Metabolism in Acute-On-Chronic Liver Failure: The Solution More than the Problem.

Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.

The Lymphatic Headmaster of the Mast Cell-Related Splanchnic Inflammation in Portal Hypertension.

Portal hypertension is a common complication of liver disease, either acute or chronic. Consequently, in chronic liver disease, such as the hypertensive mesenteric venous pathology, the coexisting inflammatory response is classically characterized by the splanchnic blood circulation. However, a vascular lymphatic pathology is produced simultaneously with the splanchnic arterio-venous impairments. The pathological increase of the mesenteric venous pressure, by mechanotransduction of the venous endothelium hyperpressure, causes an inflammatory response involving the subendothelial mast cells and the lymphatic endothelium of the intestinal villi lacteal. In portal hypertension, the intestinal lymphatic inflammatory response through the development of mesenteric-systemic lymphatic collateral vessels favors the systemic diffusion of substances with a molecular pattern associated with damage and pathogens of intestinal origin. When the chronic hepatic insufficiency worsens the portal hypertensive inflammatory response, the splanchnic lymphatic system transports the hyperplasied intestinal mast cells to the mesenteric lymphatic complex. Then, an acquired immune response regulating a new hepato-intestinal metabolic scenario is activated. Therefore, reduction of the hepatic metabolism would reduce its key centralized functions, such as the metabolic, detoxifying and antioxidant functions which would try to be substituted by their peroxisome activity, among other functions of the mast cells.

Prevalence of erectile dysfunction in Spanish primary care setting and its association with cardiovascular risk factors and cardiovascular diseases. SIMETAP-ED study / Prevalencia de la disfunción eréctil en el ámbito de la atención primaria española y su asociación con factores de riesgo cardiovasculares y enfermedades cardiovasculares. Estudio SIMETAP-ED

Introduction: Few studies conducted in primary care setting report about age-adjusted prevalence rates of erectile dysfunction (ED). Aims of SIMETAP-ED study were to determine crude and age-adjusted prevalence rates of ED diagnosis, to compare these rates with other similar studies, and to compare prevalence rates of cardiovascular risk factors (CVRF), cardiovascular diseases (CVD), metabolic diseases and chronic kidney disease (CKD) between populations with and without ED. Methods: Cross-sectional observational study conducted in primary care setting. Population-based random sample: 2934 adult men. Response rate: 66%. A clinical interview was conducted to diagnose ED using a question derived from ED definition. The medical records of patients were reviewed to identify their CVRF and diseases associated with ED. The age-adjustments were standardized to Spanish population. Results: The prevalence rates of metabolic diseases, CVD, CVRF, and CKD in population with ED were higher than population without ED, highlighting the CVD. The crude prevalence of ED was 17.2% (95% confidence interval: 15.8-18.6). The age-adjusted prevalence rates of ED were 0.71% in men under 40 years, 12.4% in men over 18 years, 10.8% in men aged 40-69 years, 18.9% in men over 40 years, and 48.6% in men over 70 years. Conclusions: SIMETAP-ED study showed association of ED with metabolic diseases, CKD, CVRF, and highlighting CVD. The age-adjusted prevalence of ED was 12.4% in adult men, 19% in men over 40 years, and almost 50% in men over 70 years

Introducción: Existen pocos estudios realizados en atención primaria sobre prevalencias ajustadas por edad de la disfunción eréctil (ED, por sus siglas en inglés). Los objetivos del estudio SIMETAP-ED fueron determinar las prevalencias crudas y ajustadas por edad del diagnóstico de la ED, comparar estas tasas con otros estudios similares, y comparar las prevalencias de factores de riesgo cardiovasculares (FRCV), enfermedades cardiovasculares (ECV), enfermedades metabólicas y enfermedad renal crónica (ERC) entre las poblaciones con y sin ED. Métodos: Estudio observacional transversal realizado en atención primaria. Muestra aleatoria base poblacional: 2.934 varones adultos. Tasa de respuesta: 66%. Se realizó una entrevista clínica para diagnosticar ED mediante una pregunta derivada de la definición de ED. Se revisaron las historias clínicas de los pacientes para identificar sus FRCV y enfermedades asociadas con la ED. Los ajustes de tasas se estandarizaron con respecto a la población española. Resultados: Las prevalencias de enfermedades metabólicas, ECV, FRCV y ERC en la población con ED fueron más altas que en la población sin ED, destacando las ECV. La prevalencia cruda de la ED fue del 17,21% (intervalo de confianza del 95%: 15,86-18,63). Las tasas de prevalencia ajustadas por edad de la ED fueron del 0,71% en menores de 40 años, del 12,4% en mayores de 18 años, del 10,8% en varones entre 40 y 69 años, del 18,9% en mayores de 40 años y del 48,6% en mayores de 70 años. Conclusiones: El estudio SIMETAP-ED mostró asociación de la ED con las enfermedades metabólicas, ERC, FRCV y, sobre todo, con ECV. La prevalencia ajustada por edad de la ED fue del 12,4% en varones adultos, del 19% en mayores de 40 años y casi del 50% en mayores de 70 años

Prevalence of erectile dysfunction in Spanish primary care setting and its association with cardiovascular risk factors and cardiovascular diseases. SIMETAP-ED study.

INTRODUCTION: Few studies conducted in primary care setting report about age-adjusted prevalence rates of erectile dysfunction (ED). Aims of SIMETAP-ED study were to determine crude and age-adjusted prevalence rates of ED diagnosis, to compare these rates with other similar studies, and to compare prevalence rates of cardiovascular risk factors (CVRF), cardiovascular diseases (CVD), metabolic diseases and chronic kidney disease (CKD) between populations with and without ED. METHODS: Cross-sectional observational study conducted in primary care setting. Population-based random sample: 2934 adult men. Response rate: 66%. A clinical interview was conducted to diagnose ED using a question derived from ED definition. The medical records of patients were reviewed to identify their CVRF and diseases associated with ED. The age-adjustments were standardized to Spanish population. RESULTS: The prevalence rates of metabolic diseases, CVD, CVRF, and CKD in population with ED were higher than population without ED, highlighting the CVD. The crude prevalence of ED was 17.2% (95% confidence interval: 15.8-18.6). The age-adjusted prevalence rates of ED were 0.71% in men under 40 years, 12.4% in men over 18 years, 10.8% in men aged 40-69 years, 18.9% in men over 40 years, and 48.6% in men over 70 years. CONCLUSIONS: SIMETAP-ED study showed association of ED with metabolic diseases, CKD, CVRF, and highlighting CVD. The age-adjusted prevalence of ED was 12.4% in adult men, 19% in men over 40 years, and almost 50% in men over 70 years.

Mast cell-mediated splanchnic cholestatic inflammation.

INTRODUCTION: Splanchnic mast cells increase in chronic liver and in acute-on-chronic liver diseases. We administered Ketotifen, a mast cell stabilizer, and measured the mast cells in the splanchnic organs of cholestatic rats. MATERIAL AND METHODS: These groups were studied: sham-operated rats (S; n = 15), untreated microsurgical cholestasic rats (C; n = 20) and rats treated with Ketotifen: early (SK-e; n = 20 and CKe; n = 18), and late (SK-l; n = 15 and CK-l; n = 14). RESULTS: The cholestatic rats showed systemic and splanchnic impairments, such as ascites, portal hypertension, and biliary proliferation and fibrosis. The rats also showed a splanchnic increase of TNF-α, IL-1ß and MCP-1, and a reduction of IL-4, IL-10 and antioxidants. An increase of VEGF in the ileum and mesenteric lymphatic complex was associated with a liver reduction of TGF-ß1. Ketotifen reduces the degree of hepatic insufficiency and the splanchnic inflammatory mediators, as well as VEGF and TGF-ß1 levels. Ketotifen also reduces the connective tissue mast cells in the mesenteric lymphatic complex of cholestatic rats, while increases the hepatic mucosal mast cells. CONCLUSIONS: In cholestatic rats, Ketotifen improves liver function and ascites, and also reduces pro-inflammatory mediators in the splanchnic area. The decrease in connective tissue mast cells in the mesenteric lymphatic complex due to the administration of Ketotifen would lead to the improvement of the inflammatory splanchnic response, and consequently the abovementioned complications.

Hepatic encephalopathy: Sometimes more portal than hepatic.

Hepatic encephalopathy is a severe complication of both chronic and acute liver diseases. The term hepatic encephalopathy stems from the belief that hepatic insufficiency is its fundamental etiopathogenic factor. However, most clinical cases show liver failure along with mesenteric venous portal hypertension. This portal hypertension would explain the abnormal mechanical forces suffered by the digestive tract in the early stages of the disorder. These forces could regulate some gut biochemical pathological pathways in a process known as mechanotransduction. Thus, portal hypertension would begin with the establishment of a mechanotransduced afferent or sensory inflammatory gut-brain pathway, resulting in functional and structural changes in the central nervous system. In this review, we will revisit the term "hepatic encephalopathy" in light of new results where portal hypertension occurs before liver failure and is accompanied by brain changes. Moreover, we will point out cellular links that can explain the microbiota, immune, gut, and brain axis disturbances found in this disorder.

Carcinogenesis: the cancer cell-mast cell connection.

BACKGROUND: In mammals, inflammation is required for wound repair and tumorigenesis. However, the events that lead to inflammation, particularly in non-healing wounds and cancer, are only partly understood. FINDINGS: Mast cells, due to their great plasticity, could orchestrate the inflammatory responses inducing the expression of extraembryonic programs of normal and pathological tissue formation. This heterogeneity of mast cells could allow a microenvironment to be recreated similar to the extraembryonic structures, i.e., amnion and yolk sac, which are needed for embryonic development. Mast cells could provide a framework for understanding the connection between inflammation and tumor growth, invasion and metastasis. In this way, the mast cells could express inflammatory phenotypes, which would enable the cancer stem cells to develop. Thus, the cancer cell uses mast cells to express the extraembryonic functions that are needed to allow the cancer stem cell to proliferate and invade. If so, then by using this appropriate inflammatory interstitial microenvironment, a cancer stem cell can reach maximum levels of growth and invasion inside the host. CONCLUSION: Therefore, the comparison of tumors with wounds that do not heal would be supported since both pathological processes use extraembryonic mechanisms by mast cells. The adoption of these mechanisms warrants tumor survival in an embryonic-like state.

Portal hypertension: The desperate search for the placenta.

We propose that the circulatory impairments produced, in both portal hypertension and liver cirrhosis, to a certain degree resemble those characterizing prenatal life in the fetus. In fact, the left-right circulatory syndrome is common in cirrhotic patients and in the fetus. Thus, in patients with portal hypertension and chronic liver failure, the re-expression of a blood circulation comparable to fetal circulation is associated with the development of similar amniotic functions, i.e., ascites production and placenta functions, and portal vascular enteropathy. Therefore, these re-expressed embryonic functions are extra-embryonic and responsible for prenatal trophism and development.

The gestational power of mast cells in the injured tissue.

The inflammatory response expressed after wound healing would be the recapitulation of systemic extra-embryonic functions, which would focus on the interstitium of the injured tissue. In the injured tissue, mast cells, provided for a great functional heterogeneity, could play the leading role in the re-expression of extra-embryonic functions, i.e., coelomic-amniotic and trophoblastic-vitelline. Moreover, mast cells would favor the production of a gastrulation-like process, which in certain tissues and organs would induce the regeneration of the injured tissue. Therefore, the engraftment of mesenchymal stem cells and mast cells, both with an extra-embryonic regenerative phenotype, would achieve a blastema, from the repaired and regenerated injured tissue, rather than by fibrosis, which is commonly made through wound-healing.

Embrionary way to create a fatty liver in portal hypertension.

Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.

Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure.

A serious complication of chronic hepatic insufficiency is acute-on-chronic liver failure, a recognized syndrome characterized by acute decompensation of cirrhosis and organ/system failure. We investigated the use of adipose-derived mesenchymal stem cells (AD-MSCs) in an experimental model of acute-on-chronic liver failure, developed by microsurgical extrahepatic cholestasis in rats. Rats undergoing microsurgical extrahepatic cholestasis were treated by intraparenchymal liver injection of human or rat AD-MSCs, undifferentiated or previously differentiated in vitro toward the hepatocyte lineage. The groups treated with rat AD-MSCs showed less ascites, lower hepato- and splenomegaly, less testicular atrophy, and an improvement in serum biochemical hepatic parameters. There was also an improvement in histological liver changes, in which the area of fibrosis and bile duct proliferation were significantly decreased in the group treated with predifferentiated rat AD-MSCs. In conclusion, an isograft of hepatocyte-predifferentiated AD-MSCs injected intraparenchymally 2 weeks after microsurgery in extrahepatic cholestatic rats prevents secondary complications of acute-on-chronic hepatic failure. These data support the potential use of autologous AD-MSCs in the treatment of human cholestasis, and specifically of newborn biliary atresia, which could be beneficial for patients awaiting transplant.

Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAA Receptor γ2 Subunit in the Cerebellum.

Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, ß, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αß binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5ß-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5ß-pregnan-3α-ol-20-one. Motor-impairing effects of 5ß-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αß or αßδ receptors lead to enhanced changes in the cerebellum-generated behavior.

Wound healing reaction: A switch from gestation to senescence.

The repair of wounded tissue during postnatal life could be associated with the upregulation of some functions characteristic of the initial phases of embryonic development. The focusing of these recapitulated systemic functions in the interstitial space of the injured tissue is established through a heterogeneous endothelial barrier which has excretory-secretory abilities which in turn, would induce a gastrulation-like process. The repair of adult tissues using upregulated embryonic mechanisms could explain the universality of the inflammatory response against injury, regardless of its etiology. However, the early activation after the injury of embryonic mechanisms does not always guarantee tissue regeneration since their long-term execution is mediated by the host organism.

A method for conducting simultaneous convergent tracer tests in multilayered aquifers.

Forced gradient tracer tests between two boreholes can be used to study contaminant transport processes at the small field scale or investigate the transport properties of an aquifer. Full depth tests, in which tracer samples are collected just from the discharge of the abstraction borehole, often give rise to breakthrough curves with multiple peaks that are usually attributed to different flow paths through the aquifer that can rarely be identified from the test results alone. Tests in selected levels of the aquifer, such as those between packer-isolated sections of the boreholes, are time consuming, expensive; and the identification of major transport pathways is not guaranteed. We present a method for simultaneously conducting multiple tracer tests covering the full depth of the boreholes, in which tracer sampling and monitoring is carried out by a novel multilevel sampling system allowing high frequency and cumulative sampling options. The method is applied to a tracer test using fluorescein conducted in the multilayered sandstone aquifer beneath the city of Birmingham, UK, producing six well-defined tracer breakthrough curves.

Splanchnic-aortic inflammatory axis in experimental portal hypertension.

Splanchnic and systemic low-grade inflammation has been proposed to be a consequence of long-term prehepatic portal hypertension. This experimental model causes minimal alternations in the liver, thus making a more selective study possible for the pathological changes characteristic of prehepatic portal hypertension. Low-grade splanchnic inflammation after long-term triple partial portal vein ligation could be associated with liver steatosis and portal hypertensive intestinal vasculopathy. In fact, we have previously shown that prehepatic portal hypertension in the rat induces liver steatosis and changes in lipid and carbohydrate metabolism similar to those produced in chronic inflammatory conditions described in metabolic syndrome in humans. Dysbiosis and bacterial translocation in this experimental model suggest the existence of a portal hypertensive intestinal microbiome implicated in both the splanchnic and systemic alterations related to prehepatic portal hypertension. Among the systemic impairments, aortopathy characterized by oxidative stress, increased levels of proinflammatory cytokines and profibrogenic mediators stand out. In this experimental model of long-term triple portal vein ligated-rats, the abdominal aortic proinflammatory response could be attributed to oxidative stress. Thus, the increased aortic reduced-nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase activity could be associated with reactive oxygen species production and promote aortic inflammation. Also, oxidative stress mediated by NAD(P)H oxidase has been associated with risk factors for inflammation and atherosclerosis. The splanchnic and systemic pathology that is produced in the long term after triple partial portal vein ligation in the rat reinforces the validity of this experimental model to study the chronic low-grade inflammatory response induced by prehepatic portal hypertension.

CRMP2 tethers kainate receptor activity to cytoskeleton dynamics during neuronal maturation.

The CRMP2 and CRMP4 proteins are strongly expressed in the developing nervous system, mediating neurite outgrowth, neuronal polarity, and axon guidance. In the present study, we demonstrate the interaction of the CRMP2 and CRMP4 proteins with the GluK5 subunit of the kainate (KA) receptor (KAR) and investigated the role of KARs in modulating the development of cultured mouse DRG neurons. We found that KARs modulate neuronal maturation and neurite outgrowth in a bidirectional manner. Accordingly, low concentrations of KA delayed maturation and enhanced neurite outgrowth, whereas maturation was promoted by higher concentrations of KA that attenuated neuritic elongation. The effects of weak KAR activation were prevented by blocking their noncanonical signaling and involved a differential regulation of CRMP2. Whereas the delay in maturation involves PKC-mediated phosphorylation of CRMP2 at T555 leading to a downregulation of membrane Cav2.2, the promotion of neurite outgrowth is achieved by dephosphorylation at T514 at the growth cones, the latter reflecting PKC-driven enhancement of GSK3ß phosphorylation at S9. Together, these findings indicate that noncanonical KAR signaling influences neuronal development by modulating CRMP2 activity.

Mapping metabolic brain activity in three models of hepatic encephalopathy.

Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups.

Surgical inflammatory stress: the embryo takes hold of the reins again.

The surgical inflammatory response can be a type of high-grade acute stress response associated with an increasingly complex trophic functional system for using oxygen. This systemic neuro-immune-endocrine response seems to induce the re-expression of 2 extraembryonic-like functional axes, i.e. coelomic-amniotic and trophoblastic-yolk-sac-related, within injured tissues and organs, thus favoring their re-development. Accordingly, through the up-regulation of two systemic inflammatory phenotypes, i.e. neurogenic and immune-related, a gestational-like response using embryonic functions would be induced in the patient's injured tissues and organs, which would therefore result in their repair. Here we establish a comparison between the pathophysiological mechanisms that are produced during the inflammatory response and the physiological mechanisms that are expressed during early embryonic development. In this way, surgical inflammation could be a high-grade stress response whose pathophysiological mechanisms would be based on the recapitulation of ontogenic and phylogenetic-related functions. Thus, the ultimate objective of surgical inflammation, as a gestational process, is creating new tissues/organs for repairing the injured ones. Since surgical inflammation and early embryonic development share common production mechanisms, the factors that hamper the wound healing reaction in surgical patients could be similar to those that impair the gestational process.