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E Christensen

Publications and source records attributed to E Christensen.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pretransplant prediction of prognosis after liver transplantation in primary sclerosing cholangitis using a Cox regression model.

Liver transplantation remains the only treatment for patients with end-stage primary sclerosing cholangitis (PSC); however, selection criteria for the procedure and its timing remains uncertain. The aim of this study was to identify pretransplant variables associated with survival after transplantation and to devise a Cox regression model for prediction of post-transplant survival. We studied 118 patients transplanted for PSC at the Queen Elizabeth Hospital, Birmingham, UK, being followed for up to 91/4 years after the procedure. The association between pretransplant data and the post-transplant survival up to 1 year was studied using the logrank test (univariate analyses) and Cox multiple regression analysis. Univariate analyses showed the following variables to be associated with a decreased post-transplant survival: high serum creatinine, high serum bilirubin, biliary tree malignancy, previous upper abdominal surgery, hepatic encephalopathy, ascites, and Crohn's disease, whereas ulcerative colitis was associated with increased post-transplant survival (all P </=.05). The final multiple Cox regression model included the following significant variables: inflammatory bowel disease, ascites, previous upper abdominal surgery, serum creatinine, and biliary tree malignancy (all P <.03). Biliary tree malignancy could be omitted from the Cox model with only slight loss of information. The results were validated using the data of 30 independent PSC patients from another center. These results can improve selection of patients with PSC for liver transplantation. The developed prognostic model for transplantation can be used in parallel with previously published prognostic models for nontransplantation. The obtained prognostic estimates will provide additional information that is useful for optimal timing of liver transplantation in the individual patient.

Adult↗
PubMed1999

Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-->A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Animals↗
PubMed1999

Optimal timing of liver transplantation for patients with primary biliary cirrhosis: use of prognostic modelling.

BACKGROUND/AIMS: Liver transplantation remains the only definitive treatment for patients with end-stage primary biliary cirrhosis, although the optimal timing of the procedure remains uncertain. The aim of the study was to use prognostic modelling to determine the optimal timing of transplantation for patients with primary biliary cirrhosis. METHODS: A prognostic model for predicting the survival of patients after transplantation was generated using the Cox regression model with data from 312 patients transplanted for primary biliary cirrhosis at the Queen Elizabeth Hospital, Birmingham. The prognosis after transplantation was compared to that without transplantation (using a previously published prognostic index for non-transplantation) both in these patients and in 98 non-transplanted primary biliary cirrhosis patients dying from the liver disease, in order to establish at what stage the prognosis with transplantation was better than without transplantation. RESULTS: The prognostic index for transplantation included the following significant prognostic variables: serum bilirubin, serum albumin, age, year of transplantation, and the presence of ascites or treatment with diuretics. Comparison of prognosis with and without transplantation showed that the predicted gain in survival after transplantation becomes increasingly positive when the 6-month survival probability in the absence of transplantation falls below 0.85. In the non-transplanted patients this occurs on average about 8 months before death. CONCLUSIONS: Comparison of the prognosis with and without transplantation provides a rational method for determining the optimum timing of the procedure which occurs approximately when the predicted 6-month survival probability without transplantation falls below 0.85.

Female↗
PubMed1999

Glutaric aciduria type I: pathomechanisms of neurodegeneration.

In organotypic corticostriatal and hippocampal slice cultures from rat brain, 3-hydroxyglutaric acid but not glutaric and glutaconic acids induced neurodegeneration by activation of NMDA receptors. Electrophysiological investigations (Xenopus laevis oocytes expressing glutamate receptors; rat mixed cortex culture) revealed no direct interaction of 3-hydroxyglutaric acid with glutamate receptors. We speculate that 3-hydroxyglutaric acid induces a mild energy deprivation that interferes with the voltage-dependent Mg(2+)-block of NMDA receptors.

Animals↗
PubMed1999

Preoperative prediction model of outcome after cholecystectomy for symptomatic gallstones.

BACKGROUND: After cholecystectomy for symptomatic gallstone disease 20%-30% of the patients continue to have abdominal pain. The aim of this study was to investigate whether preoperative variables could predict the symptomatic outcome after cholecystectomy. METHODS: One hundred and two patients were referred to elective cholecystectomy in a prospective study. Median age was 45 years; range, 20-81 years. A preoperative questionnaire on pain, symptoms, and history was completed, and the questions on pain and symptoms were repeated 1 year postoperatively. Preoperative cholescintigraphy and sonography evaluated gallbladder motility, gallstones, and gallbladder volume. Preoperative variables in patients with or without postcholecystectomy pain were compared statistically, and significant variables were combined in a logistic regression model to predict the postoperative outcome. RESULTS: Eighty patients completed all questionnaires. Twenty-one patients continued to have abdominal pain after the operation. Patients with pain 1 year after cholecystectomy were characterized by the preoperative presence of a high dyspepsia score, 'irritating' abdominal pain, and an introverted personality and by the absence of 'agonizing' pain and of symptoms coinciding with pain (P < 0.000001). In a constructed logistic regression model 15 of 18 predicted patients had postoperative pain (PVpos = 0.83). Of 62 patients predicted as having no pain postoperatively, 56 were pain-free (PVneg = 0.90). Overall accuracy was 89%. CONCLUSION: From this prospective study a model based on preoperative symptoms was developed to predict postcholecystectomy pain. Since intrastudy reclassification may give too optimistic results, the model should be validated in future studies.

Adult↗
PubMed1999

Prediction of hepatic encephalopathy in paracetamol overdose: a prospective and validated study.

BACKGROUND: Paracetamol overdose may cause hepatic encephalopathy (HE). This condition demands specialized care and, in some instances, liver transplantation evaluation. No model is available for predicting HE. We aimed to set up and validate a model for predicting the occurrence of HE in paracetamol overdose. METHODS: Prospectively, 161 patients with single-dose paracetamol overdose and no HE (defined as hepatic coma grade II or more) on admission were studied during a 26-month period. Patients admitted during the first 13-month period constituted a learning set to construct a model to predict the occurrence of HE. Patients admitted in the second 13-month period constituted the validation set. Serial biochemical variables (measured twice daily), the time line after the overdose, and demographic data were used for univariate testing, and significant factors were assessed in various multiple logistic regression analyses. RESULTS: Thirty-two patients (20%), 15 in the first period and 17 in the second, developed HE grade II. The best model (the highest chi-square) for HE included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count hours from overdose (chi-square = 41.2, P < 0.00001). In the validation set 88% (confidence interval (CI), 64%-99%) of the patients who developed HE were correctly predicted by the constructed model, whereas 90% (CI, 79%-96%) of the patients in the non-HE group were correctly predicted. CONCLUSIONS: The constructed model for predicting HE in paracetamol overdose proved sensitive and accurate in the validation set and should be valuable for transferring high-risk patients to a liver intensive care unit/transplantation facility.

Acetaminophen↗
PubMed1999

Design of a pilot study to evaluate tandem mass spectrometry for neonatal screening.

In recent years, tandem mass spectrometry has generated great interest as a method for neonatal screening. The basic principle is electronically controlled separation of analytes by their mass-to-charge ratio. The advantage of this detection system is speed, the capability to analyze for many different compounds in a single analysis, and a minimal need for auxilliary assay reagents. The prevailing screening technique uses stable isotope dilution, butylesterification, and MS/MS analysis to quantify amino acids and acylcamitines in neonatal dried blood spot samples. This allows detection of more than 30 inborn errors of metabolism of amino acids, fatty acids, and other organic acids. In Denmark, a large-scale pilot study is being implemented to evaluate the screening potential of tandem mass spectrometry. National patient registers and medical records from clinical genetics units are used to identify cohorts of healthy infants and infants with selected inborn errors of metabolism. The neonatal screening samples of these infants are retrieved from a biobank and are assayed for amino acids and acylcarnitines using tandem mass spectrometry. This study yields decision values for neonatal screening, which will be evaluated in a subsequent 2-year prospective pilot study, offering the test to 140,000 neonates as a voluntary adjunct to the existing screening program. The organization consists of integrated units for neonatal screening and clinical genetics. The effect of the program will be assessed in terms of screening efficiency, cost and short term clinical outcome.

Amino Acids↗
PubMed1998

[Multiple carboxylase deficiency].

Biotinidase deficiency and holocarboxylase synthetase deficiency are two autosomal recessively inherited disorders of biotin metabolism affecting children below the age of two years. Both cause multiple carboxylase deficiency resulting in defects of fatty acid synthesis, gluconeogenesis and amino acid catabolism. The clinical picture involves the nervous system, the skin, the respiratory system, the digestive system and the immune system, but great individual variations often makes the clinical diagnosis difficult. Early diagnosis and treatment with biotin are essential in order to prevent death from metabolic acidosis or irreversible damage to the central nervous system. Two patients with biotinidase deficiency, two patients with holocarboxylase synthetase deficiency and a review of the literature are presented. Neonatal screening for biotinidase deficiency or a higher degree of metabolic screening of the urine in children below the age of one year with seizures and unexplained clinical course are discussed.

Biotin↗
PubMed1998

Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations.

Glutaric acidemia type I (GA1) is caused by mutations in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCD). Sixty-three pathogenic mutations identified by several laboratories are presented, 30 of them for the first time, together with data on expression in Escherichia coli and relationship to the clinical and biochemical phenotype. In brief, many GCD mutations cause GA1, but none is common. There is little if any relationship between genotype and clinical phenotype, but some mutations, even when heterozygous, seem especially common in patients with normal or only minimally elevated urine glutaric acid.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I.

Glutaric acidemia type I (GAI) (McKusick 231670) is an autosomal recessive disease affecting the catabolism of the amino acids lysine, hydroxylysine and tryptophan, caused by a defect in the gene encoding glutaryl-coenzyme A dehydrogenase (GCDH) and associated with severe neurological symptoms. Several pathogenic mutations in GCDH have been reported to cause GAI. One mutation, R402W, is more common than the others, which seem to be private" mutations. Here we report the entire sequences of introns 1, 2, 3, 6, 7, 8 and 9, and part of those of introns 4, 5 and 10 as well as 21 different mutations in 20 patients with GAI, corresponding to 38 out of 40 alleles.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A.

Molybdenum cofactor (MoCo) deficiency is a rare and devastating disease resulting in neonatal seizures and other neurological symptoms identical to those of sulphite oxidase deficiency. It is an autosomal recessive disease and no therapy is known. Most patients harbour MOCS1 mutations, which are found in both open reading frames of this unusual gene encoding the first two enzymes required in the MoCo biosynthesis pathway, MOCS1 A and MOCS1 B, in a single transcript. We describe genomic details as a prerequisite for comprehensive mutation analysis. In an initial cohort of 24 MoCo deficiency patients, we identified 13 different mutations on 34 chromosomes, with a mutation detection rate of 70%. Five mutations were observed in more than one patient and together accounted for two thirds of detected mutations. These comprise the most frequent mutation, R319Q, which is restricted to England, two Danish/German mutations (one missense and one splice site mutation), a missense mutation found in England and Germany, and a "Mediterranean" frameshift mutation. All patients with identified mutations are either homozygous or compound heterozygous for mutations in either of the two open reading frames corresponding to MOCS1 A and MOCS1 B, respectively. This observation suggests the existence of more than the two previously described complementation groups in MoCo biosynthesis.

Amino Acid Sequence↗
PubMed1998

Diagnosis and management of glutaric aciduria type I.

Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs between 6 and 18 months of age and is probably linked to changes in metabolic demand caused by normal maturational changes and superimposed catabolic stress. Recognition of this biochemical disorder before the brain has been injured is essential to outcome. Diagnosis depends upon the recognition of relatively non-specific physical findings such as hypotonia, irritability and macrocephaly, and on performance of urine organic acid quantification by gas chromatography--mass spectrometry or selective searches of urine or blood specimens by tandem mass spectrometry for glutarylcarnitine. The diagnosis may also be suggested by characteristic findings on neuroimaging. In selected patients diagnosis can only be reached by enzyme assay. Specific current management by the authors of this paper includes pharmacological doses of L-carnitine, as well as dietary protein restriction. Metabolic decompensation must be treated aggressively to avoid permanent brain damage. Multicentre studies are needed to establish best methods of diagnosis and optimal therapy of this disorder.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Classification of dyspepsia. Identification of independent symptom components in 7270 consecutive, unselected dyspepsia patients from general practice.

BACKGROUND: Several attempts to classify dyspepsia into subgroups have been proposed as a basis for empirical treatment and research. However, subgrouping has proved difficult due to overlap of symptoms between subgroups, and the response to empirical therapy is difficult to predict. We aimed to study whether natural symptom combinations occur in patients seeing general practitioners because of dyspepsia and whether symptom presentation could predict the effect of proton pump inhibitor treatment. METHODS: The symptom presentation of 7270 consecutive, unselected patients with dyspepsia in general practice was studied by using principal-components analysis. The relation to the effect of omeprazole was studied in a subsample (n=471) with predominantly reflux-like or ulcer-like dyspepsia being included in a controlled clinical trial of omeprazole versus placebo. RESULTS: Four principal components (factors), explaining 36% of the total variance, were found. They describe four independent dimensions in the symptoms of dyspepsia that can be interpreted meaningfully as representing A) acid-related disease of the upper gastrointestinal tract, B) irritable bowel disorder, C) dysmotility of the stomach/duodenum, and D) dysmotility of the esophagus. In the subsample the response to proton pump inhibition therapy was associated with high component-A scores, low component-B scores, and low component-C scores. A pocket chart was devised to obtain the component scores easily in new patients. CONCLUSION: The analysis identified four characteristic, biologically meaningful dyspepsia components that express independent dimensions in the symptoms of patients with dyspepsia. The symptom scores corresponding to the four components may improve symptom-based diagnosis and thereby empirical therapy. In particular, the association between component scores and the effect of omeprazole suggests that classifying dyspepsia on the basis of these components may focus empirical omeprazole therapy even more.

Adult↗