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Biomedical subjects

W Sperl

Publications and source records attributed to W Sperl.

At least 55 records · Page 3Linked to original sources
PubMed1997

High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders.

High resolution respirometry in combination with the skinned fiber technique offers the possibility to study mitochondrial function routinely in small amounts of human muscle. During a period of 2 years, we investigated mitochondrial function in skeletal muscle tissue of 13 patients (average age = 5.8 years). In all of them, an open muscle biopsy was performed for diagnosis of their neuromuscular disorder. Mitochondrial oxidation rates were measured with a highly sensitive respirometer. Multiple substrate-inhibitor titration was applied for investigation of mitochondrial function. About 50 mg fibers were sufficient to obtain maximal respiratory rates for seven different substrates (pyruvate/malate, glutamate/malate, octanoylcarnitine/malate, palmitoylcarnitine/malate, succinate, durochinol and ascorbate/TMPD). Decreased respiration rates with reference to the wet weight of the permeabilized fiber could immediately be detected during the course of measurements. In 4 patients with mitochondrial encephalomyopathy (MEM) the respiration pattern indicated a specific mitochondrial enzyme defect, which was confirmed in every patient by measurements of the individual enzymes (one patient with PDHC deficiency, one with complex I deficiency and two patients with combined complex I and IV deficiency). In the 6 patients with spinal muscular atrophy (SMA) oxidation rates were found to be decreased of 23 +/- 5% of controls. The normalized respiration pattern was comparable to that of the controls indicating a decreased content of mitochondria in SMA muscle with normal functional properties. Also in the 3 patients with Duchenne muscular dystrophy (DMD) decreased oxidation rates (42 +/- 5%) were detected. In addition a low RCI (1.2) indicated a loose coupling of oxidative phosphorylation in the mitochondria of these patients. It is concluded that investigation of mitochondrial function in saponin skinned muscle fibers using high resolution respirometry in combination with multiple substrate titration offers a valuable tool for evaluation of mitochondrial alterations in muscle biopsies of children suffering from neuromuscular disorders.

Child↗
PubMed1996

Current therapy for Crigler-Najjar syndrome type 1: report of a world registry.

This study represents a multicenter survey on the management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of inclusion, 21 patients had received a liver transplant (37%). The average age at transplantation was 9.1 +/- 6.9 years (range, 1-23 years); the age of the patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0-23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 are alive with some degree of mental or physical handicap. In 2 patients, ages 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Seven patients underwent transplantation with some degree of brain damage at the time of the surgery; 1 of these died after retransplantation, 2 improved neurologically, and 4 remained neurologically impaired. The age of 8 patients with and 13 without brain damage at or before transplantation was 14.3 +/- 5.9 and 5.9 +/- 5.4 years (P < .01), respectively. Therapy of CNS type 1 consists of phototherapy (12 h/d), followed by liver transplantation. Phototherapy, although initially very effective, is socially inconvenient and becomes less efficient in the older age group, thus also decreasing compliance. Currently, liver transplantation is the only effective therapy. This survey shows that, in a significant number of patients, liver transplantation is performed after some form of brain damage has already occurred. From this, one must conclude that liver transplantation should be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed.

Adolescent↗
PubMed1995

Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea.

UNLABELLED: Veno-occlusive disease was diagnosed in an 18-month-old boy who had regularly consumed a herbal tea mixture since the 3rd month of life. The boy developed portal hypertension with severe ascites. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The tea contained peppermint and what the mother thought was coltsfoot (Tussilago farfara). The parents believed the tea aided the healthy development of their child. Pharmacological analysis of the tea compounds revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components by thin-layer chromatography, mass spectrometry and NMR spectroscopy. We calculated that the child had consumed at least 60 micrograms/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months. CONCLUSION: In all cases of veno-occlusive disease pyrrolizidine alkaloids ingestion should be excluded. The identity of collected plant material should be verified by pharmaceutically trained experts and information of composition, dosage and mode of administration should be included in guidelines for herbal preparations.

Hepatic Veno-Occlusive Disease↗
PubMed1995

Fulminant hepatic failure in a child as a potential adverse effect of trimethoprim-sulphamethoxazole.

UNLABELLED: Trimethoprim-sulphamethoxazole (TMP-SMZ) is considered a safe drug for treatment of infectious bacterial diseases in children. Side-effects are rare and generally take the form of a hypersensitivity reaction to the sulphamethoxazole component of the drug. Hepatic injury usually presents as a transient elevation of liver enzymes, which is of little clinical relevance. Fulminant liver failure due to TMP-SMZ has been reported in only six adults and never in children. We here report a 5-year-old girl who developed fulminant liver failure 3 weeks after her third exposure to TMP-SMZ. After a biphasic clinical course she underwent successful liver transplantation. CONCLUSION: Trimethoprim-Sulphamethoxazole may cause fulminant liver failure in children. The disease can run a biphasic clinical course and liver transplantation must be considered as the therapeutic option for these patients.

Biopsy↗
PubMed1995

On the differences between urinary metabolite excretion and odd-numbered fatty acid production in propionic and methylmalonic acidaemias.

In five subjects with methylmalonic acidaemia (MMA) and five with propionic acidaemia (PA) both the level of odd-numbered fatty acids (OLCFA) in erythrocyte lipids and the excretion of propionate-derived metabolites in urine were longitudinally analysed. At a given intake of amino acid precursors of propionyl-CoA and otherwise stable metabolic conditions, subjects with MMA excreted considerably more propionate-derived metabolites, and accumulated less OLCFA in excretion erythrocyte lipids than subjects with PA. We suggest that renal metabolite excretion indicates the efflux of organic acids from cells and might be a measure of the individually determined intracellular relief from toxic acyl-CoA esters. It does not necessarily reflect the total amount of acyl-CoA intermediates produced in the body. OLCFA levels seem to reflect the continuous burden of propionyl-CoA toxicity within the cells and thereby might serve as a reliable tool for evaluating the quality of long-term metabolic control in these disorders.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Sarcolemmal expression of dystrophin C-terminus but reduced expression of 6q-dystrophin-related protein in two DMD patients with large deletions of the dystrophin gene.

Partial deletions of the dystrophin gene are the predominant genetic lesions in Duchenne (DMD) and Becker (BMD) muscular dystrophies. According to the reading frame hypothesis [1], any deletion disrupting the translational reading frame of the mRNA cannot result in expression of the dystrophin molecule and should lead to severe phenotypes of DMD. In contrast, deletions which maintain the reading frame across the deleted exons may give rise to truncated, semifunctional proteins and milder courses of the disease (i.e. BMD). Among the notable exceptions of this hypothesis are very large "in-frame" deletions by which functionally indispensable domains of the dystrophin molecule have been removed. Here, we report on two DMD patients with large intragenic in-frame deletions. Grossly truncated, but stable dystrophin molecules with preserved C-terminal domains were detected at the sarcolemma on cryosections in both patients. However, dystrophin organization on single-teased muscle fibers revealed disarrangement of the costameric pattern, if compared to normal skeletal muscle fibers. Compared to dystrophin-deficient DMD muscle, expression of chromosome-6-encoded dystrophin-related protein (DRP) was greatly diminished in skeletal muscle of both patients. We show, that loss of more than 50% of dystrophin seems to be deleterious for the protein's function and therefore, the extent of the deletions may have an impact on construction of dystrophin mini genes. Moreover, these findings shed new light on the functional significance of the C-terminal domain of dystrophin. They also suggest a negative correlation between sarcolemmal expression of the dystrophin C-terminus and DRP expression at the sarcolemma.

Blotting, Western↗
PubMed1995

Long-chain polyunsaturated fatty acids in children with severe protein-energy malnutrition with and without human immunodeficiency virus-1 infection.

Fatty acids in plasma phospholipids were studied in 35 severely malnourished young children with a median age of 29 mo (range: 9-43 mo), who were either seronegative for human immunodeficiency virus-1 (HIV) (n = 16) or suffered from asymptomatic (stage P-1; n = 12) or symptomatic (stage P-2; n = 7) HIV disease. The malnourished children had significantly lower percentages (% by wt) of phospholipid arachidonic (20:4n-6, AA) and docosahexaenoic (22:6n-3, DHA) acids than 25 age-matched healthy control subjects (AA: 7.05% and 8.70% by wt; DHA: 0.92 and 2.61% by wt, P < 0.001). Body weights of malnourished children did not correlate with linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acid values but were significantly and positively correlated with AA and DHA values (r = 0.40, P = 0.02 and r = 0.63, P < 0.0001, respectively). Plasma concentrations (mg/L) of total phospholipid fatty acids did not differ among seronegative, stage P-1, or stage P-2 patients. Percentage contributions of AA and eicosapentaenoic acid (20:5n-3, EPA) did not differ among those seronegative or in stages P-1 and P-2. In contrast, values of dihomo-gamma-linolenic acid (20:3n-6) were significantly (P < 0.05) lower in stage P-2 (2.38 mg/L) than in either seronegative (3.47 mg/L) or stage P-1 (3.66 mg/L) patients. We conclude that the severely malnourished children developed a depletion of both AA and DHA proportional to the degree of malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acids↗
PubMed1994

A family with visceral course of Niemann-Pick disease, macular halo syndrome and low sphingomyelin degradation rate.

We report a family with six patients suffering from a sphingomyelinase-deficient form of Niemann-Pick disease, all presenting with a visceral course of the disease. Retinal changes classified as macular halos in four members indicated neuronal storage and therefore an intermediate type of the disease. For further classification of the biochemical type, [choline-methyl-14C]sphingomyelin degradation studies were carried out in fibroblast cultures of all six members. The low degradation rates measured were similar to those usually found in the neuronopathic form (type A) of Niemann-Pick disease. This family illustrates the broad heterogeneity within the sphingomyelinase deficiency group of the Niemann-Pick disease. Apparently the finding of a low sphingomyelin degradation rate in fibroblast cultures does not necessarily imply a typical serious and lethal course of the disease.

Biomarkers↗
PubMed1994

Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients.

Comprehensive data on 30 patients with propionic acidaemia, diagnosed by selective screening for inborn errors of metabolism, are presented. The most valuable diagnostic metabolites found were methylcitric-, 3-hydroxypropionic-, and 2-methyl-3-oxovaleric acids. Hyperlysinaemia and hyperlysinuria are also characteristic findings in this disease. The metabolic pattern found in propionic acidaemia is discussed extensively as are enzymatic findings. Residual activity of propionyl-CoA carboxylase is neither a predictive marker for severity nor for outcome of the disease. Propionate fixation assays were less reliable for confirmation of propionic acidaemia and of no prognostic value. Clinical presentation of the disease is discussed in detail. Besides the well-known unspecific findings (poor appetite, feeding difficulties, vomiting, dehydration, weight loss, muscular hypotonia, dyspnoea, somnolence, apathy, convulsion, coma, severe metabolic acidosis, hyperammonaemia) various skin abnormalities have been detected in about 50% of all patients. In 27% "dermatitis acidemica" was found.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Identification of CD34+ cord blood cells and their subpopulations in preterm and term neonates using three-color flow cytometry.

Three-color flow cytometry was used to identify CD34+ cord blood (CB) hematopoietic progenitors of preterm (n = 13) and term (n = 18) neonates. The frequency of CD34+ CB cells gated on the lymphocyte fraction in term neonates is about half the frequency of preterm neonates (mean 1.84 +/- 0.8 vs. 3.49 +/- 1.8, p < 0.005). The difference of absolute CD34+ cells between the 2 groups did not reach statistical significance (premature 169 +/- 161 vs. mature 108 +/- 62.6 x 10(6) cells/l). The proportion of myeloid lineage-committed CD34+ cells coexpressing the CD33 antigen in preterm neonates does not significantly differ from that found in term neonates. However, in preterm neonates a higher fraction of erythroid lineage-committed CD34+ cells coexpresses the CD71 antigen as compared with term neonates (mean 28.7 +/- 14.1 vs. 11.4 +/- 5.7, p < 0.001). The positive correlation between gestational age and the ratio of myeloid/erythroid lineage-specific progenitor cells (r = 0.61, n = 31, p < 0.0005) suggests gestational changes in lineage commitment of CD34+ cells.

Antigens, CD↗
PubMed1994

[Myoglobinuria and carnitine palmitoyltransferase deficiency. Diagnostic procedure and differential diagnosis].

Carnitine palmitoyltransferase (CPT) deficiency is the most common metabolic cause of recurrent myoglobinuria. We describe five patients with CPT deficiency who were recruited during a 24-months period. Phenotypic expression ranged from mild myalgia without myoglobinuria to severe exercise-induced attacks and a lethal course. The pathophysiological basis of the clinical heterogeneity is discussed. The diagnostic procedure includes a neurological and electromyographical examination as well as an exercise test and extensive biochemical investigations of muscle biopsy specimens. Accurate diagnosis allows an early introduction of preventive measures and clearly improves the outcome.

Adult↗
PubMed1993

Maple syrup urine disease: metabolic decompensation monitored by proton magnetic resonance imaging and spectroscopy.

Metabolic decompensation of maple syrup urine disease in a 3.5-year-old boy was monitored by means of proton magnetic resonance imaging and spectroscopy. In the acute stage, imaging showed diffuse cerebral edema. Proton spectra showed an elevation of lactate and a previously unassigned resonance at 1 ppm. This peak disappeared with normalization of branched-chain amino acids and oxoacids in the plasma and cerebrospinal fluid. In vitro spectroscopy of these metabolites at 1.5 T confirmed the chemical shift position of their methyl resonances at 1 ppm. The duration of lactate elevation correlated with the presence of brain edema and coma. These results demonstrate that magnetic resonance imaging can monitor therapeutic effects, and suggest that proton spectroscopy can detect cerebral accumulation of branched-chain amino acids and oxoacids in maple syrup urine disease.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1993

Interleukin-3, interleukin-6, granulocyte-macrophage colony-stimulating factor and erythropoietin cord blood levels of preterm and term neonates.

The cascade of known haematopoietic growth factors controlling granulomonopoiesis and erythropoiesis includes interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). Elevated endogenous IL-3 and IL-6 cord blood levels in infection-free premature and mature neonates may reflect their possible role for expansion of haematopoietic progenitor cells, granulocytes and monocytes. Within the erythroid lineage a synergistic action of IL-3, IL-6 and EPO can be assumed. To identify the regulatory role in fetal haematopoietic expansion cord blood plasma levels of these haematopoietic growth factors were assessed in 19 premature and 20 mature infants using commercial enzyme-linked immunosorbent assay and enzyme-amplified sensitivity immuno assay test kits. Peripheral blood IL-3, GM-CSF and EPO were studied in 5 and 10 premature infants respectively. Compared with cord blood levels we found a decline in EPO levels but no decrease of IL-3 and GM-CSF during the 1st month of life. We conclude that postnatal decrease in plasma burst-promoting activity levels in preterm infants is mainly explained by low postnatal EPO levels.

Erythropoietin↗
PubMed1993

Measurement of totally activated pyruvate dehydrogenase complex activity in human muscle: evaluation of a useful assay.

A sensitive radiochemical method for the determination of the pyruvate dehydrogenase complex (PDHC) activity in skeletal muscle tissue, based on the decarboxylation of [1-14C]-pyruvate to 14CO2, is described. Measurements can be carried out either in muscle homogenate or in 600-g supernatant, both obtainable from a small muscle biopsy specimen (20 mg). In addition to NAD+, thiamine pyrophosphate and coenzyme A in the incubation mixture, a preparation of NADH:cytochrome c reductase (NADHCR) together with cytochrome c has a stimulating effect on the PDHC activity. NADHCR constitutes an oxidation system for NADH to prevent feedback inhibition. Addition of L-carnitine also results in stimulation of PDHC by trapping the produced acetyl-CoA as acetylcarnitine. Special care for radioactive pyruvate, with freeze drying and storage at -20 degrees C under nitrogen, and determination of the purity during every PDHC assay, is required. In the presented assay a Km value of 0.084 mmol/l was found for pyruvate. Nonsigmoidal kinetics was found with a Hill coefficient of 1.63. With the described method, a totally Mg2+,Ca(2+)-stimulated PDHC activity is measured. Addition of a purified specific pyruvate dehydrogenase phosphatase did not yield a higher PDHC activity. Finally, comparison of total PDHC activity with [1-14C]-pyruvate oxidation rates, both measured in the supernatant prepared from fresh muscle, shows an equimolar correlation, indicating that total PDHC activity is rate limiting in the assay for the pyruvate oxidation rate. Neonatal muscle exhibits five to ten times lower PDHC activities and pyruvate oxidation rates than controls (age > 3 years).

Adolescent↗