PubMed Health⌕ Search

Biomedical subjects

L Dorland

Publications and source records attributed to L Dorland.

At least 19 recordsLinked to original sources
PubMed2006

Removal of chloroform from biodegradable therapeutic microspheres by radiolysis.

Radioactive holmium-166 loaded poly(l-lactic acid) microspheres are promising systems for the treatment of liver malignancies. These microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method using chloroform. After preparation the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. It was observed that relatively large amounts of residual chloroform (1000-6000 ppm) remained in the microspheres before neutron irradiation. Since it is known that chloroform is susceptible for high-energy radiation, we investigated whether neutron and gamma irradiation could result in the removal of residual chloroform in HoAcAc-loaded and placebo PLLA-MS by radiolysis. To investigate this, microspheres with relatively high and low amounts of residual chloroform were subjected to irradiation. The effect of irradiation on the residual chloroform levels as well as other microsphere characteristics (morphology, size, crystallinity, molecular weight of PLLA and degradation products) were evaluated. No chloroform in the microspheres could be detected after neutron irradiation. This was also seen for gamma irradiation at a dose of 200 kGy phosgene, which can be formed as the result of radiolysis of chloroform, was not detected with gas chromatography-mass spectrometry (GC-MS). A precipitation titration showed that radiolysis of chloroform resulted in the formation of chloride. Gel permeation chromatography and differential scanning calorimetry showed a decrease in molecular weight of PLLA and crystallinity, respectively. However, no differences were observed between irradiated microsphere samples with high and low initial amounts of chloroform. In conclusion, this study demonstrates that neutron and gamma irradiation results in the removal of residual chloroform in PLLA-microspheres.

Biodegradation, Environmental↗
PubMed2005

Prolonged exercise testing in two children with a mild Multiple Acyl-CoA-Dehydrogenase deficiency.

BACKGROUND: Multiple Acyl-CoA-Dehydrogenase deficiency (MADD) is an inherited metabolic disorder characterized by impaired oxidation of fatty acids and some amino acids. METHODS: We were interested whether children with MADD could tolerate a prolonged low-intensity exercise test and if this test could have any additional diagnostic value. Therefore, we performed a maximal exercise test and a low-intensity prolonged exercise test in 2 patients with MADD and in 5 control subjects. During a prolonged exercise test the subjects exercised on a cycle ergometer at a constant workload of 30% of their maximum for 90 minutes and heart rate, oxygen uptake, fuel utilization and changes in relevant blood and urinary parameters were monitored. RESULTS: The tests were tolerated well. During the prolonged exercise test the fatty acid oxidation (FAO) was quite low compared to 5 control subjects, while characteristic metabolites of MADD appeared in plasma and urine. CONCLUSION: We suggest that the prolonged exercise test could be of diagnostic importance and might replace the fasting test as a diagnostic procedure in some cases, particularly in patients with anamnestic signs of intolerance for prolonged exercise.

Journal Article↗
PubMed2005

Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation.

We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Energy expenditure in patients with propionic and methylmalonic acidaemias.

Resting energy expenditure (REE) was investigated in 8 children with propionic and methylmalonic acidaemias because a lowered REE has been reported in the literature. We observed a marginally elevated REE and think that adequate caloric intake and the use of a synthetic amino acid mixture are responsible for this.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids.

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.

Carbohydrate Dehydrogenases↗
PubMed2002

Glutaric aciduria type III: a distinctive non-disease?

Glutaric aciduria type III is a rare metabolic abnormality leading to persistent isolated glutaric acid excretion. We report the clinical and biochemical phenotypes of three affected children. The first patient is a boy with dysmorphic features and a chromosomal deletion (monosomy 6q26-qter) in whom a persistent glutaric aciduria (500 mmol/mol creatinine, normal <10) was detected during a routine metabolic investigation. The second boy suffered from acute gastroenteritis and hyperthyroidism, when an excessively high urinary glutaric acid excretion was identified (1460 mmol/mol creatinine). The third patient is a girl with constantly elevated glutaric acid in her urine (290 mmol/mol creatinine) but no symptoms of significant disease. In all our patients, glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency), glutaric aciduria type II (multiple acyl-CoA dehydrogenation defect), and secondary forms of glutaric aciduria (for example due to intestinal infections or mitochondrial dysfunction) could be excluded. Loading with the precursor amino acid lysine in all patients as well as with pipecolic acid in the third case led to an increase in urinary glutaric acid excretion, proving the endogenous origin of glutarate. Glutaric aciduria type III (a defect reported to be caused by peroxisomal glutaryl-CoA oxidase deficiency) is our presumptive diagnosis. However, peroxisomal glutaryl-CoA oxidase is not well characterized and no reliable approach for the direct determination of this enzyme is available to us. To our knowledge, in the English language literature only a single patient with glutaric aciduria type III has been described. Our cases reported here confirm the earlier assumption that glutaric aciduria type III is not related to a distinctive phenotype. Glutaric aciduria type III appears to be a rare metabolic abnormality, presumably of peroxisomal metabolism. However, its pathophysiological impact still needs further investigation.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.

Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 micromol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH4) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH4 loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH4 load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH4 biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1-4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH4.

Biopterins↗
PubMed2001

Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome.

BACKGROUND: The hyperimmunoglobulinaemia D and periodic fever syndrome is a hereditary periodic fever, caused by deficiency of the enzyme mevalonate kinase. It is unclear how this defect leads to recurrent fever episodes. AIM: To assess the involvement of cysteinyl leukotrienes in the pathogenesis of fever attacks as reflected by urinary leukotriene E(4) (LTE(4)) excretion. METHODS: Urinary LTE(4) was measured in seven patients while febrile and afebrile. RESULTS: LTE(4) was raised during fever in all subjects (46-199 nmol/mol creatinine, mean 92; normal <40). Urinary LTE(4) was normal between attacks, as well as in normal children with fever as a result of miscellaneous causes. CONCLUSION: Our results suggest that cysteinyl leukotrienes play a role in the pathophysiology of this disorder. As no effective treatment is yet available, leukotriene receptor antagonists might offer a new therapeutic approach for patients with the hyperimmunoglobulinaemia D and periodic fever syndrome.

Adolescent↗
PubMed2000

Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib).

CDG-Ib is the "gastro-intestinal" type of the congenital disorders of glycosylation (CDG) and a potentially treatable disorder. It has been described in patients presenting with congenital hepatic fibrosis and protein losing enteropathy. The symptoms result from hypoglycosylation of serum- and other glycoproteins. CDG-Ib is caused by a deficiency of mannose-6-phosphate isomerase (synonym: phosphomannose isomerase, EC 5.3.1.8), due to mutations in the MPI gene. We determined the genomic structure of the MPI gene in order to simplify mutation detection. The gene is composed of 8 exons and spans only 5 kb. Eight (7 novel) different mutations were found in seven patients with a confirmed phosphomannose isomerase deficiency, analyzed in the context of this study: six missense mutations, a splice mutation and one insertion. In the last, the mutation resulted in an unstable transcript, and was hardly detectable at the mRNA level. This emphasizes the importance of mutation analysis at the genomic DNA level.

Congenital Disorders of Glycosylation↗
PubMed2000

Congenital hepatic fibrosis in 3 siblings with phosphomannose isomerase deficiency.

Congenital hepatic fibrosis is a rare disorder of intrahepatic bile ducts with the persistence of embryological bile duct structures in ductal plate configuration. Three siblings aged 18, 17 and 14 years old were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme phosphomannose isomerase. The clinical symptoms were recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly. The biochemical abnormalities included elevated serum transferases during attacks, clotting factor deficiencies and persistent hypoalbuminemia. In the youngest patient protein-losing enteropathy was present. Liver biopsies of the three patients taken when they were 1, 3 and 14 years old showed an excess of bile duct structures in ductal plate configuration with mild fibrosis in the portal triads. In one patient the liver biopsy was repeated after 18 years and showed only a mild progression of fibrosis in the portal triads. Duodenal biopsies taken in infancy in two of the three patients did not show any abnormalities. Recognition of phosphomannose isomerase deficiency in association with congenital hepatic fibrosis and protein-losing enteropathy is important, because some of the clinical symptoms are potentially treatable by oral mannose therapy.

Adolescent↗
PubMed2000

Carnitine-acylcarnitine translocase deficiency: metabolic consequences of an impaired mitochondrial carnitine cycle.

We describe a patient with carnitine-acylcarnitine translocase deficiency (MIM 212138), who presented with neonatal generalized seizures, heart failure, and coma. Laboratory evaluation revealed hypoglycemia, hyperammonemia, lactic acidemia, hyperuricemia, and mild dicarboxylic aciduria. The fact that total plasma carnitine (7.1 micromol/l [20-30]) and free carnitine (1.9 micromol/l [12-18]) were low together with a high acylcarnitine/free carnitine ratio of 2.7 [0.4-1.0] prompted acylcarnitine analysis. This revealed the presence of large amounts of long-chain derivatives including C(16:0), C(16:1), C(18:1), C(18:2). Based on these findings carnitine-acylcarnitine translocase deficiency was suspected which was confirmed by enzyme studies in fibroblasts. The underlying complex metabolic consequences of this defect are reviewed. Prenatal diagnosis was performed in a subsequent pregnancy and a defect ruled out by measurement of carnitine-acylcarnitine translocase activity in cultured chorionic villi cells. As the clinical recognition of a life-threatening fatty acid oxidation disorder may be difficult, defects in this pathway should be considered in any child with coma, an episode of a Reye-like syndrome, and cardiomyopathy. Since routine laboratory tests often do not provide clues about potential disorders and profiles of urinary organic acids may not be characteristic, we recommend to measure free carnitine and acylcarnitines in plasma in any child with hyperammonemia, hypo/hyperketotic hypoglycemia or lactic acidemia for prompt treatment, proper genetic counseling, and potential prenatal diagnosis.

Ammonia↗