Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of ...neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the
anterior cingulate cortex
in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, ‘Parkinsonism in cirrhosis’. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.
Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell‐specific marker proteins have ...demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N‐acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti‐inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood‐brain cytokine transfer and receptor‐mediated cytokine signal transduction as well as a role for liver‐related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure. (HEPATOLOGY 2011;)
Systemic inflammation is common in liver failure and its acquisition is a predictor of hepatic encephalopathy severity. New studies provide convincing evidence for a role of neuroinflammation ...(inflammation of the brain per se) in liver failure; this evidence includes activation of microglia, together with increased synthesis in situ of the proinflammatory cytokines TNF, IL-1β and IL-6. Liver-brain signalling mechanisms in liver failure include: direct effects of systemic proinflammatory molecules, recruitment of monocytes after microglial activation, brain accumulation of ammonia, lactate and manganese, and altered permeability of the blood-brain barrier. Ammonia and cytokines might act synergistically. Existing strategies to reduce ammonia levels (including lactulose, rifaximin and probiotics) have the potential to dampen systemic inflammation, as does albumin dialysis, mild hypothermia and N-acetylcysteine, the latter two agents acting at both peripheral and central sites. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain oedema and encephalopathy in liver failure, as does the anti-TNF agent etanercept.
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. Summary: L-ornithine L-aspartate ...(LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6–9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA’s ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.
Abstract An “abscopal” effect occurs when localized irradiation perturbs the organism as a whole, with consequences that can be either beneficial or detrimental. Mechanistic explanations of this ...effect are challenging. From the oncologist’s perspective, the term refers to distant tumor regression after localized irradiation. On the other hand, from a biologist’s point of view, abscopal effects include induction of genomic instability, cell death, and oncogenic transformation in normal tissues. This conceptual dichotomy is explored in this review, with a focus on clinically documented cases of anti-tumor abscopal effects and abscopal effects in normal tissues. This review also outlines several suggested mechanisms for abscopal effects.
Multidimensional optical spectra are measured from the response of a material system to a sequence of laser pulses and have the capacity to elucidate specific molecular interactions and dynamics ...whose influences are absent or obscured in a conventional linear absorption spectrum. Interpretation of complex spectra is supported by theoretical modeling of the spectroscopic observable, requiring implementation of quantum dynamics for coupled electrons and nuclei. Performing numerically correct quantum dynamics in this context may pose computational challenges, particularly in the condensed phase. Semiclassical methods based on calculating classical trajectories offer a practical alternative. Here I review the recent application of some semiclassical, trajectory-based methods to nonlinear molecular vibrational and electronic spectra.
Hospitals use rates from the best quartile or decile as benchmarks for quality improvement aims, but to what extent these aims are achievable is uncertain.
To determine the proportion of neonatal ...intensive care units (NICUs) in 2014 that achieved rates for death and major morbidities as low as the shrunken adjusted rates from the best quartile and decile in 2005 and the time it took to achieve those rates.
A total of 408 164 infants with a birth weight of 501 to 1500 g born from January 1, 2005, to December 31, 2014, and cared for at 756 Vermont Oxford Network member NICUs in the United States were evaluated. Logistic regression models with empirical Bayes factors were used to estimate standardized morbidity ratios for each NICU. Each ratio was multiplied by the overall network rate to calculate the 10th, 25th, 50th, 75th, and 90th percentiles of the shrunken adjusted rates for each year. The proportion in 2014 that achieved the 10th and 25th percentile rates from 2005 and the number of years it took for 75% of NICUs to achieve the 2005 rates from the best quartile were estimated.
Death prior to hospital discharge, infection more than 3 days after birth, severe retinopathy of prematurity, severe intraventricular hemorrhage, necrotizing enterocolitis, and chronic lung disease among infants less than 33 weeks' gestational age at birth.
Of the 756 hospitals, 695 provided data for 2014. The mean unadjusted infant-level rate of death before hospital discharge decreased from 14.0% in 2005 to 10.9% in 2014. In 2014, 689 of 695 NICUs (99.1%; 95% CI, 97.4%-100.0%) achieved the 2005 shrunken adjusted rates from the best quartile for death prior to discharge, 678 of 695 (97.6%; 95% CI, 95.8%-99.6%) for late-onset infection, 558 of 681 (81.9%; 95% CI, 77.2%-86.6%) for severe retinopathy of prematurity, 611 of 693 (88.2%; 95% CI, 81.7%-97.0%) for severe intraventricular hemorrhage, 529 of 696 (76.0%; 95% CI, 71.8%-81.2%) for necrotizing enterocolitis, and 286 of 693 (41.3%; 95% CI, 36.1%-45.6%) for chronic lung disease. It took 3 years before 445 NICUs (75.0%) achieved the 2005 shrunken adjusted rate from the best quartile for death prior to discharge, 5 years to achieve the rate from the best quartile for late-onset infection, 6 years to achieve the rate from the best quartile for severe retinopathy of prematurity and severe intraventricular hemorrhage, and 8 years to achieve the rate from the best quartile for necrotizing enterocolitis.
From 2005 to 2014, rates of death prior to discharge and serious morbidities decreased among the NICUs in this study. Within 8 years, 75% of NICUs achieved rates of performance from the best quartile of the 2005 benchmark for all outcomes except chronic lung disease. These findings provide a novel way to quantify the magnitude and pace of improvement in neonatology.
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