Similarities and differences between biliary sludge and microlithiasis: Their clinical and pathophysiological significances

The terms biliary sludge and cholesterol microlithiasis (hereafter referred to as microlithiasis) were originated from different diagnostic techniques and may represent different stages of cholesterol gallstone disease. Although the pathogenesis of biliary sludge and microlithiasis may be similar, microlithiasis could be preceded by biliary sludge, followed by persistent precipitation and aggregation of solid cholesterol crystals, and eventually, gallstone formation. Many clinical conditions are clearly associated with the formation of biliary sludge and microlithiasis, including total parenteral nutrition, rapid weight loss, pregnancy, organ transplantation, administration of certain medications, and a variety of acute and chronic illnesses. Numerous studies have demonstrated complete resolution of biliary sludge in approximately 40% of patients, a cyclic pattern of disappearing and reappearing in about 40%, and progression to gallstones in nearly 20%. Although only a minority of patients with ultrasonographic demonstration of biliary sludge develop gallstones, it is still a matter of controversy whether microlithiasis could eventually evolve to cholesterol gallstones. Biliary sludge and microlithiasis are asymptomatic in the vast majority of patients; however, they can cause biliary colic, acute cholecystitis, and acute pancreatitis. Biliary sludge and microlithiasis are most often diagnosed ultrasonographically and bile microscopy is considered the gold standard for their diagnosis. Specific measures to prevent the development of biliary sludge are not practical or cost-effective in the general population. Laparoscopic cholecystectomy offers the most definitive therapy on biliary sludge. Endoscopic sphincterotomy or surgical intervention is effective for microlithiasis-induced pancreatitis. Ursodeoxycholic acid can effectively prevent the recurrence of solid cholesterol crystals and significantly reduce the risk of recurrent pancreatitis. Keywords: Biliary sludge, Cholesterol microlithiasis, Acute cholecystitis, Acute pancreatitis, Biliary colic, Cholesterol monohydrate crystals, Lithogenic bil

A Pleiotropic Role for the Orphan Nuclear Receptor Small Heterodimer Partner in Lipid Homeostasis and Metabolic Pathways

Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed

New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones. The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver. The sources of cholesterol for hepatic secretion into bile have been extensively investigated; however, to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state. Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion, the genetic mechanisms that cause supersaturated bile have not been defined yet. Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation. In this review article, we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology. A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel, effective, and noninvasive therapies for patients with gallstones, which would reduce the morbidity, mortality, and costs of health care associated with gallstones, a very prevalent liver disease worldwide. Keywords: Bile flow, Bile acid, Biliary secretion, Lith gene, Micelle, Vesicl

Liquid-like thermal conduction in a crystalline solid

A solid conducts heat through both transverse and longitudinal acoustic phonons, but a liquid employs only longitudinal vibrations. Here, we report that the crystalline solid AgCrSe2 has liquid-like thermal conduction. In this compound, Ag atoms exhibit a dynamic duality that they are exclusively involved in intense low-lying transverse acoustic phonons while they also undergo local fluctuations inherent in an order-to-disorder transition occurring at 450 K. As a consequence of this extreme disorder-phonon coupling, transverse acoustic phonons become damped as approaching the transition temperature, above which they are not defined anymore because their lifetime is shorter than the relaxation time of local fluctuations. Nevertheless, the damped longitudinal acoustic phonon survives for thermal transport. This microscopic insight might reshape the fundamental idea on thermal transport properties of matter and facilitates the optimization of thermoelectrics.Comment: four figures, supplemental informatio

Oxygen vacancy induced structural variations of exfoliated monolayer MnO2 sheets

We report findings on the structural stability of exfoliated monolayer MnO2 sheets. Our study reveals that monolayer MnO2 sheets display two specific kinds of structural modification under electron irradiation. An atomic reconstruction (2 x 1) and a phase of MnO, induced by ordered oxygen vacancies, were identified by transmission electron microscopy techniques and further characterized by comparison with density-functional theory calculations. These findings are expected to significantly broaden current knowledge of the structural stability of ultrathin layered sheets

Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease

The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD

Magellanic Cloud X-ray Sources: III. Completion of a ROSAT Survey

This paper concludes a series of three papers presenting ROSAT High-Resolution Imager (HRI) observations of unidentified Einstein and serendipitous ROSAT X-ray sources in the direction of the Magellanic Clouds. Accurate positions and fluxes have been measured for these sources. Optical photometry and spectroscopy were obtained to search for identifications in order to determine the physical nature of these sources. The present paper includes new data for 24 objects; identifications are given or confirmed for 30 sources. For six sources optical finding charts showing the X-ray positions are provided. The results from this program are summarized, showing the populations of luminous X-ray sources in the Magellanic Clouds are quite different from those in the Galaxy.Comment: 28 pages, 2 figures; to appear in Astronomical Journa

Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFL

The Role Of Diet In The Pathogenesis Of Cholesterol Gallstones

Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans, motivating a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation