Anatomical basis of the coordination between smooth and striated urethral and anal sphincters: loops of regulation between inferior hypogastric plexus and pudendal nerve. Immuno-histological study with 3D reconstruction.

PURPOSE: (1) Describe both nervous pathways to the sphincters, and highlight the anatomical support of their coordination. (2) Obtain a 3D representation of this complex innervation system. METHODS: A computer-assisted anatomical dissection technique was used. Serial histological sections were cut in the pelvis of four female human foetuses (aged 19-32 weeks of gestation). The sections were treated with conventional staining, and with seven different immunostainings. The sections were digitalized and, finally, a 3D representation was built from the corresponding images. RESULTS: Myelinated and sensory fibres were detected at the inferior hypogastric plexus (IHP) level. Our analysis showed that most of the afferent sensory fibres come from the urinary and anal sphincters through the anterior and posterior branches of the IHP respectively. A highly positive nitrergic (anti-NOS1) and sensitive (anti-CGRP) labelling was found in the external layer of the urethral sphincter. The 3D representation allowed describing the two components of the innervation system. A sensory-motor regulation loop was found for both sphincters. CONCLUSION: A 3D description of the components of both nervous pathways to the sphincters has been established. Our findings on the innervation of the sphincters tend to question the classical infra/supra levatorian muscle description. The coordinated work of the internal and external layers of the anal and urethral sphincter is probably mediated by multiple roles regulation.

Is low tie ligation truly reproducible in colorectal cancer surgery? Anatomical study of the inferior mesenteric artery division branches.

AIM: Curative surgery is the standard treatment for colorectal cancer. The ligation level of the inferior mesenteric artery (IMA) is still debated, as neither low tie (LT) nor high tie ligation (HT) has shown any benefit on the patients' overall survival. We examined whether LT is standardizable and easily reproducible from an anatomical point of view. METHOD: One hundred CT angiographies of healthy patients were analysed for the anatomy of the IMA and its division branches: left colic artery (LCA), sigmoid arteries trunk and superior rectal artery. Data analysed comprised angles between the IMA and the aorta, diameters of the IMA and its branches, repartition of the branches and distances between the origin of the branches and the origin of the IMA. RESULTS: IMA anatomy showed no variation. In contrast, its division branches showed important variability in terms of distance to the origin and repartition: in 19.9% of the patients, the IMA directly splits into three branches, and in 17.6% of the patients, the LCA originated at more than 5 cm from the origin of the IMA. These frequent variations led us to assume that the standardization of LT is very difficult in a context of neoplasm, where the quality of the lymphadenectomy is fundamental. CONCLUSION: The division branches of the IMA are extremely subject to interindividual variations, making it difficult if not impossible to reproduce identically a surgical procedure based on their anatomy. HT appears to us as the only relevant procedure for colorectal cancer.

Quality of life in colostomy patients practicing colonic irrigation: An observational study.

AIMS OF THE STUDY: The presence of colostomy has a major impact on quality of life that could potentially be improved by performing colonic irrigation (CI), yet few studies have assessed the impact of this technique on quality of life. The aim of this study was to assess the quality of life between two groups of patients having a colostomy; those practicing CI vs those not practicing CI. PATIENTS AND METHODS: The French Federation of Ostomy (FFO) members were evaluated by a self-questionnaire assessing their experience of CI. Quality of life as assessed by the Stoma-QOL questionnaire was compared between patients practicing CI or not. RESULTS: In total 752 patients were eligible for the study. The median age was 75 years, and 47.26% were men. The median duration between stoma surgery and questionnaire completion was 12.3 years. Forty-one percent of the patients practiced CI. The median quality of life score was significantly higher for the patients practicing the CI: (69.26 vs 58.33, P<0.001). In multivariable analysis, the risk factors for not performing CI were age, obesity, the presence of colostomy for less than six years, and a non-oncologic indication for operation. CONCLUSIONS: CI appeared to improve the quality of life of patients with colostomy. This care is a therapeutic education issue and should be proposed to all patients. Supervision by the enterostomal therapy nurse is recommended especially for patients with a high risk of failure.

Interferon gamma induces synthesis of complement alternative pathway proteins by human endothelial cells in culture.

Human umbilical vein endothelial cells grown in vitro under standard conditions contain a high level of mRNA specific for the complement regulatory factors H and I. An additional 1.8-kb mRNA encoding a truncated form of factor H is also present. IFN-gamma stimulation of the cells causes a 6-7 fold increase in both factor H mRNA species, and a greater than 10-fold increase in factor I mRNA. IL-1 and LPS slightly suppressed factor H mRNA, while TNF had no effect. mRNA for factor B is also detectable in IFN-gamma-stimulated cells, but messengers for C1q, C4bp, and CR3 beta chain were not found. Secretion of factor H protein was also stimulated by IFN-gamma. The presence of mRNA for factors H, B, and I, together with C3 secretion, demonstrated by others, suggests that endothelial cells can assemble the complete alternative complement pathway. Endothelial cell complement may be involved in leukocyte-endothelium interactions mediated by leukocyte C3 receptors.

[Expression of the elastic fibers components during the fœtal liver development]. / Expression des composants de la matrice élastique au cours du développement hépatique fœtal.

Elastic fibers are composed of microfibrils containing fibrillin-1 and an elastic component, elastin. Microfibrils may not be associated with elastin. In the adult liver, fibrillin-1 and elastin are coexpressed within the stroma and portal tracts vessel walls. Fibrillin-1 is expressed alone around the bile ducts and within the Disse space. There is little work that has studied the elastic fiber organization during the fœtal liver development. Here, we studied the expression of fibrillin-1 and elastin by immunohistochemistry on 20 cases of fœtal liver. During the development of the portal tract, the two components are coexpressed on interstitial elastic fibers and within vessel walls. Fibrillin-1 is expressed alone around the bile structures during their maturation. Unlike adult liver, fibrillin-1 is expressed on thin and very irregular microfibrils within the Disse space. Our study shows that the elastic matrix development in the portal tract follows the development of the different structures, notably biliary structures. In the Disse space, microfibrils are not continuous. Their maturation may be in relation with the change of the hepatic blood flow after birth.

Chitosan-based hydrogels for developing a small-diameter vascular graft: in vitro and in vivo evaluation.

AIMS: Vascular grafts made of synthetic polymers perform poorly in small-diameter applications (cardiac and peripheral bypass). Chitosan is a biocompatible natural polymer that can provide a novel biological scaffold for tissue engineering development. The goal of this study was to demonstrate the biocompatibility of a novel chitosan preparation in vitro and in vivo, and to assess its potential as a scaffold for vascular applications. METHODS AND RESULTS: A series of experiments of increasing complexity, ranging from in vitro biocompatibility and hemocompatibility tests to in vivo studies in small and large animals (rats and sheep), was performed to provide a comprehensive analysis of chitosan hydrogels' biological properties. In vitro studies established that: (i) chitosan supported human endothelial progenitor cells adhesion, proliferation and resistance to physiological shear stress; (ii) chitosan did not activate platelets, the complement system, or the intrinsic coagulation pathway. In vivo results showed: (iii) no resorption of chitosan and no chronic inflammation at 60 days in a rat heterotopic implantation model (magnetic resonance imaging and histology); (iv) no flow obstruction (Doppler ultrasound) and no thrombus formation (histology and scanning electron microscopy) at 2 h after a carotid arteriotomy repair with chitosan patches in sheep. Finally, two chitosan tubes were implanted as carotid interposition grafts for 3 days in sheep showing that chitosan was strong enough to be sutured, to withstand arterial pressure, and no flow obstruction was observed through this short period. CONCLUSION: Chitosan-based hydrogels displayed promising in vitro biocompatibility and hemocompatibility properties as well as in vivo short-term performance.

All-trans retinoic acid potentiates the inhibitory effects of interferon alpha on chronic myeloid leukemia progenitors in vitro.

All-trans retinoic acid (ATRA) has recently been shown to synergize with the inhibitory effect of interferon alpha (IFN alpha) on the growth of malignant cells isolated from solid tumors. We investigated whether ATRA could potentiate the inhibitory effects of IFN alpha on the proliferation of leukemic progenitors in chronic myeloid leukemia (CML). CD34+ cells from chronic phase, newly diagnosed patients, were incubated in short-term liquid culture with ATRA, IFN alpha or a combination of both molecules and then plated on semi-solid cultures for colony-forming cell assay. IFN alpha was found to inhibit preferentially the generation of late progenitors. ATRA at a concentration of 10(-8) M was found strongly to inhibit CFU-M colonies. Addition of ATRA to IFN alpha dramatically potentiated the inhibitory effects of INF alpha on CFU-GM growth. In the presence of both molecules the inhibition of day 14 CFU-GM from CD34+ cells was lowered to 27 +/- 4% of control. CFU-M colonies were completely inhibited. RT-PCR analysis of the colonies resulting from the action of the combination IFN alpha plus ATRA showed the presence of an increased number of BCR-ABL-negative colonies relatively to what was observed with IFN alpha alone. FISH analysis showed a higher percentage of Ph-negative cells in the ATRA plus IFN alpha-treated samples, confirming PCR experiments. These results indicate that, in vitro, the combination of IFN alpha and ATRA effectively inhibits CFU-GM colony formation in CML and suggest that it has a potential interest for the treatment of CML.

Expression of Flt3-ligand by the endothelial cell.

Flt3-ligand (FL) is a cytokine that is of paramount importance in the proliferation of primitive hematopoietic progenitors. In this study, we show that endothelial cells (EC) produce large amounts of soluble FL and express a membrane-bound form of the molecule. Bone marrow microvascular EC also produce FL, suggesting that EC are an important source of FL in the bone marrow. High concentrations of FL in EC supernatants contrast with its undetectable levels in long-term bone marrow cultures. A single mRNA for FL is detected, suggesting that soluble FL derives from the membrane-bound species by proteolytic release. FL mRNA is stable with a half-life of about 3 h. II-1alpha increases FL mRNA levels and membrane and soluble FL expression. Glucocorticoids, known inhibitors for many hematopoietic growth factors do not down-regulate the expression of FL. On the contrary, GC increase the expression of both species of FL. The neutralization of FL in cocultures EC/ hematopoietic progenitors results in an acceleration of the maturation of the progenitors. IFN-alpha, MIP-1 alpha and TGF-beta stimulate production of membrane-bound and soluble FL. This stimulation is essential to explain their modulatory effect on the generation of clonogenic cells in cocultures EC/hematopoietic progenitors. Leukemia (2000) 14, 153-162.

Endothelial cell support of hematopoiesis is differentially altered by IL-1 and glucocorticoids.

We investigated the ability of endothelial cells (EC) to support hematopoiesis in contact and non-contact cocultures with isolated CD34+ or CD34/CD38low cells. In the absence of exogenous cytokines, umbilical vein EC (HUVEC) efficiently support proliferation of hematopoietic cells and generation of colony-forming cells (CFC). Cytokines (IL-6, LIF, G-CSF, GM-CSF, M-CSF, but not IL-1, IL-3, IL-7) were detected in HUVEC coculture supernatants. Neutralization of these cytokines profoundly inhibited the ability of EC supernatants to support the differentiation of hematopoietic progenitors and led to an accumulation of immature cells. Contact cocultures were significantly more efficient than non-contact cocultures. The expanded cell population essentially belonged to the myeloid and monocytic lineages. Contact cocultures generated cells expressing the CD61 or CD41 antigens. Interleukin-1alpha (IL-1alpha) augmented EC capacity to support hematopoiesis, this property resulting from the upregulation of cytokine expression. Glucocorticoids (GC) reduced this capacity by downregulating the biosynthesis of cytokines by EC and not by a direct effect on the progenitor cells. EC from the bone marrow microvasculature (BMEC) support the proliferation and the differentiation of hematopoietic progenitors. Synergistic increase in progenitor cells expansion and generation of CFC occurred when EC cocultures were added with exogenous cytokines. Supernatants of IL-1alpha-stimulated EC potentiated the effects of an association of IL-1, IL-3, IL-6, LIF, SCF, Flt3-ligand, TPO, G-CSF, GM-CSF, M-CSF and IL-11 on the proliferation of hematopoietic progenitors suggesting that EC may produce other soluble growth factors potentiating the action of the above set of cytokines.

Localization of a hydrophobic domain in human C5.

The fifth component of human complement (C5), under physiological salt conditions, bound firmly to phenyl-Sepharose. This indicated the presence of hydrophobic sites on C5. These sites may play an important role in C5 haemolytic activity since this activity was inhibited by chaotropic ions (Mg2+, SCN-, I-) at relatively low concns (0.6-1 M). Charge shift experiments performed on purified C5 provided further evidence for the presence of hydrophobic sites within C5. Bidirectional charge shifts of C5 mobility were observed with the two detergent systems TX-100 + DOC and TX-100 + CTAB. In order to localize these sites, C5 was subjected to trypsin digestion. Three major fragments were evidenced by two-dimensional electrophoresis (agarose/SDS-PAGE and SDS-PAGE/SDS-PAGE), and were isolated by hydrophobic affinity chromatography. The first fragment, C5FI, was composed probably of a mixture of six alpha chain fragments (alpha 1-alpha 6) linked to the beta chain by disulphide bridges. The second fragment, C5FII, was composed of the beta chain linked to two alpha chain fragments: alpha 2 (Mr = 58 K) and alpha 4 (Mr = 32 K). The third fragment, C5FIII, contained two covalently linked chains (beta chain and alpha 4). The rank order for mol. wt, agarose gel electrophoretic mobility and hydrophobicity was respectively: C5 greater than or equal to C5FI greater than C5FII greater than C5FIII; C5 less than or equal to C5FI less than or equal to C5FII much less than C5FIII; and C5FII greater than or equal to C5 greater than C5FI much greater than C5FIII. From the relative hydrophobicity, the hydrophobic sites of C5 can be localized to the alpha 2 fragment (Mr = 58 K) since C5FIII lacked the alpha 2 fragment and was not hydrophobic. Cleavage and the liberation of the N-terminal part of C5 induced an increase in hydrophobicity of the remaining part of C5 (C5b and C5FII), suggesting a possible role of the hydrophobic sites in association of C5b with membranes.

Differential modulation of complement factor H and C3 expression by TNF-alpha in the rat. In vitro and in vivo studies.

The biosynthesis of alternative regulatory complement protein factor H was investigated using both an in vivo rat model and an in vitro rat hepatocyte culture system, and compared to that of C3 component. Subcutaneous injection of a single dose of 20 micrograms of recombinant murine tumor necrosis factor-alpha (rmTNF-alpha) had no effect on factor H liver mRNA levels, while it increased C3 mRNA levels. In correlation with this, serum factor H levels remained unchanged after rmTNF-alpha injection, whereas C3 levels were increased. In contrast in vitro studies showed that rmTNF-alpha had no effect on factor H and C3 expression by rat hepatocytes. Recombinant human interleukin-1 alpha (rhIL-1 alpha) did not alter the expression of factor H, whereas it increased C3 expression, and recombinant human interleukin-6 (rhIL-6) stimulated expression of both proteins. This study shows that TNF-alpha is not directly responsible for the increased levels of factor H observed in vivo during induced inflammation in the rat. Its in vivo effect on C3 secretion might be secondary to the TNF-alpha-induced release of IL-1 and/or IL-6.

Inhibition of chronic myelogenous leukemia cells harboring a BCR-ABL B3A2 junction by antisense oligonucleotides targeted at the B2A2 junction.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the BCR-ABL hybrid gene. Two types of hybrid BCR-ABL mRNA have been found, B2A2 and B3A2. As the BCR-ABL rearrangement is specific to leukemic cells, selective inhibition of leukemic cell growth by BCR-ABL antisense oligonucleotides (ASO) has been reported in vitro for CML patients and cell lines. However, controversial results have been obtained from preclinical studies using anti-BCR-ABL ASO, as nonspecific inhibition of leukemic cell growth was evidenced in some cases. B3 exon secondary structure was deduced from its sequence and found to be a loop. According to this predictive structure of exon B3, a 56-mer antisense oligonucleotide targeting the polypurine bases from the B2A2 junction was devised which would inhibit proliferation (MTT assay) of B3A2 junction cell lines (K562 and a murine cell line Ba/F3 transfected with the B3A2 junctional sequence). This ASO had a hairpin-like secondary structure and was found to be much more resistant to the action of nucleases than control 18-mer standard oligonucleotides. Hybridization to its target mRNA occurs via formation of a triplex structure. A concentration of 5 microM of specific 56-mer B2A2 ASO was necessary to demonstrate 50% optical density (OD) reduction for K562 cell line and Ba/F3 transformed by B3A2 cDNA. Sense and non-sense 56-mer sequence or 18-mer linear ASO showed no effect for these concentrations. Western blot showed a partial inhibition of P210 protein; expression of P145abl remains unchanged. The 56-mer ASO also inhibited the proliferation of B2A2 junction cell line BV173 at the same concentration and showed no effect on the HL60 cell line used as control.

The rat Mist1 gene: structure and promoter characterization.

Transcription factors of the basic Helix-Loop-Helix (bHLH) protein family play key roles in several developmental processes. Mist1 belongs to this group of proteins and shares several properties with the other family members. For example, Mist1 is capable of dimerization with the ubiquitously expressed E2A bHLH proteins and exhibits a strong DNA-binding activity to the core E-box sequence. Using in-situ hybridization and Northern blot hybridization, Mist1 mRNA has been detected in a variety of embryonic and adult rodent tissues. To understand the molecular mechanisms involved in the expression of the gene, we have cloned the rat Mist1 gene and analyzed 2.5 kb of its 5' flanking region. The Mist1 gene spans over 5 kilobases and is composed of two exons separated by a unique intron. The entire coding region is localized in the second exon. Sequence analysis of the promoter region indicated an absence of TATA-box or CAAT-box sequence, but several consensus Sp1-binding sites were present near the transcription start site. Deletion analysis of the promoter region identified a 272 bp proximal fragment to be sufficient to drive expression of a reporter gene in NIH3T3 fibroblasts. Subsequent deletion of potential Sp1 sites results in a marked decrease in promoter activity. Electrophoretic mobility shift assays revealed that Sp1 binds to two different regions in the proximal promoter, a typical Sp1 site located at (-38; -33) and a G/C-rich region between (-67; -62). These data suggest that the basal expression of this TATA-less gene might be driven by general transcription factors, such as Sp1.

Effect of antisense oligonucleotides on CD34+ cells from chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by a specific hybrid gene BCR-ABL (formed as a result of t(9;22)). This leads to two possible mRNA usually present in leukemic cells, either B2A2 or B3A2. Targeting these mRNA by antisense oligonucleotides (AS) might offer the opportunity to decrease leukemic growth. We have tested the ability of AS to inhibit the in vitro proliferation of CD34 positive (CD34+) blood cells from 16 patients with newly diagnosed CML. CD34+ cells were isolated by an immunomagnetic technique and incubated for 16 to 18 hours with an 18 mer AS (0.25 mM). Sense oligonucleotides served as controls. The effects of AS were evaluated by clonogenic test (production of CFU-GM). Moreover, colonies were picked out and studied by RT-PCR to analyse the presence of BCR-ABL transcript. For nine patients with B3A2 transcript, the median inhibition of CFU-GM formation at day 14 was 64.0 +/- 11.2% (68.0 +/- 11.4% at day 21) and for the seven patients with a B2A2 transcript: 59.0 +/- 11.4% (72.5 +/- 12.0% at day 21). AS showed no effect on CD34+ cells from three normal volunteer donor cells. However, for every patient studied, colonies picked out remained BCR-ABL positive with the RT-PCR technique.

Ex vivo cytokine expansion of peripheral blood Ph-negative cells in chronic myeloid leukaemia.

Hematopoietic progenitors can be expanded ex vivo in the presence of various cytokine combinations. Since normal early progenitor or stem cells persist in the blood and bone marrow of patients with Philadelphia chromosome [Ph]-positive chronic myeloid leukaemia (CML), the selection of normal (Ph-negative) progenitor cells from CML patients would be of considerable clinical value for ex vivo purging and autologous transplantation. To obtain these cells, CD34-positive (progenitor) cells from the peripheral blood (PB) of CML patients were either pretreated or not with 5-fluorouracil (5FU) and then grown in suspension culture for 7 days with a combination of cytokines. We compared different combinations of cytokines containing interleukin-1 alpha (IL1), interleukin-3 (IL3), stem cell factor (SCF), leukemia inhibitor factor (LIF), Flt3-ligand (FLT3L), and thrombopoietin (TPO). 5FU decreased cell proliferation in the liquid culture but concurrently increased the expansion of CFU-GM. While the addition of cytokines such as FLT3L and TPO improved CFU-GM expansion. FISH and RT-PCR analysis showed that this method significantly favored a higher frequency of Ph-negative cells after expansion in liquid culture. Therefore ex vivo expansion of putatively normal hematopoietic progenitor cells from cytapheresis is feasible in CML.

Expression of thrombopoietin by umbilical vein endothelial cells.

Current data suggest that the primary source of thrombopoietin (TPO) is the liver. Extra-hepatic sites for TPO production have been demonstrated essentially through the study of the expression of TPO mRNA. In this work, we report that TPO is expressed at low levels by endothelial cells (EC) derived from the umbilical vein (HUVEC). Both TPO mRNA and the protein are expressed and the protein is functional as assessed by biological assay. Expression of TPO by HUVEC may be useful to study the regulation of the production of this cytokine and to understand the apparent specific interactions between mature megakaryocytes and EC in the bone marrow.

Sequence analysis of a cDNA clone encoding the C-terminal end of human complement factor H.

Peptide sequencing of the complement system regulatory protein, factor H, permitted the synthesis of a mixed sequence oligonucleotide probe. Human liver cDNA libraries were screened and factor H-specific clones selected. No full-length clone was obtained, but the largest available clone, R2a, was found to encode the C-terminal 657 amino acids of factor H. The derived amino acid sequence consists of 10 contiguous internally homologous segments, each about 60 amino acids long. Sequences homologous to these are found in several other complement and non-complement proteins. Such sequences are likely to represent a particular type of tertiary structure subunit.

Partial characterization of human complement factor H by protein and cDNA sequencing: homology with other complement and non-complement proteins.

Factor H, a control protein of the human complement system, is closely related in functional activity to two other complement control proteins, C4b-binding protein (C4bp) and complement receptor type 1 (CR1). C4bp is known to have an unusual primary structure consisting of eight homologous units each about 60 amino acids long. Such units also occur in the N-terminal regions of the complement proteins C2 and factor B, and in the non-complement serum glycoprotein beta 2I. Amino acid sequencing, and sequencing of a factor H cDNA clone, show that factor H also contains internal repeating units, and is homologous to the proteins listed above.

[Study of the complement system. General principles and perspectives]. / L'exploration du système du complément. Principes généraux et perspectives.

Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.

Blood platelets and inflammation: their relationship with liver and digestive diseases.

An expansion of knowledge from basic and clinical research has highlighted the critical role of platelets in inflammation and tissue repair in addition to their established contribution to hemostasis. Activated platelets are a rich source of mediators participating to inflammation and tissue regeneration. Platelet-derived microparticles recapitulate essential platelet functions and their contribution to the pathogenesis of inflammatory diseases has been emphasized. Recent findings suggest that platelets are both friends and foes for the liver. Platelets are essential to liver regeneration, platelet-derived serotonin being critical. However platelets can also exacerbate liver damage, as in immune-mediated injury. The dual role of platelets has recently been exemplified in animal models of liver fibrosis. Platelets release profibrogenic mediators, such as CXC Chemokine Ligand 4, that is instrumental in the progression of liver fibrosis. On the other hand, thrombocytopenia aggravates liver fibrosis, an outcome linked to the downregulation of hepatic stellate cell collagen production by platelet derived hepatocyte growth factor. CD154, a key molecule in inflammation, is expressed by platelets and is a pathogenic mediator in inflammatory bowel disease. Here, we summarize some of the mechanisms linking platelets with inflammation and comment few recent articles indicating why platelets may prove to be important pathogenic mediators in liver and gastrointestinal diseases.