, 1.43-2.03 mg/kg; range 0.96-4 mg/kg). Bland-Altman plots demonstrated a mean difference of IOP between eyes near zero at all time points. The largest predicted difference from baseline IOP occurred at 15 minutes, with an estimated change of 1.09 mm Hg (95% confidence interval, -0.37 to 2.55). The association between ketamine dose and mean IOP was not statistically significant or clinically meaningful (P = .90; estimated slope, 0.119 [95% confidence interval, -1.71 to 1.95]). There were no clinically meaningful levels of increased measured average IOP reached at any time point. CONCLUSIONS At dosages of 4 mg/kg or less, there are not clinically meaningful associations of ketamine with elevation of IOP.

Home hospitalization unit: an alternative to standard inpatient hospitalization from the emergency department.

Objective To assess the characteristics of the patients admitted to a home hospitalization unit (HHU) after a first emergency department (ED) visit. Methods This was a descriptive, retrospective study. The setting of the study was the ED of a 500-bed teaching hospital, which treats 125 000 emergency visits per year. HHU admits patients from the ED when hospitalization is imminent. Participants were all patients attending our ED from 1 January 2005 to 31 December 2005 and finally admitted to HHU. Variables were age, sex, diagnostic, mean length of stay, and readmission rate. Results A cohort composed of 250 patients admitted to HHU directly from the ED was identified. Mean age was 75 years. One hundred and fifty-eight were males (63%). The most common diagnoses were acute exacerbation of chronic obstructive pulmonary disease (127 of 250 patients, 50.8%), acute exacerbation of chronic heart failure (32 of 250 patients, 12.8%), pneumonia (24 of 250 patients, 9.6%), urinary tract infection (20 of 250 patients, 8%), and leg deep venous thrombosis (14 of 250 patients, 5.6%). Mean length of stay was 8 days. Readmission rate was 9%. Conclusion A HHU proved to be effective and safe for acutely ill individuals who required hospitalization.

Octodon degus: A Model for the Cognitive Impairment Associated with Alzheimer's Disease

Octodon degus (O. degus) is a diurnal rodent that spontaneously develops several physiopathological conditions, analogous in many cases to those experienced by humans. In light of this, O. degus has recently been identified as a very valuable animal model for research in several medical fields, especially those concerned with neurodegenerative diseases in which risk is associated with aging. Octodon degus spontaneously develops β‐amyloid deposits analogous to those observed in some cases of Alzheimers disease (AD). Moreover, these deposits are thought to be the key feature for AD diagnosis, and one of the suggested causes of cell loss and cognitive deficit. This review aims to bring together information to support O. degus as a valuable model for the study of AD.

Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease.

HIGHLIGHTSThe kynurenine pathway is one of the major regulators of the immune response and is also implicated in the inflammatory and neurotoxic events in Parkinsonism.Kynurenic acid produced by astrocytes confers neuroprotection whereas quinolinic acid, released by activated microglia, can lead to excitotoxicity and amplify the inflammatory response. ABSTRACT Parkinsons disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Neuroinflammation leads to microglia activation and release of a large number of proinflammatory mediators. The kynurenine pathway (KP) of tryptophan catabolism is one of the major regulators of the immune response and is also likely to be implicated in the inflammatory and neurotoxic events in Parkinsonism. Several neuroactive compounds are produced through the KP that can be either a neurotoxic, neuroprotective or immunomodulator. Among these metabolites kynurenic acid (KYNA), produced by astrocytes, is considered as neuroprotective whereas quinolinic acid (QUIN), released by activated microglia, can activate the N‐methyl‐d‐aspartate (NMDA) receptor‐signalling pathway, leading to excitotoxicity and amplify the inflammatory response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that some of the KP metabolites could be used as prognostic biomarkers and that pharmacological modulators of the KP enzymes could represent a new therapeutic strategy for PD.

Age variability in pediatric injuries from falls

OBJECTIVE The objective of this study is to examine the nature and circumstances surrounding pediatric fall-related injuries for specific age groups and their implications for age-appropriate injury prevention efforts. METHODS This is a retrospective analysis of data (October 2006 to April 2009) from the trauma registry of a level 1 pediatric trauma center. Inclusion criteria are patients admitted because of fall-related injury younger than 15 years (n = 675). Injury mechanism specifics were obtained from medical records. RESULTS Falls were the leading cause of admissions and accounted for 37% of all cases during this period. Most pediatric fall-related injuries (73%) occurred between 1 and 9 years of age. Although infants accounted for only 8% of fall injuries, a greater proportion of these children were more severely injured. The mean Injury Severity Score for infants was significantly greater than the overall average (P < .001). Causes of fall injuries vary by age and have been discussed. CONCLUSIONS The high incidence of pediatric fall injuries warrants dedicated injury prevention education. Injury prevention efforts need to be age appropriate in terms of focus, target audience, and setting. Recommendations for injury prevention are discussed.

Derivación sin visita desde los servicios de urgencias hospitalarios: cuantificación, riesgos y grado de satisfacción

Fundamento y objetivo: Desde hace unos anos, algunos centros hospitalarios redirigen a los pacientes que acuden a urgencias con enfermedades menores hacia niveles asistenciales mas adecuados sin que se les visite. A continuacion se presenta la experiencia de 2 hospitales que aplican modelos diferenciales y se analiza la idoneidad de esta medida. Pacientes y metodo: A los pacientes con sintomas menores que consultan en la Unidad de Urgencias de Medicina (UUM) del Servicio de Urgencias Hospitalario (SUH), del Hospital Clinic de Barcelona (HCB), se les propone que se les visite en un centro externo de urgencias extrahospitalarias que depende del propio hospital, mientras que el Hospital Mutua de Terrassa (HMT) los remite a los centros de asistencia primaria correspondientes. Durante un ano, se ha medido la actividad de ambos hospitales, se ha cuantificado el porcentaje de derivaciones propuestas (DP) por los medicos de la UUM, de derivaciones aceptadas (DA) por los pacientes, de derivaciones consumadas (DC, pacientes que acuden realmente al centro externo), de derivaciones retornadas (DR) al SUH, la causa de las DR y el porcentaje de ingresos. Ademas se ha realizado una encuesta de satisfaccion. Resultados: Durante el periodo de estudio se visitaron 44.764 pacientes y a un 16,3% se les propuso acudir al centro externo sin visita previa. El porcentaje de DA y DC fue del 94,3 y del 75,3%, respectivamente. El de DP fue superior en el HMT (el 18,7 frente al 13,1%; p < 0,001), mientras que el HCB tuvo mayores porcentajes de DA (el 98,9 frente al 92,0%; p < 0,001) y DC (el 93,7 frente al 65,0%; p < 0,001). Se registro un 1,5% de DR, que fueron superiores en el HCB (el 2,8 frente al 0,4%; p < 0,001). El indice global de ingresos fue del 0,17%. Solo al 41% de los pacientes le parecio bien de entrada acudir a otro recurso asistencial, pero tras la experiencia el 93% afirmo que volveria a aceptarla. El HMT fue mas rapido en facilitar la informacion (p < 0,05), mientras que el HCB tuvo una mejor valoracion global del sistema (p < 0,01) y del grado de resolucion del problema (p < 0,05) y genero un menor numero de consultas medicas posteriores (p < 0,05). Conclusiones: Es posible derivar sin visita previa a un porcentaje sustancial de pacientes que consultan por situaciones menores desde una UUM del SUH a un centro externo, sin que ello signifique un riesgo para ellos. Estos pacientes muestran mayor satisfaccion con un modelo en el que el centro externo depende del propio hospital que con uno en que el centro externo sea el propio centro de asistencia primaria.

Memantine prevents reference and working memory impairment caused by sleep deprivation in both young and aged Octodon degus

Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition. The Octodon degus (O. degus) has been recently proposed as a potential model relevant for neurodegenerative diseases. However, there are no previous studies investigating the effect of pharmacological treatments for age-related cognitive impairment in this rodent. In this work we aimed to evaluate the effect of memantine on sleep deprivation (SD)-induced memory impairment in young and old O. degus. Young and old animals were trained in different behavioral paradigms validated for memory evaluation, and randomly assigned to a control (CTL, n=14) or an SD (n=14) condition, and treated with vehicle or memantine (10-mg/Kg i.p.) before the SD started. We demonstrate that SD impairs memory in both young and old animals, although the effect in the old group was significantly more severe (P<0.05). Memantine pretreatment was able to prevent the cognitive impairment caused by SD in both age groups, while it had no negative effect on CTL animals. The positive effect of memantine in counteracting the negative effect of SD on the retrieval process even in the aged O. degus further supports the translational potential of both the challenge and the species, and will enable a better understanding of the behavioral features of memantine effects, especially related with reference and working memories.