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Biomedical subjects

O Bernard

Publications and source records attributed to O Bernard.

At least 73 records · Page 4Linked to original sources
PubMed1999

Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.

BACKGROUND/AIM: Variceal bleeding is the most severe complication in patients with cystic fibrosis-associated liver cirrhosis, who often do not have severe respiratory failure. The advent of liver transplantation has broadened the treatment options. The purpose of this study was to report our experience with the management of portal hypertension. METHODS: Clinical and biochemical features, outcome of liver disease and management of portal hypertension were analyzed retrospectively in 44 children with cystic fibrosis-associated liver cirrhosis. RESULTS: The mean age at diagnosis of liver cirrhosis was 9 years. Eighty-six per cent of the children developed esophageal varices, 50% of whom bled early in their second decade. Injection sclerotherapy of esophageal varices did not prevent recurrence of bleeding in five of seven children. Elective surgical portosystemic shunting was successfully performed in nine of 11 patients considered being at high risk of bleeding or with recurrent bleeding episodes but without severe pulmonary failure and liver dysfunction, allowing prolonged post-operative survival up to 15 years. Two of three children who underwent isolated liver transplantation for severe portal hypertension died post-operatively. CONCLUSIONS: Management emphasis in cystic fibrosis patients with liver cirrhosis should be on control of bleeding and variceal decompression. These results suggest that surgical portosystemic shunting may be considered to relieve portal hypertension in patients without progressive liver failure and severe lung disease as an alternative to liver transplantation. With this policy, patients may be stabilized for many years until progression of liver or lung diseases indicates liver or lung-liver transplantation.

Adolescent↗
PubMed1999

Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFbeta1) in biliary atresia and paucity of intrahepatic bile ducts during infancy.

BACKGROUND/AIMS: Biliary atresia and paucity of intrahepatic bile ducts are the main causes of neonatal cholestasis leading to hepatic fibrosis. Fibrotic evolution is slow in paucity of bile ducts as compared to the rapid progression to biliary cirrhosis in biliary atresia when cholestasis persists despite hepatoportoenterostomy. Our aim was to compare the expression of collagens type I and IV, alpha-smooth muscle actin, osteonectin and transforming growth factor beta1 in biliary atresia and paucity of bile ducts. METHODS: Liver biopsies were obtained in 12 children with biliary atresia and in five with paucity of bile ducts. Collagens type I and IV, alpha-smooth muscle actin were detected with immunostaining. Collagens type I and IV, osteonectin and transforming growth factor beta1 mRNAs were detected by in situ hybridization. RESULTS: Expression of mRNA and proteins was roughly parallel. In ductular proliferation areas of biliary atresia: (1) the expression of collagens type I and IV and osteonectin was increased, and was localized to periductular myofibroblasts; (2) transforming growth factor beta1 was expressed around biliary ductules, probably in inflammatory cells, and also in biliary cells. Osteonectin expression was also increased in the lobules. In paucity of bile ducts, there was no overexpression of collagens type I and IV and transforming growth factor beta1, except in the only child with marked fibrosis. However, osteonectin expression was enhanced at the periphery of the lobules, even when fibrosis was mild or absent. CONCLUSIONS: These findings suggest that in biliary atresia ductular proliferation areas are the site of a marked production of extracellular matrix proteins in periductular myofibroblasts, probably secondary to transforming growth factor beta1 production by inflammatory cells and by biliary cells. The weak expression of transforming growth factor beta1 could explain the slow progression of fibrosis in paucity of bile ducts.

Actins↗
PubMed1999

Peliosis hepatis with initial presentation as acute hepatic failure and intraperitoneal hemorrhage in children.

Peliosis hepatis, a condition characterized by the presence of blood-filled lacunar spaces in the liver, usually has a chronic presentation pattern and is mainly reported in adult patients in association with chronic wasting disorders and after administration of various drugs. The present report concerns two previously healthy young children in whom peliosis hepatis initially presented as acute hepatic failure and who had Escherichia coli pyelonephritis. Both patients had active intraperitoneal hemorrhage from the peliotic liver lesions, and liver ultrasonography showed multiple hypoechoic areas of different sizes, which in this context should suggest the diagnosis. One child died from hypovolemic shock and the other recovered. This study indicates that acute peliosis hepatis can be a serious life-threatening disease in children.

Acute Disease↗
PubMed1999

[Favorable outcome of treatment with NTBC of acute liver insufficiency disclosing hereditary tyrosinemia type I].

BACKGROUND: Hereditary tyrosinemia type I is a disease with a severe prognosis. Main causes of death are acute liver failure, neurologic crises and hepatocarcinoma. NTBC, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites involved in hepatic, renal and neurologic lesions. CASE REPORTS: Results of NTBC therapy used in three infants with type I tyrosinemia who presented with acute liver failure are reported. The diagnosis relied on the finding of high plasmatic levels of tyrosine and methionine, and abnormal urinary excretion of succinyl acetone and delta aminolevulinic acid. Treatment with NTBC was initiated within 2 to 8 days from onset of symptoms. Signs of liver failure resolved after 3 weeks therapy. After 12 to 39 months of follow-up, outcome remains favorable. CONCLUSION: The results reported here highlight the efficiency of NTBC in type I tyrosinemia with early acute onset. However, the long term outcome needs to be determined with regards to prevention of hepatocarcinoma and toxicity of the drug.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1999

Long-term outcome of liver transplantation in patients with glycogen storage disease type Ia.

Liver transplantation may be indicated in patients with GSD type Ia when dietary treatment fails or when hepatic adenomas develop, because they carry a risk of liver cancer or severe intratumoral haemorrhage. Published reports on the results of liver transplantation in patients with GSD Ia include 10 patients and provide little information on long-term outcome. In particular, it is not known whether liver transplantation prevents renal failure due to focal segmental glomerulosclerosis. We report here on 3 patients with GSD Ia in whom liver transplantation was performed at 15, 17 and 23 years of age because of multiple hepatic adenomas in all 3 patients with a fear of malignant transformation, and of poor metabolic balance and severe growth retardation in the youngest one. Renal function was normal in all patients. During the 6-8 years following transplantation, the quality of life has initially greatly improved, with none of the previous dietary restraints and a spectacular increase in height. However, long-term complications included chronic hepatitis C in one patient, gouty attacks in another and focal segmental glomerulosclerosis with progressive renal insufficiency in the third. These results: (1) confirm that liver transplantation restores a normal metabolic balance in patients with GSD Ia, allows catch-up growth and improves the quality of life; (2) suggest that liver transplantation may be considered in teenagers with unresectable multiple adenomas because of a lack of clear-cut criteria to detect malignant transformation early; and (3) suggest that liver transplantation does not prevent focal segmental glomerulosclerosis associated with GSD Ia.

Adenoma↗
PubMed1999

Percutaneous endoscopic gastrostomy for continuous feeding in children with chronic cholestasis.

BACKGROUND: Malnutrition associated with chronic cholestasis in children often requires continuous enteral feeding through a nasogastric tube, which may be poorly tolerated. METHOD: Percutaneous endoscopic gastrostomy was performed in five children (age range, 20 months to 13 years) with severe cholestasis (Alagille syndrome in four; biliary atresia in one) and severe malnutrition (mean weight, -2.6 standard deviations; mean height, -2.7 standard deviations) who were awaiting liver transplantation. The pull-through technique was used in patients under general anesthesia, and the button was set within 2 months. RESULTS: Minor wound infection required antibiotic therapy in one patient. In the four children with Alagille syndrome, enteral feeding by means of percutaneous endoscopic gastrostomy was used until liver transplantation for a mean period of 14 months with a mean weight gain of 350 g/mo and a mean height gain of 0.53 cm/mo. Seventeen months to 3 years, 3 months after liver transplantation, all four children were alive and in good clinical condition with normal readings in liver function tests. The technique had to be discontinued in the child with biliary atresia because of secondary occurrence of ascites, gastric intolerance, and refractory wound infection. CONCLUSION: Percutaneous endoscopic gastrostomy may be a valuable alternative to nasogastric tube for nutritional support in children with cholestasis and mild portal hypertension.

Adolescent↗
PubMed1998

Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase.

Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymerization of actin filaments. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs that induces stabilization of F-actin structures in transfected cells. Dominant-negative LIM-kinasel inhibits the accumulation of the F-actin. Phosphorylation experiments in vivo and in vitro provide evidence that cofilin is a physiological substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.

3T3 Cells↗
PubMed1998

Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity.

The protooncogene bcl-2 inhibits neuronal apoptosis during normal brain development as well as that induced by cytotoxic drugs or growth factor deprivation. We have previously demonstrated that neurons of mice deficient in Bcl-2 are more susceptible to neurotoxins and that the dopamine (DA) level in the striatum after systemic 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) administration was significantly lower than in wild-type mice. In the present study we have used transgenic mice overexpressing human Bcl-2 under the control of neuron-specific enolase promoter (NSE-hbcl-2) to test the effects of the neurotoxins 6-hydroxydopamine (6-OHDA) and MPTP on neuronal survival in these mice. Primary cultures of neocortical neurons from normal and transgenic mice were exposed to these dopaminergic neurotoxins. Addition of 6-OHDA resulted in cell death of essentially all neurons from normal mice. In contrast, in cultures generated from heterozygous NSE-hbcl-2 transgenic mice, only 69% of the cells died while those generated from homozygous transgenic mice were highly resistant and exhibited only 34% cell death. A similar effect was observed with neurons treated with MPP+. Moreover, while the striatal dopamine level after MPTP injections was reduced by 32% in the wild type, the concentration remained unchanged in the NSE-hbcl-2 heterozygous mice. In contrast levels of glutathione-related enzymes were unchanged. In conclusion, overexpression of Bcl-2 in the neurons provided protection, in a dose-dependent manner, against neurotoxins known to selectively damage dopaminergic neurons. This study provides ideas for inhibition of neuronal cell death in neurodegenerative diseases and for the development of efficient neuroprotective gene therapy.

Animals↗
PubMed1998

Physiological and induced neuronal death are not affected in NSE-bax transgenic mice.

Bax, a family member of the survival protein Bcl-2, is expressed in the nervous system during development and throughout adulthood. Bax deficiency has been demonstrated to prevent developmental and trophic factor deprivation-induced neuronal death. To further clarify the role of Bax in naturally occurring neuronal death and in neuronal death following apoptotic stimuli, we generated several lines of transgenic mice expressing the human Bax protein specifically in neurons, under the control of the neuron-specific enolase promoter. Transgene expression was first detected around E10.5 and E12.5, depending on the transgenic line. The total number of ganglion cells in the retina and of pyramidal cells in the hippocampus, both expressing the transgene, was similar in control and transgenic mice. In addition, in our model system, Bax overexpression did not appear to influence the in vitro survival of sensory neurons isolated from dorsal root ganglia after nerve grwoth factor (NFG) deprivation or the apoptotic death of motor neurons following axotomy.

Animals↗
PubMed1998

Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.

Class III multidrug resistance (MDR) P-glycoproteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phospholipid excretion and develop progressive liver disease, characterized histologically by portal inflammation, proliferation of the bile duct epithelium, and fibrosis. This disease phenotype is very similar to a subtype of progressive familial intrahepatic cholestasis, hallmarked by a high serum gamma-glutamyltransferase (gamma-GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progressive familial intrahepatic cholestasis patients with high serum gamma-GT. Canalicular staining for MDR3 P-gp was negative in liver tissue of both patients. Reverse transcription-coupled PCR sequencing of the first patient's sequence demonstrated a homozygous 7-bp deletion, starting at codon 132, which results in a frameshift and introduces a stop codon 29 codons downstream. The second patient is homozygous for a nonsense mutation in codon 957 (C --> T) that introduces a stop codon (TGA). Our results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum gamma-GT. The histopathological picture in these patients is very similar to that in the corresponding mdr2(-/-) mouse, in which mdr2 P-gp deficiency induces complete absence of phospholipid in bile.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

Deregulated expression of the TAL1 gene by t(1;5)(p32;31) in patient with T-cell acute lymphoblastic leukemia.

TAL1 gene deregulation is frequent in T-cell acute lymphoblastic leukemia (T-ALL) and can result from translocations involving 1p32 or, more frequently, from a cytogenetically undetectable interstitial deletion of chromosome 1. This study presents a case of T-ALL with a t(1;5)(p32;q31) involving TAL1, in which the breakpoint occurs approximately 10kbp 5' to the gene and leads to transcriptional activation and synthesis of a TAL1 protein, and extends the spectrum of recognized TAL1 gene translocations associated with T-ALL.

Adult↗
PubMed1998

Influence of the oxygen uptake slow component on the aerobic energy cost of high-intensity submaximal treadmill running in humans.

During high-intensity running, the oxygen uptake (VO2) kinetics is characterised by a slow component which delays the attainment of the steady-state beyond the 3rd min of exercise. To assess if the aerobic energy cost of running measured at the 3rd min (C3) adequately reflects the variability of the true aerobic energy cost measured during the steady-state (Css), 13 highly-trained runners completed sessions of square-wave running at intensities above 80% maximal oxygen uptake (VO2max) on a level treadmill. To evaluate the time at which the steady-state VO2 was attained (tss), the VO2 responses were described using a general double-exponential equation and tss was defined as the time at which VO2 was less than 1% below the asymptotic value given by the model. All the subjects achieved a steady state for intensities equal to or greater than 92% VO2max, and 8 out of 13 achieved it at 99% VO2max. In all cases, tss was less than 13 min. For intensities greater than 85% VO2max, Css was significantly higher than C3 and was positively related to %VO2 max (r=0.44; P < 0.001) while C3 remained constant. The C3 only explained moderately the variability of Css (0.39 < r2 < 0.72, depending on the velocity or the (relative intensity at which the relationship was calculated). Moreover, the excess aerobic energy cost of running the (difference between Css and C3) was well predicted by age (0.90 < r2 < 0.93). Therefore, when the aerobic profile of runners is evaluated, it is recommended that their running efficiencies at velocities which reflect their race intensities should be determined, with VO2 data being measured at the true steady-state.

Adult↗
PubMed1998

Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension.

BACKGROUND/AIMS: Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension. Some severe pulmonary vascular anomalies associated with portal hypertension disappear after isolated liver transplantation. Evolution of pulmonary artery hypertension due to plexogenic arteriopathy is controversial, as this association is still considered a contraindication to isolated liver transplantation. Outcome of pulmonary hypertension after isolated liver transplantation is reported in three patients with portal hypertension. METHODS: After echocardiographic diagnosis, the patients had a complete hemodynamic exploration, and two had a lung biopsy. After liver transplantation, the survivors had echocardiographic follow up and a second hemodynamic exploration. RESULTS: In two children, pulmonary pressures and resistances returned to near-normal values 1 and 6 years after successful isolated liver transplantation. The third patient, with the most severe arteriopathy, had to wait 1 year for a donor, and the attempted transplantation was complicated by ventricular tachycardia; death occurred 2 days after surgery. CONCLUSIONS: Liver transplantation can reverse pulmonary artery hypertension due to high pulmonary resistances complicating liver disease with portal hypertension, provided it is carried out at an early stage. Early detection of pulmonary hypertension by systematic echocardiography may thus be crucial in these children with portal hypertension.

Adolescent↗
PubMed1998

Transient neonatal cholestasis: origin and outcome.

We studied, retrospectively, 92 children who were first seen with neonatal cholestasis and who were followed up until liver test results normalized. Among the 92 children, 81 displayed factors responsible for chronic and/or acute perinatal distress. Onset of jaundice was recorded at a mean age of 7 days, and mean duration was 3.5 months. Stools, initially discolored in 39 children, were normally colored at a mean age of 1.7 months. Hepatomegaly present in 90 children resolved at a mean age of 13 months. Liver test results were normal at the age of 1 year in 83 children and normalized at a mean age of 10 months. Liver histologic examination, performed in 70 children, showed moderate portal and lobular fibrosis, multinucleated giant hepatocytes, and hematopoietic foci; findings in follow-up liver biopsy specimens from 15 children were normal or improved. Spontaneously resolving forms of neonatal cholestasis may result from the association of several factors, including immaturity of bile secretion and perinatal disease leading to hepatic hypoxia or ischemia.

Alanine Transaminase↗
PubMed1998

[Early diagnosis of neonatal cholestatic jaundice].

Neonatal cholestasis should be considered in every baby in whom jaundice persists after day 10. Biliary atresia is the main cause of neonatal cholestasis and its prognosis is highly dependent on the early age at which surgery is performed. Finding the cause of cholestasis before day 30 is therefore crucial. This relies, in most instances, on simple clinical, biochemical, radiological and ophthalmologic criteria, the most important of which is a careful study of the degree and duration of stool discoloration.

Cholestasis↗
PubMed1997

Mouse LIM-kinase 2 gene: cDNA cloning, genomic organization, and tissue-specific expression of two alternatively initiated transcripts.

LIM-kinase 1 and LIM-kinase 2 (LIMK1 and LIMK2) are members of a novel protein kinase subfamily containing LIM motifs at the N-terminus. There are two isoforms of Limk2 transcripts coding proteins with distinct N-terminal structures: LIMK2a, containing two LIM motifs, and LIMK2b, with one and one-half LIM motifs. Here we report the cDNA and genomic structures of mouse LIMK2. The deduced 638-aminoacid sequence of mouse LIMK2a shows 98% identity with that of rat LIMK2a. The mouse Limk2a gene consists of at least 16 exons and spans more than 50 kb. Exon/intron boundaries of the mouse Limk2a gene are exactly conserved with those of the mouse Limk1 gene. An additional exon encoding the Limk2b-specific 5'-terminal sequence was found to be located between exons 2 and 3, suggesting that Limk2a and 2b mRNAs are transcribed from a single Limk2 gene by an alternative usage of exons near the 5' end of the gene. Limk2a and Limk2b transcripts were expressed at different ratios in a variety of mouse tissues.

Alternative Splicing↗