Human serum fetuin A/α2HS-glycoprotein level is associated with long-term survival in patients with alcoholic liver cirrhosis, comparison with the Child-Pugh and MELD scores

BACKGROUND: Serum concentration of fetuin A/α2HS-glycoprotein (AHSG) is a good indicator of liver cell function and 1-month mortality in patients with alcoholic liver cirrhosis and liver cancer. We intended to determine whether decreased serum AHSG levels are associated with long-term mortality and whether the follow-up of serum AHSG levels can add to the predictive value of the Child-Pugh (CP) and MELD scores. METHODS: We determined serum AHSG concentrations in 89 patients by radial immunodiffusion. Samples were taken at the time of enrolment and in the 1(st), 3(rd), 6(th), and the 12(th )month thereafter. RESULTS: Forty-one patients died during the 1-year follow-up period, 37 of them had liver failure. Data of these patients were analysed further. Deceased patients had lower baseline AHSG levels than the 52 patients who survived (293 ± 77 vs. 490 ± 106 μg/ml, mean ± SD, p < 0.001). Of all laboratory parameters serum AHSG level, CP and MELD scores showed the greatest difference between deceased and survived patients. The cutoff AHSG level 365 μg/ml could differentiate between deceased and survived patients (AUC: 0.937 ± 0.025, p < 0.001, sensitivity: 0.865, specificity: 0.942) better than the MELD score of 20 (AUC: 0.739 ± 0.052, p < 0.001, sensitivity: 0.595, specificity: 0.729). Initial AHSG concentrations < 365 μg/ml were associated with high mortality rate (91.4%, relative risk: 9.874, 95% C.I.: 4.258–22.898, p < 0.001) compared to those with ≥ 365 μg/ml (9.3%). Fourteen out of these 37 fatalities occurred during the first month of observation. During months 1–12 low AHSG concentration proved to be a strong indicator of mortality (relative risk: 9.257, 95% C.I.: 3.945–21.724, p < 0.001). Multiple logistic regression analysis indicated that decrease of serum AHSG concentration was independent of all variables that differed between survived and deceased patients during univariate analysis. Multivariate analysis showed that correlation of low serum AHSG levels with mortality was stronger than that with CP and MELD scores. Patients with AHSG < 365 μg/ml had significantly shortened survival both in groups with MELD < 20 and MELD ≥ 20 (p < 0.0001 and p = 0.0014, respectively). CONCLUSION: Serum AHSG concentration is a reliable and sensitive indicator of 1-year mortality in patients with alcoholic liver cirrhosis that compares well to the predictive value of CP score and may further improve that of MELD score

Putative Nanobacteria Represent Physiological Remnants and Culture By-Products of Normal Calcium Homeostasis

Putative living entities called nanobacteria (NB) are unusual for their small sizes (50–500 nm), pleomorphic nature, and accumulation of hydroxyapatite (HAP), and have been implicated in numerous diseases involving extraskeletal calcification. By adding precipitating ions to cell culture medium containing serum, mineral nanoparticles are generated that are morphologically and chemically identical to the so-called NB. These nanoparticles are shown here to be formed of amorphous mineral complexes containing calcium as well as other ions like carbonate, which then rapidly acquire phosphate, forming HAP. The main constituent proteins of serum-derived NB are albumin, fetuin-A, and apolipoprotein A1, but their involvement appears circumstantial since so-called NB from different body fluids harbor other proteins. Accordingly, by passage through various culture media, the protein composition of these particles can be modulated. Immunoblotting experiments reveal that antibodies deemed specific for NB react in fact with either albumin, fetuin-A, or both, indicating that previous studies using these reagents may have detected these serum proteins from the same as well as different species, with human tissue nanoparticles presumably absorbing bovine serum antigens from the culture medium. Both fetal bovine serum and human serum, used earlier by other investigators as sources of NB, paradoxically inhibit the formation of these entities, and this inhibition is trypsin-sensitive, indicating a role for proteins in this inhibitory process. Fetuin-A, and to a lesser degree albumin, inhibit nanoparticle formation, an inhibition that is overcome with time, ending with formation of the so-called NB. Together, these data demonstrate that NB are most likely formed by calcium or apatite crystallization inhibitors that are somehow overwhelmed by excess calcium or calcium phosphate found in culture medium or in body fluids, thereby becoming seeds for calcification. The structures described earlier as NB may thus represent remnants and by-products of physiological mechanisms used for calcium homeostasis, a concept which explains the vast body of NB literature as well as explains the true origin of NB as lifeless protein-mineralo entities with questionable role in pathogenesis

Plasma proteins present in human cortical bone: enrichment of the alpha2HS-glycoprotein.

The spectrum of plasma proteins present in human cortical bone and permanent dentine has been determined. One plasma glycoprotein, the alpha2HS-glycoprotein, was found to be present at a high concentration in both bone and dentine and was shown to be concentrated in the mineralized tissues with respect to the other plasma proteins by factors of between 30 and 100. In this respect the alpha2HS-glycoprotein is analogous to the G2B-glycoprotein and alpha-glycoprotein of bovine and rabbit b one, respectively. The binding of alpha2HS-glycoprotein and albumin to calcium phosphates generated within serum samples has been studied at different serum:precipitate ratios. In each case all the alpha2HS-glycoprotein was removed from the samples and the alpha2HS-glycoprotein was concentrated with respect to albumin by factors ranging from 370 at the highest serum:precipitate ratio to 25 at the lowest ratio. The plasma alpha2HS-glycoprotein concentrations of patients with Paget's disease of bone were shown to be substantially lower than the normal range, with significant negative correlation between the alpha2HS-glycoprotein concentration and the plasma alkaline phosphatase activity

Building a consensus regarding the nature and origin of mesenchymal stem cells

Mesenchymal stem cells (MSCs) are believed to be the common precursors to differentiated cell lineages found in bone and bone marrow, including adipocytes, chondrocytes, osteoblasts, and hematopoiesis-supporting stroma. Apart from this fact, most aspects of MSC biology, including their ontogeny, anatomical location in marrow, and in vivo functions remain vague. Attempts to clarify these issues have produced confounding results, principally due to the fact that many researchers employ different methods to culture MSCs, assess their differentiation potential, and evaluate their capacity for self-renewal. Accordingly, the current status of the field appears fragmentary with no clear consensus on how to define the cells. In describing past and present contributions to the field of MSC research, I will demonstrate that the apparent incongruity of the literature is misleading, and that an unbiased interpretation reveals a fairly cohesive picture of MSC biology. © 2002 Wiley-Liss, Inc

Initiation and enhancement of bone formation. A review.

Knowledge of some of the fundamental biochemical factors that may influence the initiation and continued growth of bone-forming cell lines is presented. The discussion is limited to those factors shown experimentally to be present locally in bone tissue and synthesized in the environment of bone-forming cells. The current state of knowledge of basic research findings on osteogenic factors is given in detail. Cooperative actions of these locally produced and systemic factors are the primary stimuli that result in increased bone growth and volume

Binding of calcium and strontium by alginates.

SODIUM alginates markedly inhibit the intestinal absorption of strontium in rats1-4 and man5,6 without an appreciable effect on calcium absorption so that they are of interest as possible therapeutic agents in cases of ingestion of strontium-90. Alginic acid is obtained from certain seaweeds and is a polymer of D-mannuronic acid and L-guluronic acid7 joined by 1,4 linkages8. It has been shown that guluronic-rich fractions of alginate are the most effective in reducing strontium absorption in rats in vivo and in vitro4,9. © 1968 Nature Publishing Group

Plasma proteins present in human cortical bone: enrichment of the alpha2HS-glycoprotein.

The spectrum of plasma proteins present in human cortical bone and permanent dentine has been determined. One plasma glycoprotein, the alpha2HS-glycoprotein, was found to be present at a high concentration in both bone and dentine and was shown to be concentrated in the mineralized tissues with respect to the other plasma proteins by factors of between 30 and 100. In this respect the alpha2HS-glycoprotein is analogous to the G2B-glycoprotein and alpha-glycoprotein of bovine and rabbit b one, respectively. The binding of alpha2HS-glycoprotein and albumin to calcium phosphates generated within serum samples has been studied at different serum:precipitate ratios. In each case all the alpha2HS-glycoprotein was removed from the samples and the alpha2HS-glycoprotein was concentrated with respect to albumin by factors ranging from 370 at the highest serum:precipitate ratio to 25 at the lowest ratio. The plasma alpha2HS-glycoprotein concentrations of patients with Paget's disease of bone were shown to be substantially lower than the normal range, with significant negative correlation between the alpha2HS-glycoprotein concentration and the plasma alkaline phosphatase activity

Building a consensus regarding the nature and origin of mesenchymal stem cells

Mesenchymal stem cells (MSCs) are believed to be the common precursors to differentiated cell lineages found in bone and bone marrow, including adipocytes, chondrocytes, osteoblasts, and hematopoiesis-supporting stroma. Apart from this fact, most aspects of MSC biology, including their ontogeny, anatomical location in marrow, and in vivo functions remain vague. Attempts to clarify these issues have produced confounding results, principally due to the fact that many researchers employ different methods to culture MSCs, assess their differentiation potential, and evaluate their capacity for self-renewal. Accordingly, the current status of the field appears fragmentary with no clear consensus on how to define the cells. In describing past and present contributions to the field of MSC research, I will demonstrate that the apparent incongruity of the literature is misleading, and that an unbiased interpretation reveals a fairly cohesive picture of MSC biology. © 2002 Wiley-Liss, Inc

Stem cells and the philosopher's stone.

Stem cell biology is now one of the most exciting and rapidly advancing areas of scientific endeavor. Promises of cures of a wide variety of diseases by specific replacement of damaged or malfunctional tissues by use of totipotent or multipotent stem cells is on the horizon in clinical practice. Stem cells derived from the embryo and from adult tissues have been shown to have extensive potentials for self-renewal and differentiation. In addition, the plasticities of phenotype exhibited in vivo by some of these cell populations challenge the doctrine of irreversibility of cell commitment after particular developmental stages. This brief review considers certain aspects of these recent findings of the many unexpected potentials of stem cells to differentiate into alternative processes, and their potential value for use in tissue reconstruction procedures are prominent areas that require further study. Rigorous investigation of these topics will lead to realistic approaches in the future for stem cell therapy in a variety of human diseases and other clinical problems