Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by an abnormal and blunted response to physiologic, pathologic, or pharmacologic stress but normal to increased cardiac output and contractility at rest. As many as 50% of cirrhotic patients undergoing liver transplantation show signs of cardiac dysfunction, and 7% to 21% of deaths after orthotopic liver transplantation result from overt heart failure. In this review, we critically evaluate the existing literature on the pathophysiology and clinical implications of cirrhotic cardiomyopathy

Requirement for Ergosterol in V-ATPase Function Underlies Antifungal Activity of Azole Drugs

Ergosterol is an important constituent of fungal membranes. Azoles inhibit ergosterol biosynthesis, although the cellular basis for their antifungal activity is not understood. We used multiple approaches to demonstrate a critical requirement for ergosterol in vacuolar H+-ATPase function, which is known to be essential for fungal virulence. Ergosterol biosynthesis mutants of S. cerevisiae failed to acidify the vacuole and exhibited multiple vma− phenotypes. Extraction of ergosterol from vacuolar membranes also inactivated V-ATPase without disrupting membrane association of its subdomains. In both S. cerevisiae and the fungal pathogen C. albicans, fluconazole impaired vacuolar acidification, whereas concomitant ergosterol feeding restored V-ATPase function and cell growth. Furthermore, fluconazole exacerbated cytosolic Ca2+ and H+ surges triggered by the antimicrobial agent amiodarone, and impaired Ca2+ sequestration in purified vacuolar vesicles. These findings provide a mechanistic basis for the synergy between azoles and amiodarone observed in vitro. Moreover, we show the clinical potential of this synergy in treatment of systemic fungal infections using a murine model of Candidiasis. In summary, we demonstrate a new regulatory component in fungal V-ATPase function, a novel role for ergosterol in vacuolar ion homeostasis, a plausible cellular mechanism for azole toxicity in fungi, and preliminary in vivo evidence for synergism between two antifungal agents. New insights into the cellular basis of azole toxicity in fungi may broaden therapeutic regimens for patient populations afflicted with systemic fungal infections

Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

Introduction: Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods: Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum level

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE

Antifungal activity of nonantifungal drugs.

The antifungal activity of synthetic, nonchemotherapeutic compounds, antineoplastic agents and antibacterial drugs, such as sulphonamides, has been known since the early 20th century (1932). In this context, the term "nonantifungal" is taken to include a variety of compounds that are employed in the management of pathological conditions of nonfungal infectious etiology but have been shown to exhibit broad-spectrum antifungal activity. In this review, the antifungal properties of compounds such as chlorpromazine, proton pump inhibitors, antiarrhythmic agents, cholesterol-lowering agents, antineoplastic and immunosuppressive agents, antiparasitic drugs and antibiotics are described. Since fungi are eukaryotic cells, they share many pathways with human cells, thus increasing the probability of antifungal activity of "nonfungal drugs". The potential of these drugs for treatment of fungal infections has been investigated sporadically using the drugs alone or in combination with "classic" antifungal agents. A review of the literature, supplemented with a number of more recent investigations, suggests that some of these compounds enhance the activity of conventional antifungal agents, eliminate natural resistance to specific antifungal drugs (reversal of resistance) or exhibit strong activity against certain fungal strains in vitro and in animal models. The role of these agents in the epidemiology and in the clinical manifestations of fungal infections and the potential of certain drugs for treatment of invasive fungal infections require further investigation

Prevention of invasive aspergillosis in AIDS by sulfamethoxazole.

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El Interferon gamma incrementa la sobrevida de un modelo experimental murino de criptococosis

Systemic disease by Cryptococcus neoformans (C. neoformans) is a common opportunistic infection in immunodeficient patients. Cellular immunity seems to be the most important determinant of resistance. The aim of this study was to assess the effect of recombinant rat interferon gamma (IFN-gamma) in murine cryptococcosis (Balb/c mice infected by IP route with the Rivas strain of C. neoformans), evaluating survival time, macroscopic and microscopic examination of the organs, and massive seeding of brain homogenate. IFN-gamma treatment, at a daily dose of 10,000 IU, did not modify significantly these variables when mice were challenged with a high inoculum (10(7) yeasts) and treatment was delayed to 5 days after infection (median survival 21 days in control mice vs. 23 days in IFN-treated). Another set of experiments suggested that IFN-gamma treatment, at a dose of 10,000 IU/day, begun at the moment of infection could be useful (it prolonged survival from 20 to 28 days, although the difference did not achieve statistical signification). When used simultaneously with infection by 3.5 x 10(5) yeasts, IFN-gamma at 10,000 IU/day for 15 days significantly prolonged survival of mice (p = 0.004). These results suggest that, depending on the experimental conditions, IFN-gamma can improve survival of mice infected with a lethal dose of C. neoformans.Se evaluó la efectividad del interferon-gamma (IFN-gamma) recombinante de rata en un modelo experimental de criptococosis desarollado en ratones Balb/C inoculados por vía intraperitoneal con la cepa Rivas de Cryptococcus neoformans (C. neoformans). Se tuvieron en cuenta el tiempo de sobrevida de los animales, el aspecto macroscópico de los órganos en la autopsia, la presencia de levaduras capsuladas en los tejidos y la siembra masiva de un homogenato de cerebro. El tratamiento con IFN-gamma, en dosis diarias de 10.000 UI, no modificó estos parámetros cuando la dosis infectante fue de 10(7) levaduras y el tratamiento se retardó 5 días post-infección (media de sobrevida de 21 vs. 23 días en los grupos de control y tratados con IFN-gamma, respectivamente). En otros experimentos observamos una prolongación del tiempo de sobrevida (aunque no significativo) de 20 a 28 días, cuando el tratamiento con 10.000 UI/día de IFN-gamma comenzó en el momento de la infección experimental. Cuando el IFN-gamma, a razón de 10.000 UI/día durante 15 días, fue administrado simultáneamente con una dosis infectante de 3,5 x 10(5) levaduras, el tiempo de sobrevida de los animales aumentó significativamente (p=0.004). Los resultados obtenidos sugieren que, dependiendo de las condiciones experimentales, IFN-gamma prolonga el tiempo de sobrevida de ratones infectados con una dosis letal de C. neoformans