1,721,499 research outputs found
Gallbladder and Bile in Health and Gallstone disease. The role of motility, gallstones and bile lipid composition
No full textColchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare
No full textFamilial Mediterranean Fever (FMF) is a rare autosomal recessive autoinflammatory disorder involving the innate immunity and affecting almost exclusively populations with Mediterranean origin. Clinical features include recurrent episodes of fever, leukocitosis, serositis (peritonitis or pleuritis, arthritis), myalgia or erysipelas-like skin lesions, lasting 12-72 hrs. The MEFV gene mutations on chromosome 16p13.3 encodes the abnormal pyrin (marenostrin), a protein expressed in granulocytes, monocytes, serosal and synovial fibroblasts and involved in the activation of caspase-1 and the processing and release of active pro-inflammatory IL-1β. Since the first report in 1972, maintenance therapy with colchicine, a tricyclic neutral alkaloid, remains the mainstay of treatment in symptomatic FMF patients since it reduces the disease activity and prevents the development of secondary amyloidosis and renal damage. Adjunctive symptomatic therapy to colchicine includes nonsteroideal antinflammatory drugs and corticosteroids. In a small group of colchicine-intolerant or colchicine-resistant FMF patients, alternative treatments must be considered. Evolving experiences have focussed on the potential effectiveness of biologic agents working as TNF-α inhibitors (etanercept, infliximab), IL-1 trap (Rilonacept), IL-1 inhibitors (Anakinra, Canakinumab) and IL-6 receptor antibody (Tocilizumab). Interferon-α and thalidomide have also been employed in FMF patients. Still, clinical trials are mainly uncontrolled and restricted to few cases, thus requiring definitive conclusions. Old, and new treatments are discussed in the rare FMF disease, with the concept that any ideal treatment has to stand the test of time
Non-alcoholic steatohepatitis (NASH): approaching more tailored and effective therapies
Full text linkNAFLD, MAFLD, and beyond: one or several acronyms for better comprehension and patient care
Full text linkThe term non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common type of chronic liver disease. NAFLD points to excessive hepatic fat storage and no evidence of secondary hepatic fat accumulation in patients with "no or little alcohol consumption". Both the etiology and pathogenesis of NAFLD are largely unknown, and a definitive therapy is lacking. Since NAFLD is very often and closely associated with metabolic dysfunctions, a consensus process is ongoing to shift the acronym NAFLD to MAFLD, i.e., metabolic-associated fatty liver disease. The change in terminology is likely to improve the classification of affected individuals, the disease awareness, the comprehension of the terminology and pathophysiological aspects involved, and the choice of more personalized therapeutic approaches while avoiding the intrinsic stigmatization due to the term "non-alcoholic". Even more recently, other sub-classifications have been proposed to concentrate the heterogeneous causes of fatty liver disease under one umbrella. While awaiting additional validation studies in this field, we discuss the main reasons underlying this important shift of paradigm
The power of science diplomacy, a lesson from the Nobel laureate Peter Agre
No full textThe Prize marked a life of research in the field of membrane
channel proteins, leading to the seminal experiments proving
the molecular identity (1987-91) [3–5] and function (1992) [6] of
erythrocyte water channels. The first water channel was initially
named CHIP28 (CHannel-like Integral membrane Protein
of 28 kDa) and afterwards rechristened aquaporin-1 (AQP1) to
indicate its molecular conductance [7].
In line with his flair of perspicacious investigator, the discovery
of AQP channels is a typical example of serendipity. In
fact Peter Agre, when studying the biochemical characteristics
of the erythrocyte Rh blood group antigen, came across the
‘elusive’ water channel protein in 1987 although investigating
something else [4].
Soon after the functional characterization of the first animal
water channel (AQP1), other members of the AQP family were
identified and localized in all body districts, by homology
cloning. Mammals express thirteen distinct homologues
(AQP0-12) exerting pleiotropic roles throughout the body [2].
AQPs were also soon found in the plant [8] and microbial
kingdoms [9], testifying their pivotal relevance in living
organisms
Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis
No full textBackground A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Objective We performed a meta-analysis of available studies to better define the effect of metformin on colon neoplasia (cancer and polyps) in patients with type 2 diabetes. Methods Medical literature searches for human studies were performed through December 2015, using suitable keywords. Pooled estimates were obtained using fixed or random-effects models. Heterogeneity between studies was evaluated with the Cochran Q test whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the Begg and Mazumdar adjusted rank correlation test and by the Egger's regression test. In addition subgroup and sensitivity analyses were performed. Results A total number of 709,980 patients, with type 2 diabetes, were included in 17 studies eligible for meta-analysis [1 RCT and 16 observational studies (13 cohort and 3 case–controls)]. The risk of colon neoplasia was significantly lower among metformin users than controls (non-metformin users) [pooled RRs (95% CI) = 0.75 (0.65–0.87), test for overall effect Z = − 3.95, p < 0.001]. This observation applied separately for colon cancer [0.79 (0.69–0.91), Z = − 3.34, p < 0.001] and for colon polyps [0.58 (0.42–0.80), Z = − 3.30, p < 0.001]. Conclusion This meta-analysis shows that the use of metformin in patients with type 2 diabetes is associated with significantly lower risk of colon neoplasia
Comment on: Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever—reply
No full textNo abstract availabl
Intestinal absorption, hepatic synthesis, and biliary secretion of cholesterol: Where are we for cholesterol gallstone formation?
Full text linkWith a 10%-15% prevalence, gallstone disease is one of the most prevalent and costly digestive diseases in Western countries.
About two-thirds of gallstones are cholesterol gallstones, while the remaining are pigment stones that contain less than 30% cholesterol. The prevalence of gallstones increases with age and is associated with a number of major risk factors. Overall, cholesterol gallstone disease is deemed as the gallbladder/bile expression of the metabolic syndrome, as it is often associated with obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia. The combination of multiple disturbances affecting cholesterol homeostasis in bile is essential for cholesterol gallstone formation. The interactions of five primary defects result in
rapid cholesterol nucleation and crystallization in bile, the key step for gallstone formation1,5: (1) LITH genes and genetic defects; (2) unphysiological sustained
supersaturation of bile with cholesterol due to hepatic hypersecretion; (3) enhanced intestinal cholesterol absorption; (4) accelerated phase transitions of cholesterol; and (5) prolonged gallbladder stasis due to disrupted gallbladder motility accompanied with immunomediated gallbladder inflammation, as well as
hypersecretion of mucins and accumulation of mucin gel in the gallbladder lumen.1,6,7 Growth of solid, platelikecholesterol monohydrate crystals to form gallstones.
is a consequence of persistent hepatic hypersecretion of
biliary cholesterol together with enhanced gallbladder
mucin secretion and incomplete evacuation by the
gallbladder due to its impaired motility function
Water channel proteins in bile formation and flow in health and disease. When immiscible becomes miscible.
No full textAn essential function of the liver is the formation and secretion of bile, a complex aqueous solution of organic and inorganic compounds essential as route for the elimination of body cholesterol as unesterified cholesterol or as bile acids. In bile, a considerable amount of otherwise insoluble cholesterol is solubilized by carriers including two other classes of lipids, namely phospholipid and bile acids. Formation of bile and generation of bile flow are driven by the active secretion of bile acids, lipids and electrolytes into the canalicular and bile duct lumens followed by the parallel movement of water. Thus, water has to cross rapidly into and out of the cell interior driven by osmotic forces. Bile as a fluid, results from complicated interplay of hepatocyte and cholangiocyte uptake and secretion, concentration, by involving a number of transporters of lipids, anions, cations, and water. The discovery of the aquaporin water channels, has clarified the mechanisms by which water, the major component of bile (more than 95%), moves across the hepatobiliary epithelia.
This review is focusing on novel acquisitions in liver membrane lipidic and water transport and functional participation of aquaporin water channels in multiple aspects of hepatobiliary fluid balance. Involvement of aquaporins in a series of clinically relevant hepatobiliary disorders are also discussed
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