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Biomedical subjects

S Lindstedt

Publications and source records attributed to S Lindstedt.

At least 19 recordsLinked to original sources
PubMed2004

Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis.

AIM: To follow two children with isolated glycerol kinase deficiency (GKD) with severe symptoms into adulthood. METHODS: The patients were followed during approximately 20 y and interviewed about symptoms, diet and physical activity. Fasting provocations, bicycle ergometer tests, dietary registrations, enzyme and mutation analysis were performed by standard protocols. RESULTS: The activity of glycerol kinase (GK) in fibroblasts was <10% of reference. One case had a deletion of exon 17, the other a mutation in exon 7 of the GK gene (601 A-->G). Both mothers were heterozygotes. Two maternal male cousins in one of the families were hemizygotes without symptoms. Tests performed in childhood documented pronounced sensitivity to fasting and physical exercise, whereas such tests at 23 and 31 y of age were essentially normal but with pronounced ketonaemia. After puberty, the boys had no hypoglycaemic symptoms and now report no problems with their condition; thus, their phenotype has changed over time. CONCLUSION: The greater importance of glycerol as a gluconeogenetic substrate in children than in adults may explain the episodes in young patients with GKD, often elicited by catabolic stress. With meals at frequent intervals, access to glucose and avoidance of strenuous sports, the prognosis is good for a normal adult life of a young child with isolated GKD and symptoms of hypoglycaemia.

Acetoacetates↗
PubMed2001

Cytotoxic treatment of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare, aggressive tumor that is often detected in an advanced stage. Medical treatment with the adrenotoxic drug mitotane has been used for decades, but critical prospective trials on its role in residual disease or as an adjuvant agent after surgical resection are still lacking. The concept of a critical threshold plasma level of the drug must be confirmed in controlled studies. Because individual responsiveness cannot be predicted, the use mitotane is still advised for nonresectable disease. In case of cortisol or other steroid overproduction, several drugs (e.g., ketoconazole or aminoglutethimide) may be used. Chemotherapy with single agents (e.g., doxorubicin or cisplatin) have been disappointing, with low response rates (< 30%) and a short response duration. Part of this refractoriness may be explained by the fact that ACC tumors express the multidrug-resistance gene MDR-1. Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. The best results were achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane, achieving a response rate of 54%, including individual complete responses. To be able to make progress in treating advanced ACC disease, adjuvant multicenter trials must be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.

Adrenal Cortex Neoplasms↗
PubMed2000

Nontransplant treatment of tyrosinemia.

NTBC treatment has greatly improved the survival of patients with acute tyrosinemia and has reduced the need for liver transplantation during early childhood. In patients in whom treatment with NTBC was started early in life, 2 cases (1%) of HCC have occurred during the first year of treatment, but no further cases have occurred among these patients, who have been followed for up to 9 years. In patients with late start of NTBC treatment, there is a considerable risk for liver malignancy. The risk for malignancy in this group of patients must be evaluated on an individual basis, taking into account the phenotype and clinical status of the patient. Porphyric crises are not seen in patients who comply with the medication regimen. NTBC is a well-tolerated drug with few adverse effects.

Age Factors↗
PubMed1998

Adrenocortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up.

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. It has been difficult to establish a strict treatment program for ACC, and better treatment alternatives and diagnostic tools must be sought. Even though surgery is the treatment of choice, the role of surgery in advanced disease has been questioned. Eighteen consecutive patients were treated at our unit over a 22-year period (1975-1997). All patients underwent surgery and were followed by our protocol, which includes urinary steroid profiles, clinical examinations, analysis of steroid hormones, and radiologic investigations. Twelve patients received mitotane with drug concentration measurements to deliver an effective, nontoxic dose. The median duration of mitotane treatment was 12 months. Few side effects were observed. Four patients with low-stage tumors underwent second-look operations with no pathologic findings. Five patients were subjected to repeat operations, and the mean duration of the disease-free interval before repeat surgery for these patients was 59 months. There was a significant positive correlation between the disease-free interval and the observed survival after repeat surgery. Eleven patients with intentionally curative surgery had their urinary steroid profiles tested several times postoperatively. For five patients preoperative urine samples were also available. Steroid profiles indicated recurrent disease despite normal radiologic findings in two of these five patients. The follow-up ranged from 6 weeks to 24 years. The predicted 5-year survival was 58% according to the Kaplan-Meier method. We conclude that monitoring serum concentrations of mitotane makes long-term treatment possible with few side effects; steroid profile analysis can be used for early detection of tumor recurrence; and repeat surgery for recurrence is of value for patients with long disease-free intervals.

17-Hydroxycorticosteroids↗
PubMed1998

Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).

In tyrosinaemia type I (McKusick 276700), fatal liver disease results either because of liver failure during infancy or early childhood or because of development of hepatocellular carcinoma during childhood or adolescence. This is caused by toxic metabolites which accumulate because of deficiency of fumarylacetoacetase, the last enzyme in the tyrosine catabolic pathway. NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia. Since the first trial of NTBC treatment for tyrosinaemia type I in 1991, over 220 patients have been treated by the drug using a protocol which includes regular follow-up with reports of clinical and laboratory investigations to the study centre in Gothenburg, where additional analysis of critical variables is done on regularly collected samples. The course of the disease in patients with acute tyrosinaemia has changed dramatically. Only 10% of the patients have not clinically responded to NTBC treatment. In half of these patients, successful liver transplantation has been performed which has further reduced the mortality rate during infancy to 5%. The international NTBC study has now been going for 5 years and data have emerged that indicate a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. There are now 101 patients aged 2-8 years who have started NTBC treatment before 2 years of age, and no cancer has developed after 2 years of age among these patients. However, there is no safe age with respect to occurrence of liver cancer, which has been recognized at diagnosis at 1 year of age in one patient and after a few months of treatment in an infant who was given NTBC at 5 months of age.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1997

Human 4-hydroxyphenylpyruvate dioxygenase gene (HPD).

Overlapping DNA fragments spanning approximately 21 kb of genomic DNA and encompassing the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) have been cloned by screening a human leukocyte genomic library and by PCR amplification of human fibroblastic DNA. A continuous gene sequence of 20,890 nucleotides was established, including 1957 bp of the 5'-flanking region. The 4-hydroxyphenylpyruvate dioxygenase gene is composed of 14 exons interrupted by 13 introns, all exhibiting conventional vertebrate splicing. Computer analysis of the DNA sequence revealed 12 complete repetitive Alu elements, 1 in the 5'-flanking region and 11 in the intervening segments of the gene. The transcriptional initiation site was mapped to a position 35 nt upstream of the translational start point. The computer analysis also identified several potential transcription regulatory elements, including one CRE site, two AP-2 sites, and two Sp1 sites, in the sequence upstream of the transcription initiation site. Functional analysis of promoter activity by transient transfection of chloramphenicolacetyl transferase reporter plasmids revealed a possible involvement of cyclic adenosine monophosphate in the regulation of transcription. The highest level of expression of 4-hydroxyphenylpyruvate dioxygenase was found in human liver tissue as demonstrated by Northern blot analysis.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1996

Pivalic acid-induced carnitine deficiency and physical exercise in humans.

To study the effect of carnitine depletion on physical working capacity, healthy subjects were administered pivaloyl-conjugated antibiotics for 54 days. The mean carnitine concentration in serum decreased from 35.0 to 3.5 mmicromol/L, and in muscle from 10 to 4.3 micromol/g noncollagen protein (NCP). Exercise tests were performed before and after 54 days' administration of the drug. At submaximal exercise, there was a slight increase in the concentration of 3-hydroxybutyrate in serum, presumably caused by decreased fatty acid oxidation in the liver. There was also a decreased consumption of muscle glycogen, indicating decreased glycolysis in the skeletal muscle. The muscle presumably had enough energy available, since there was no significant decrease in the concentration of adenosine triphosphate (ATP) and creatine phosphate during exercise. The work at maximal oxygen uptake (VO2max) and the maximal heart rate were reduced. Since VO2max is considered dependent on heart function, carnitine depletion seemed to affect cardiac function.

Adolescent↗
PubMed1996

Structural correlates of speed and endurance in skeletal muscle: the rattlesnake tailshaker muscle

The western diamondback rattlesnake Crotalus atrox can rattle its tail continuously for hours at frequencies approaching 90 Hz. We examined the basis of these fast sustainable contractions using electromyography, data on oxygen uptake and the quantitative ultrastructure of the tailshaker muscle complex. The tailshaker muscle has no apparent unique structures; rather, the relative proportions of the structures common to all skeletal muscles appear to be present (1) to minimize activation, contraction and relaxation times via an extremely high volume density of sarcoplasmic reticulum (26 %) as well as, (2) to maximize ATP resysnthesis via a high volume density of mitochondria (26 %). The high rate of ATP supply is reflected in the in vivo muscle mass-specific oxygen uptake of this group of muscles which, at 585 ml O2 kg-1 min-1 during rattling at 30 &deg;C body temperature, exceeds that reported for other ectotherm and many endotherm muscles. Since the change in oxygen uptake paralleled that of the rattling frequency over the range of measured body temperatures, there was a nearly constant O2 cost per muscle contraction (0.139&plusmn;0.016 &micro;l O2 g-1). Electromyo-graphic analysis suggests that each of the six muscles that make up the shaker complex may be a single motor unit. Finally, the maximum rate of mitochondrial oxygen uptake is similar to that of various mammals, a hummingbird, a lizard, an anuran amphibian and of isolated mitochondria (at 10 000-40 000 molecules O2 s-1 &micro;m2 of cristae surface area, when normalized to 30 &deg;C), suggesting a shared principle of design of the inner mitochondrial membrane among the vertebrates.

Journal Article↗
PubMed1995

Effect of short-term treatment with pivalic acid containing antibiotics on serum carnitine concentration--a risk irrespective of age.

Treatment with pivalic acid containing prodrugs has been shown to cause carnitine depletion by loss of pivaloyl carnitine in urine. A 7-day standard pivmecillinam treatment of adults lead to a marked decrease of the free serum carnitine concentration (44.6 to 12.9 mumol/liter), whereas no change was seen in those given norfloxacine (40.0 to 40.5 mumol/liter). In some patients irrespective of age the free serum carnitine concentration was decreased to levels (around 10 mumol/liter) at which an impaired ketone-body production may occur. Therefore, there is reason for cautious use of this type of drug irrespective of the age of the patients.

Adolescent↗
PubMed1995

Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.

Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Diagnosis and management of tyrosinemia type I.

Hereditary tyrosinemia type I (HTI) (MIM 276700) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (EC 3.7.1.2), which is the last enzyme in the tyrosine degradation pathway. The enzyme block causes accumulation of toxic metabolites in the liver and kidneys, which are the organs where tyrosine is mainly degraded. The disorder is characterized by severe liver disease, which either causes liver failure in infancy or may take a more protracted course, with death often occurring during childhood or adolescence because of hepatoma development. Treatment with a diet restricted in phenylalanine nd tyrosine does not prevent progression of the liver disease and development of hepatocellular carcinoma. Liver transplantation was previously the only option for these patients. Important achievements from metabolic and molecular biology studies of the disease include a new treatment for patients with HTI using an enzyme inhibitor, detection of self-induced correction of the genetic defect in regenerative liver nodules in HTI patients, identification and development of useful animal models for HTI, and studies of the molecular genetics of HTI. These advances will have great implications for our understanding of pathogenetic mechanisms, which is the basis for improved diagnostic methods and improved treatment of patients with HTI.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1995

Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid.

OBJECTIVE: To study the effect of induced carnitine depletion on myocardial structure and function. SUBJECTS AND DESIGN: 7 healthy adult volunteers given 1200 mg pivmecillinam per day for 7-8 weeks were studied by echocardiography before and after 7-8 weeks of treatment and a 15 months follow up after the treatment period. SETTING: Teaching hospital. MAIN OUTCOME MEASURES: Carnitine concentration in serum, urine, and muscle and echocardiographic measurements. RESULTS: After 7-8 weeks of treatment the median free serum carnitine concentration was reduced to 7% and the median total muscle carnitine concentration to 46% of the pretreatment levels. The median diastolic interventricular septum thickness decreased by 14% (mean 26%, P = 0.028) and the median left ventricular mass by 10% (mean 20%, P = 0.018). Fifteen months later these dimensions had increased but not completely returned to pretreatment values. CONCLUSIONS: Extended treatment with pivalic acid containing antibiotics causes carnitine depletion which may lead to changes in cardiac structure.

Adolescent↗
PubMed1995

Treatment of growth hormone-deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters.

In a double-blind, placebo-controlled trial, the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), monoamine metabolites, neuropeptides and endogenous opioid peptides. Twenty patients, 10 patients in each of 2 groups, with adult-onset, growth hormone deficiency were treated for 1 month with recombinant human growth hormone (0.25 U/kg/week) or placebo. All the patients received the appropriate thyroid, adrenal and gonadal hormone replacement. In cerebrospinal fluid, the mean concentration of growth hormone increased from 13.3 +/- 4.4 to 149.3 +/- 22.2 muU/l (p = 0.002), during recombinant human growth hormone treatment. The cerebrospinal fluid IGF-I concentration increased from 0.67 +/- 0.04 to 0.99 +/- 0.10 micrograms/l (p = 0.005) and the IGFBP-3 concentration rose from 13.4 +/- 1.25 to 17.5 +/- 1.83 micrograms/l (p = 0.002). The dopamine metabolite homovanillic acid decreased from 282.1 +/- 36.0 to 234.3 +/- 26.5 nmol/l (p = 0.02) and the vasoactive intestinal peptide decreased from 4.1 +/- 0.6 to 3.7 +/- 0.4 pmol/l (p = 0.03). Cerebrospinal fluid immunoreactive beta-endorphin increased from 24.4 +/- 1.8 to 29.9 +/- 2.1 pmol/l (p = 0.002). There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins, dynorphin A, the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl-ethyleneglycol, the serotonin metabolite 5-hydroxyindoleacetic acid, gamma-aminobutyric acid, somatostatin or corticotropin-releasing factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Regional assignment of the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) to 12q24-->qter by fluorescence in situ hybridization.

Using a panel of human-rodent somatic cell hybrids, we have previously mapped the gene (HPD, previously called PPD) encoding 4-hydroxyphenylpyruvate dioxygenase to the distal half of the long arm of human chromosome 12, region q14-->qter. To obtain a genomic probe useful for fluorescence in situ hybridization (FISH) analysis we screened a human leukocyte genomic library and isolated a 13.4-kb phage clone, which by restriction fragment and sequence analyses was shown to contain exons 1-10 of HPD and approximately 2-kb upstream sequences. We now report the subregional localization of HPD to 12q24-->qter based on two color FISH analysis employing this clone.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1994

Impaired ketogenesis in carnitine depletion caused by short-term administration of pivalic acid prodrug.

Long-term treatment with pivalic acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty acid oxidation in the liver during short-term treatment with drugs conjugated with pivalic acid.

Adult↗
PubMed1993

gamma-Butyrobetaine hydroxylase. Structural characterization of the Pseudomonas enzyme.

gamma-Butyrobetaine hydroxylase is a 2-oxoglutarate-dependent dioxygenase that catalyzes the hydroxylation of gamma-butyrobetaine to carnitine, the last step in the biosynthesis of carnitine from lysine. The primary structure of the enzyme from Pseudomonas sp. AK1 has been determined. Sequence analysis of the intact protein and of peptides from essentially three different digests established the presence of a peptide chain containing 383 residues, and an N-terminal truncated form of 382 residues. The two chains have molecular masses of 43,321 Da and 43,207 Da, respectively, and are identical except for the presence or absence of an N-terminal asparagine residue; the shorter form starts with an alanine residue. In preparations of the dimeric protein, the two chains occur in an approximate ratio of 1:1. There are nine cysteine residues and 13 histidine residues, i.e. amino acids which have been postulated as ligands for iron binding. In spite of functional similarities, there appears to be no clear sequence similarities with any of the other mammalian 2-oxoglutarate-dependent dioxygenases so far characterized.

Amino Acid Sequence↗