ABSTRACT
The progressive increase in life expectancy of the world population has fostered a major concern in order to find effective avenues for diagnosis of treatment of Alzheimer's disease (AD). Even tough AD pathogenesis is still unclear, new advances have allowed to understand that exposure of individuals to a series of environmental risk factors, named to as damage signals, play a main role in triggering the disease. This is important for AD prevention but also for the search of new treatment approaches. Activation of innate immunity in the central nervous system (CNS), essentially microglial cells, appears to be a key element in the neurodegenerative pathway As a matter of fact, when microglia cells are exposed continuously to damage signals such as metabolites from conditions of hyperlipidemia, hyperglycemia, oxidative stress, head injury and trauma, recurrent infections, in addition to supramolecular aggregates such as tau filaments or b-amyloid oligomers, among other anomalous protein filaments, they respond by triggering the inflammatory cascade. On this basis, we have postulated the neuroimmunomodulation hypothesis for Alzheimer's Disease. Therefore, we postulates that a long-term activation of brain innate immunity by a converging set of damage signals constitute a unifying mechanism that triggers the inflammatory cascade, thus leading to irreversible alteration in the neuronal cytoskeleton. These concerted alterations in signaling mechanisms will lead in neuronal cells to a final common pathway, tau hyperphosphorylations, with the consequent self-aggregation of modified tau and formation of paired helical filaments (PHFs), as the main triggering event for neurodegenration in AD.
El constante aumento en la expectativa de vida en la población mundial ha incrementado la preocupación hacia la búsqueda de la comprensión de la Enfermedad de Alzheimer (EA), así como de su diagnóstico temprano y tratamiento. Actualmente la etiopatogenia que conduce al desarrollo de la EA es aún difusa, pero se ha llegado a comprender que la exposición a una serie de distintos factores de riesgo, o señales de daño, está asociada al desencadenamiento de la EA. Esto es muy importante no solo para la prevención de esta devastadora enfermedad sino también para la búsqueda de avenidas efectivas para su tratamiento. En efecto, la activación de la inmunidad innata en el sistema nervioso central (SNC), esencialmente por las células microgliales, son un elemento clave en el proceso neurodegenerativo, cuando éstas son expuestas por períodos prolongados a señales de daño. Entre éstas están la hiperlipidemia, hiperglicemia, estrés oxidativo, traumatismos, infecciones recurrentes, oligomeros de -amiloide, agregados de tau, entre otros factores, los que desencadenarían una respuesta pro-inflamatoria persistente que conduce a la cascada neurodegenerativa. En base a esto, hemos postulado la teoría de la neuroinmunomodulación en la EA, y proponemos que la activación a largo plazo del sistema inmune innato por un conjunto de señales de daño constituye un mecanismo unificado que gatillo, una cascada inflamatoria que conduce a alteraciones irreversibles en el citoesqueleto. Estos mecanismos anómalos de señalización molecular llevarían a una vía final común que es la hiperfosforilación de la proteína tau, su autoagregación y formación de los PHFs, como desencadenantes claves en la neurodegeneración y desarrollo de la EA.
Subject(s)
Humans , Alzheimer Disease/immunology , Inflammation/immunology , Central Nervous System/immunology , Cytokines , Immunity, Innate/immunology , Microglia/immunology , Neuroimmunomodulation , Neurofibrillary Tangles/immunology , Precipitating Factors , Risk Factors , tau ProteinsABSTRACT
Background: Plasmapheresis is a therapeutic alternative for diseases in which a "humoral factor" has pathogenetic relevance. However it is not devoid of adverse effects. Aim: To review the indications, number of procedures, morbidity and clinical evolution of plasmapheresis in critical patients. Patients and Methods: A retrospective and descriptive study in four intensive care units of an University hospital. The severity of patients was evaluated with APACHE II and SOFA scores. Results: Twenty patients were studied. The most common indications of plasmapheresis were thrombotic thrombocytopenic purpura (TTP) in 50% of subjects and small vessel vasculitides in 30%. The number of procedures per patient oscillated between 2 and 14 (mean: 7.1±3.3). The registered adverse effects were hypocalcemia in 50% of patients, hypotension in 42.1%, coagulopathy in 35%, hypokalemia in 29%, rash in 20%, procedure related infections in 18% and fever in 10%. There was a significant decrease of 17±28% in prothrombin time, after the procedures. Seventy five percent of patients had a favorable evolution. Global mortality rate was 15%. All deaths occurred in patients with TTP and were attributed to the progression of the disease. No death was attributed to the procedure. The initial APACHE II and SOFA scores were 12.4±8.4 and 5.3±2.9, respectively. Both scores decreased after the procedure. Among other therapeutic measures, 15% of the patients received immunosuppressant treatment, 27% were dialyzed and 32% were mechanically ventilated. Conclusions: The most common indication of plasmapheresis was TTP. Adverse effects were frequent, however there was no procedure related mortality. The global mortality rate was 15% and all deaths occurred in patients with TTP.
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Critical Care , Critical Illness/therapy , Plasmapheresis , Purpura, Thrombotic Thrombocytopenic/therapy , APACHE , Chile/epidemiology , Hospitalization , Intensive Care Units , Plasmapheresis/adverse effects , Plasmapheresis/standards , Purpura, Thrombotic Thrombocytopenic/mortality , Retrospective StudiesABSTRACT
Background: Cardiac output can be measured non invasively by transesophageal Doppler. This is an alternative to measure it by thermodilution with a catheter in the pulmonary artery. Aim: To compare both methods of cardiac output measurement. Material and methods: Simultaneous measurement of cardiac output by transesophageal Doppler and thermodilution with a catheter in the pulmonary artery in four male critical patients, aged 60±12 years, hospitalized in a University Hospital. The Bland and Altman method to compare the concordance between two measurements, was used. Results: Forty measurements were performed. The results of both methods had a correlation coefficient of 0.98. According to the Bland and Altman method, the difference between both methods was -0.5 L with a precision of 0.52 L/min (95% confidence interval -1.51 to 0.52 L/min). Considering that a change between two sequential measurements is considered significant when the difference is more than 15%, both measurements agreed in 83% of cases, that there was a change in cardiac output. Conclusions:Transesophageal Doppler is a promising non invasive technique to measure cardiac output in critical care patients. It becomes a valid alternative to the thermodilution technique. This preliminary experience must be confirmed in a larger series.
Subject(s)
Humans , Male , Middle Aged , Cardiac Output/physiology , Catheterization, Swan-Ganz , Echocardiography, Doppler/methods , Echocardiography, Transesophageal/methods , Thermodilution/methods , Critical Care , Echocardiography, Doppler/standards , Echocardiography, Transesophageal/standards , Prospective Studies , Thermodilution/standardsABSTRACT
Background: The clinical role of blood cultures (BC) in the management of hospitalized patients with community-acquired pneumonia (CAP) is controversial. Aim: To evaluate the clinical usefulness of blood cultures in CAP. Material and methods: We prospectively studied 244 immunocompetent adults with two or more BC obtained at admission. The diagnostic yield of BC and its impact on antibiotic therapy were assessed. Results: Mean age (xñsd) of patients was 67ñ20 years, 80 percent had underlying diseases and 29 percent received antibiotics prior to admission. Hospital length of stay was 10.4ñ10 days and global mortality was 7 percent. The diagnostic yield of BC was only 8.2 percent (20 patients). Mortality was significantly higher in patients with positive BC (20 percent) than in those with negative BC (5.8 percent). In only one of the 20 patients with positive BC (0.4 percent of total study population), attending physicians changed empiric antimicrobial therapy based on these results. Conclusions: This study confirms that the diagnostic yield of BC in CAP hospitalized patients is low, that mortality in bacteremic patients is high and suggests that clinical usefulness of BC to guide changes on empiric antimicrobial therapy is limited, in part because attending physicians seldom use such information