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Biomedical subjects

M Guizzetti

Publications and source records attributed to M Guizzetti.

At least 19 recordsLinked to original sources
PubMed2005

Orthotopic liver transplantation for biliary atresia.

Biliary atresia (BA) represents the most frequent indication for liver transplantation (OLTX) in the pediatric population. The aim of this paper was to present a series collected over the last 7 years from October 1997 through July 2004, including 260 pediatric OLTX in 231 patients. BA was the indication in 137 patients. There were 69 boys and 68 girls of mean weight 10.68 kg and median age 0.9 years. As a primary transplant, 99 patients received a LLS graft; 27 a whole graft; four a I+IV-VIII segment, and two a I-IV segment. Mean follow up was 1047 days (range, 1-2496 day). Infections were diagnosed in 45 patients, vascular complications in 27 patients. Surgical complications that required reintervention occurred in 25 patients. In 41 cases biliary complications occurred, 11 requiring reintervention. 16 patients were retransplanted. In two cases another re-OLTx was performed. Currently 126 patients are alive, showing an actuarial 1 year survival of 92% and 5 year 91%, with actuarial graft survivals of 85% at 1 year and 82% at 3 and 5 years. Our results confirm the effectiveness of OLTx for the treatment of children with BA and a failed Kasai procedure. Split liver grafts represent an excellent organ supply for these patients, achieving optimal results with no mortality on the waiting list.

ABO Blood-Group System↗
PubMed2005

Early portal vein thrombosis after pediatric split liver transplantation with left lateral segment graft.

Early portal vein thrombosis (PVT) represents a serious complication after liver transplantation (OLTx). From October 1997 through July 2004, 260 OLTx were performed in 231 children, including 189 of left lateral segments (LLS). We retrospectively analyzed the incidence and the outcome of early PVT in this group. A daily doppler US scan was performed during the first week after transplantation. Early PVT occurred in 14 patients (8%), 10 males and four females of median age 0.77 years. The main indication for primary transplantation was biliary atresia (10), followed by Byler's disease (2), acute liver failure on cryptogenetic cirrhosis (1), and Alagille syndrome (1). Four children underwent retransplantation; three cases of thrombectomy and revision of the anastomosis, two children were treated with beta blockers, one of whom had a later failed attempt at percutaneous revascularization and eventually a meso-caval shunt. Five patients were followed with observation and no treatment. Among the four patients who died, three were in the retransplantation group and one in the thrombectomy and revision of the anastomosis group; the overall mortality was 28%. With a median follow up of 399 days, 10 patients are alive with an actuarial survival at 1 and 5 years of 72%, and graft survival rates at 1 and 5 years of 64%. PVT represents a serious complication after pediatric OLTx with LLS grafts. Prompt detection and aggressive surgical treatment in selected cases are required to reduce the mortality and graft loss.

Cadaver↗
PubMed2005

Orthotopic liver transplantation for alagille syndrome.

Alagille syndrome (AS) is a dominantly inherited, multisystem disorder involving the liver, heart, eyes, face, and skeleton. From October 1997 through July 2004, 260 pediatric orthotopic liver transplantations (OLTx) were performed in 231 patients. This report describes 21 patients of median age 1.95 years (range, 0.7-16.7) who had alagille syndrome. We present the technical features of the OLTx, incidence and type of complications, medical conditions related to the syndrome, need for retransplantation, as well as patient and graft survival rates. A split liver technique was used in 16 patients (76%) who received a left lateral segment (LLS) graft whereas 7 patients (33%) received a whole liver. Only cadaveric donors were used. The major surgical complications requiring reintervention in 11 patients (52%) included biliary problems (19%) and vascular complications (17%). One case of hepatic artery thrombosis required retransplantation. Three recipients (14%) died. All other patients are alive with an actuarial survival rate of 90% at 1 year and 80% at 5 years. The actuarial graft survival rate is 85% at 1 year and 75% at 5 years. Patients with AS, despite the associated cardiovascular anomalies, can be treated successfully by a combined approach between cardiologist, radiologist, cardiothoracic, and liver transplant surgeons. With careful planning and operative management, the results are comparable with those obtained with other more common cholestatic diseases.

Actuarial Analysis↗
PubMed2005

Transplantation for acute liver failure in children.

We reviewed the clinical data of 30 children-hospitalized for acute liver failure in the last 6 years. Ten patients were not listed for liver transplantation OLTX. Their clinical conditions gradually improved and they are all alive without deficit. Among 20 patients listed, 15 underwent urgent OLTX. Two children died on the waiting list and three were suspended from waiting list after few days because of improvement. Survival according to age class was analyzed dividing the patients into two groups: A, age 1 year or less versus B, age between 1 and 16 years. The patient survival was 86% at 6 months and 61% both at 1 and 2 years. Survival at 6 months and 1 and 2 years was 88%, 67%, and 45% for the patients in group A and 83%, 83%, and 83% for the patients in group B (P = NS). Observing graft-to-recipient weight ratio and donor-to-recipient weight ratio most patients received an optimal sized graft. The split-liver technique is considered the preferred method of liver transplantation even in the pediatric patients with acute liver failure; especially in the setting of a cooperative system in which all livers that are suitable for split-liver transplantation are shared between centers. In order to have the best chance for survival, children with acute liver failure should be referred as soon as possible to an highly specialized pediatric liver transplantation center that can offer all the treatment modalities that are currently available.

Adolescent↗
PubMed2005

Liver transplantation in children weighting less than 6 kg: the Bergamo experience.

Liver transplantation (OLT) remains a major medical and surgical challenge in small patients. From October 1997 through July 2004, 17 babies less than 6 kg underwent 18 OLTs. Median age and weight were 3 months (range = 1 to 9) and 4.7 kg (range = 2.2 to 5.8). Two whole, one reduced, and 15 split-liver grafts (left lateral segments) were obtained from donors of median age and weight of 11.6 years (range = 0.5 to 62) and 50 kg (range = 7 to 63). Donor-to-recipient median weight ratio (D/R) was 9.1 kg (range = 1.3 to 17.6) and median graft-to-recipient weight ratio (GRWR) was 5% (range = 3.1 to 10). The incidence of biliary complications was 23%. The only vascular complication was a portal vein thrombosis (6%). Fourteen patients (79%) are alive with good graft function at a median follow-up of 39 months (range = 0.5 to 74). Three patients (all status 1) died on postoperative day 285 (brain death), 17 (multiorgan failure), and 229 (cardiovascular failure during retransplantation). Actuarial patient survivals at 6 months and 6 years are 94% and 78% while graft survivals are 89% and 74%, respectively. Currently all the patients listed as UNOS status 2 and 3 (73%) at the time of transplant are alive. During the same period one premature neonate (1.8 kg) who presented with fulminant hepatic failure died on the waiting list after 12 days. Our data confirm that the extensive use of a split-liver technique from small adult or pediatric cadaveric donors can offer the benefits of liver transplantation to small pediatric candidates with excellent results.

Adolescent↗
PubMed2005

Use of extended right grafts from in situ split livers in adult liver transplantation: a comparison with whole-liver transplants.

INTRODUCTION: We report our experience of in situ split-liver transplantation (SLT) for adult patients and compare the results with those achieved with whole-liver transplantation (WLT). METHOD: From November 1997 to December 2003, 109 liver transplantation were performed in 104 adult patients including 90 WLT (83%) and 19 SLT (17%) grafts. Fifteen extended right grafts (ERG, segments I + IV to VIII) were obtained with in situ split-liver procedures, generating also left lateral segment grafts, which were transplanted at our institution or elsewhere. Four left lobe (LL, segments I to IV) and right lobe (segments V to VIII) grafts were obtained by a modified in situ procedure for adult recipients. UNOS status, percentage of primary or secondary transplantation, and underlying liver disease were similar among patients receiving whole versus split grafts. Donors were older in whole than ERG cohorts (53 vs 26 years, P < .001). Procurement parameters and intraoperative profiles of transplant procedure were comparable among the groups. RESULTS: Median follow-up was 18 months (range: 1 to 73). Four patients with whole (4%) and no patient with ERG underwent retransplantation (P = NS). One- and 3-year patient survivals were 86% and 79% with WLT versus 93% and 93% with ERG (P = NS). One- and 3-year graft survivals were 84% and 75% with WLT versus 93%, and 93% with ERG (P = NS). Incidence of vascular complications was 8% with WLT, 13% with ERG (P = NS). The incidence of biliary complications was 13% in WLT, 27% in ERG (P = NS). CONCLUSIONS: The use of ERG from in situ split livers for adult transplantation allowed us to obtain results comparable or even better than those obtained with WLT. Split-liver transplantation is an effective, safe mechanism to expand the cadaveric donor pool.

Adult↗
PubMed2005

Orthotopic liver transplantation for Byler's disease.

In this study we analyzed the features of 12 patients who underwent liver transplantation for progressive familial intrahepatic cholestasis (Byler's disease [BD]) in view of the technical features of the OLTx, incidence and type of complications, need for retransplantation, as well as patient and graft survivals. BD was the indication in 12 patients of median age 1.32 years and median weight 10 kg. Median follow-up was 670 days. Major surgical complications requiring reintervention occurred in three patients. No thrombosis of the hepatic artery was observed. Infections with positive blood cultures were diagnosed in four patients. One patient had a biliary anastomotic stenosis successfully treated by percutaneous techniques. Four patients had episodes of acute rejection treated with steroids. Two patients were retransplanted, both of whom died in the early postoperative period due to hepatic vein thrombosis and venoenteric fistula. The actuarial patient and graft survival was 83% at 1 year and 83% at 5 years. Split-liver grafts represent an excellent organ supply for these patients, achieving good results with no mortality on the waiting list.

Adolescent↗
PubMed2004

Signal transduction mechanisms involved in the antiproliferative effects of ethanol in glial cells.

Central nervous system dysfunctions (most notably microencephaly and mental retardation) are among the most significant effects of in utero exposure to ethanol. Ethanol causes alterations of both neuronal and glial cells. In particular, ethanol has been shown to inhibit proliferation of astroglial cells stimulated by certain, but not all mitogens. Here, we review evidence that acetylcholine, by activating the M(3) subtype of muscarinic receptors, increases DNA synthesis in rat and human astroglial cells and that this effect is inhibited by low ethanol concentrations (10-100mM). Of the several signal transduction pathways activated by these receptors in astrocytes or astrocytoma cells, ethanol appears to target activation of phospholipase D, leading to a decrease in phosphatidic acid, a decreased activation of the atypical protein kinase C zeta and decreased down-stream activation of p70S6 kinase and of nuclear factor-kappaB. Inhibition of this pathway by ethanol occurs at the same concentrations which effectively inhibit proliferation. Inhibition of astroglial cell proliferation by ethanol may contribute to the microencephaly present in most children diagnosed with the fetal alcohol syndrome.

Animals↗
PubMed2003

Nuclear factor kappaB activation by muscarinic receptors in astroglial cells: effect of ethanol.

Activation of muscarinic receptors leads to proliferation of astroglial cells and this effect is inhibited by ethanol. Among the intracellular pathways involved in the mitogenic action of muscarinic agonists, activation of the atypical protein kinase C zeta (PKC zeta) appears to be of most importance, and is also affected by low ethanol concentrations. PKC zeta has been reported to activate nuclear factor kappaB (NF-kappaB), a transcription factor that has been shown to play an important role in cell proliferation. The aim of this study was, therefore, to determine whether muscarinic receptors would activate NF-kappaB in astroglial cells, whether such activation would play a role in the mitogenic action of muscarinic agonists, and whether it would represent a possible target for ethanol. Carbachol activated NF-kappaB in human 1321N1 astrocytoma cells, as evidenced by translocation of the p65 subunit of NF-kappaB to the nucleus, phosphorylation and degradation of IkappaBalpha in the cytosol, and increase NF-kappaB binding to DNA. Carbachol also induced translocation of p65 to the nucleus in primary rat astrocytes. Carbachol-induced NF-kappaB activation was mediated by the M3 subtype of muscarinic receptors and appeared to involve Ca(2+) mobilization and activation of PKC epsilon and PKC zeta, but not PI3-kinase and mitogen-activated protein kinase. The NF-kappaB peptide inhibitor SN50, but not the inactive peptide SN50M, strongly inhibited carbachol-induced astrocytoma cells proliferation and p65 translocation to the nucleus. Increased DNA synthesis was also antagonized by the IkappaBalpha kinase inhibitor BAY 11-7082. Ethanol (25-100 mM) inhibited the translocation of p65 and the binding of NF-kappaB to DNA in both 1321N1 astrocytoma cells and primary rat cortical astrocytes. Together, these results suggest that activation of NF-kappaB by muscarinic receptors in astroglial cells is important for carbachol-induced DNA synthesis and that ethanol-mediated inhibition of cell proliferation may be due in part to inhibition of NF-kappaB activation.

Astrocytes↗
PubMed2002

Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria.

Developmental neurotoxicity can be ascribed to in utero exposure to exogenous substances or to exposure of the fetus to endogenous compounds that accumulate because of genetic mutations. One of the best recognized human neuroteratogens is ethanol. The Fetal Alcohol Syndrome (FAS) is characterized by growth deficiency, particular facial features, and central nervous system (CNS) dysfunctions (mental retardation, microencephaly and brain malformations). Abuse of toluene by pregnant women can lead to an embryopathy (fetal solvent syndrome, (FSS)) whose characteristics are similar to FAS. Phenylketonuria (PKU) is a genetic defect in phenylalanine (Phe) metabolism. Offspring of phenylketonuric mothers not under strict dietary control are born with maternal PKU (mPKU), a syndrome with similar characteristics as FAS and FSS. While ethanol has been shown to cause neuronal death, no such evidence is available for toluene or Phe and/or its metabolites. On the other hand, alterations in astrocyte proliferation and maturation have been found, mostly in in vitro studies, which may represent a potential common mode of action for at least some of the CNS effects found in FAS, mPKU, and FSS. Further in vivo and in vitro studies should validate this hypothesis and elucidate possible molecular targets.

Alcohol-Induced Disorders, Nervous System↗
PubMed2001

Activation of phosphatidylinositol 3 kinase by muscarinic receptors in astrocytoma cells.

Stimulation of Gq-coupled acetylcholine muscarinic receptors leads to proliferation of astroglial cells, but the signal transduction pathway(s) that mediate this mitogenic response have not been fully elucidated. In this study, we report on the ability of carbachol to stimulate the phosphorylation of Akt/PKB, an important target of phosphatidylinositol 3 kinase (PI3 kinase) in 1321N1 human astrocytoma cells. Carbachol induced a dose-dependent phosphorylation of Ser473 on Akt, peaking after 15 min. This effect was mediated by activation of the M3 subtype of muscarinic receptors and was inhibited by two PI3 kinase inhibitors. Inhibitors of protein kinase C, mitogen-activated protein kinase and p70S6 kinase, had no effect on carbachol-induced Akt phosphorylation. Carbachol-induced DNA synthesis was strongly inhibited by two PI3 kinase inhibitors, wortmannin and LY294002, suggesting that PI3 kinase activation plays an important role in carbachol-induced proliferation 1321N1 astrocytoma cells.

Androstadienes↗
PubMed2001

Intracellular signal transduction pathways as targets for neurotoxicants.

The multiple cascades of signal transduction pathways that lead from receptors on the cell membrane to the nucleus, thus translating extracellular signals into changes in gene expression, may represent important targets for neurotoxic compounds. Among the biochemical steps and pathways that have been investigated are the metabolism of cyclic nucleotides, the formation of nitric oxide, the metabolism of membrane phospholipids, the activation of a multitude of protein kinases and the induction of transcription factors. This brief review will focus on the interactions of three known neurotoxicants, lead, ethanol and polychlorinated biphenyls, with signal transduction pathways, particularly the family of protein kinase C isozymes, and discusses how such effects may be involved in their neurotoxicity.

Animals↗
PubMed2001

Activation of mitogen-activated protein kinase by muscarinic receptors in astroglial cells: role in DNA synthesis and effect of ethanol.

Mitogen-activated protein kinase (MAPK) can be phosphorylated by mitogens binding to G-protein-coupled receptors and is considered a major pathway involved in cell proliferation. In this study, we report on the activation of MAPK by muscarinic acetylcholine receptors in astroglial cells, namely the 1321N1 human astrocytoma cell line, primary rat cortical astrocytes, and fetal human astrocytes. Carbachol caused a rapid and transient phorphorylation of MAPK (ERK1/2) in all cell types, with an increase in MAPK activity, without changing the levels of MAPK proteins. Human astrocytoma cells were used to characterize the effect of carbachol on MAPK. Experiments with M2- and M3-receptor subtype-selective antagonists, and with pertussis toxin, indicated that the M3 subtype is responsible for activating MAPK in glial cells. Pretreatment of cells with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, or downregulation of PKC by 24-h treatment with the phorbol ester TPA inhibited carbachol-induced MAPK activation. Additional experiments with PKC alpha- or PKC epsilon-specific compounds indicated that the epsilon isozyme of PKC is primarily involved in MAPK activation by carbachol. Chelation of calcium also inhibited MAPK activation by carbachol. Two MEK (MAPK kinase) inhibitors inhibited carbachol-induced DNA synthesis but only at concentrations that exceeded those sufficient to block carbachol-induced MAPK activation. Ethanol (< or =200 mM) had no effect on MAPK when present alone and did not affect carbachol-induced MAPK activation under various experimental conditions, although it inhibits carbachol-induced DNA synthesis at low concentrations (10-100 mM). These results suggest that activation of MAPK by carbachol may be necessary but not sufficient for its mitogenic effect in astroglial cells, and that does not represent a target for ethanol-induced inhibition of DNA synthesis elicited by muscarinic receptors.

Animals↗
PubMed2001

Inorganic lead stimulates DNA synthesis in human astrocytoma cells: role of protein kinase Calpha.

As lead has been shown to activate protein kinase C (PKC), and gliomas are reported to be highly dependent on PKC for their proliferation, this study was undertaken to investigate whether lead may act as a mitogen in human astrocytoma cells, and to determine the role of PKC in this effect. Lead acetate (from 100 nM to 100 microM) induced a concentration- and time-dependent increase in DNA synthesis, as measured by incorporation of [methyl-3H]thymidine into cell DNA, without causing any cytotoxicity. Flow cytometric analysis showed that lead was able to stimulate the cell cycle transition from the G0/G1 phase to the S/G2 phase, resulting in increased percentage of cells in the latter phase. Western blot analyses showed that lead induced translocation of PKCalpha, but not of PKCepsilon or PKCzeta, from the cytosolic to the particulate fraction, with a concomitant increase in PKC enzyme activity. Prolonged exposure to lead caused down-regulation of PKCalpha, but not of PKCepsilon. The effect of lead on DNA synthesis was mediated through PKC as evidenced by the finding that two PKC inhibitors, GF 109203X and staurosporine, as well as down-regulation of PKC through prolonged treatment with 12-O-tetradecanoylphorbol 13-acetate, blocked lead-induced DNA synthesis. Further experiments using a pseudosubstrate peptide targeting classical PKCs and selective down-regulation of specific PKC isoforms indicated that the effect of lead on DNA synthesis was mediated by PKCalpha. Altogether, these results suggest that lead stimulates DNA synthesis in human astrocytoma cells by a mechanism that involves activation of PKCalpha.

Astrocytes↗
PubMed2001

Modulation of DNA synthesis by muscarinic cholinergic receptors.

Acetylcholine muscarinic receptors are a family of five G-protein-coupled receptors widely distributed in the central nervous system and in peripheral organs. Activation of certain subtypes of muscarinic receptors (M1, M3, M5) has been found to modulate DNA synthesis in a number of cell types. In several cell types acetylcholine, by activating endogenous or transfected muscarinic receptors, can indeed elicit cell proliferation. In other cell types, however, or under different experimental conditions, activation of muscarinic receptors has no effect, or inhibits DNA synthesis. A large number of intracellular pathways are being investigated to define the mechanisms involved in these effects of muscarinic receptors; these include among others, phospholipase D, protein kinases C and mitogen-activated-protein kinases. The ability of acetylcholine to modulate DNA synthesis through muscarinic receptors may be relevant in the context of brain development and neoplastic growth.

Acetylcholine↗
PubMed2000

Possible role of protein kinase C zeta in muscarinic receptor-induced proliferation of astrocytoma cells.

Recent studies have shown that protein kinase C zeta (PKC zeta) is part of a pathway that plays a key role in a wide range of physiological processes including mitogenesis, cell survival, and transcriptional regulation. Most studies on PKC zeta have been done by stimulating cells with tyrosine kinase receptor agonists, or by transfecting the cells with either constitutively active PKC zeta or negative mutants of PKC zeta. Less is known about the ability of endogenous G-protein-coupled receptors to generate a mitogenic signal through activation of endogenous PKC zeta. In the present paper, we showed that in 123-1N1 human astrocytoma cells, which express the G-protein-coupled M2, M3, and M5 muscarinic receptors, PKC zeta is activated by carbachol in a concentration-dependent manner, resulting in the translocation of PKC zeta from the cytoplasm to granules in the perinuclear region. The effect of carbachol was long-lasting (up to 24 hr) and appeared to be mediated by activation of M3 muscarinic receptors. A selective PKC zeta inhibitor peptide (peptide Z) inhibited PKC zeta translocation as well as carbachol-induced DNA synthesis. Inhibition of both phosphatidylinositol 3-kinase and phospholipase D decreased carbachol-induced [(3)H]thymidine incorporation and blocked carbachol-induced PKC zeta translocation, suggesting an involvement of both pathways in these effects.

Astrocytoma↗