Biomedical subjects

A Oldfors

Publications and source records attributed to A Oldfors.

At least 37 records · Page 2Linked to original sources

PubMed2002

Inclusion body myositis: morphological clues to correct diagnosis.

The aim of this study was to investigate variability of morphological changes found in patients with sporadic inclusion body myositis, to assess the diagnostic value of muscle biopsy. The study included all 43 definite inclusion body myositis patients (86 biopsies) diagnosed at Sahlgrenska University Hospital, Gothenburg, Sweden, between 1984 and 2000. Invasion of mononuclear inflammatory cells in non-necrotic muscle fibres was found in 72 of 86 specimens, while all investigated biopsies showed up-regulation of major histocompatibility complex class I. Cytochrome c oxidase-negative muscle fibres were demonstrated in 84 of 86 biopsies. Rimmed vacuoles were present in all specimens from the vastus lateralis and tibialis muscles, and in 43 of 51 biopsies from the deltoid muscle. In cases with clinical suspicion of inclusion body myositis, where the muscle biopsy does not show inflammatory cell infiltration and rimmed vacuoles, inclusion body myositis should still be considered if there are cytochrome c oxidase-negative fibres and up-regulation of major histocompatibility complex class I. In such cases repeat muscle biopsy may be helpful.

Adult↗

PubMed2002

Expression of Bcl-2 in inclusion body myositis.

OBJECTIVES: On the background of the possible role of the anti-apoptotic protein Bcl-2 to inhibit apoptosis induced by the Fas/Fas ligand system in inflammatory myopathies we investigated the expression of Bcl-2 in inclusion body myositis (IBM). MATERIAL AND METHODS: We examined muscle tissue from seven IBM patients and controls by immunocytochemistry using antibodies against Bcl-2, Fas (a member of the tumor necrosis factor receptor family) and the regeneration marker, neural cell adhesion molecule (N-CAM). We also investigated the occurrence of DNA fragmentation by the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)-method. RESULTS: Both Bcl-2 and Fas were up-regulated in muscle fibers in IBM and disease controls. Bcl-2 was expressed by regenerating muscle fibers while Fas was expressed by non-regenerating muscle fibers associated with inflammatory cell infiltrates. Bcl-2 and Fas were also expressed by inflammatory cells. There were scattered TUNEL positive nuclei and most of these appeared to be inflammatory cells. CONCLUSION: The low occurrence of apoptotic myonuclei is not related to Bcl-2 expression, which is confined to regenerating muscle cells in IBM and other myopathies.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis.

Mitochondrial transcription factor A (Tfam) is required for mtDNA maintenance, and mitochondrial Tfam protein levels directly affect mtDNA copy number. Previous studies have shown significant reduction of Tfam protein levels in mitochondria together with the appearance of abundant testis-specific Tfam mRNA isoforms as spermatogenesis proceeds in both mouse and man. Interestingly, an abundant testis-specific nuclear Tfam protein isoform of unknown function is found in the mouse, but not in humans. We have now characterized Tfam expression in rat testis to identify conserved features in mammalian spermatogenesis. The nuclear Tfam protein isoform is absent in the rat and is thus dispensable for mammalian spermatogenesis. Similar to mice and humans, we found expression of alternate Tfam transcripts, downregulation of mitochondrial Tfam protein levels, and downregulation of mtDNA copy number during rat spermatogenesis. These features are thus common to all mammals and may provide one of several mechanisms preventing paternal mtDNA transmission.

Amino Acid Sequence↗

PubMed2001

Mitochondrial myopathies.

The first description of a patient with mitochondrial myopathy and deficient respiratory chain function was reported by Luft and coworkers almost 40 years ago. Subsequent studies in the 1970s and 1980s relied on a combination of morphological and biochemical methods to identify patients with mitochondrial disorders. However, the aetiology and pathogenesis remained largely unsolved and there was poor correlation between laboratory findings and clinical phenotypes. The fact that both mitochondrial DNA (mtDNA) and nuclear genes are necessary for the biogenesis of the respiratory chain, suggested that mutations of either genome might cause mitochondrial myopathy. This prediction has been verified during the last decade and pathogenic mutations of both genomes have been identified. This rapid accumulation of genetic information has lead to many good correlations between genotype and phenotype in mitochondrial disorders. The challenge for the future will be to elucidate molecular details of pathogenic processes and to develop effective treatments for patients with respiratory chain dysfunction.

DNA, Mitochondrial↗

PubMed2001

Inclusion body myositis: genetic factors, aberrant protein expression, and autoimmunity.

Sporadic inclusion body myositis (s-IBM) is an inflammatory myopathy mainly affecting elderly individuals. It has a chronic progressive course leading to severe disability. Immunosuppressive treatment is in most instances ineffective. S-IBM is morphologically characterized by mononuclear cell infiltrates and vacuolated muscle fibers with pathologic accumulation of a large number of different proteins. Recent research has focused on the expression of various factors that may contribute to the inflammatory reaction and the typical inclusions. This review summarizes the new information on genetic factors, abnormal protein expression and inflammation, which provides a basis for linking the different typical morphologic features of s-IBM to a cascade of pathogenic events.

Autoimmunity↗

PubMed2001

The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities.

In this study we present incidence, point prevalence, and mortality figures of mitochondrial encephalomyopathies in a population-based study of children from western Sweden. Through the screening of registers and review of medical records, we identified 32 patients under 16 years of age from the study population who were diagnosed between January 1, 1984, and December 31, 1998. The incidence of mitochondrial encephalomyopathies in preschool children (<6 years of age) was 1 out of 11,000. The preschool incidence of Leigh's syndrome was 1 out of 32,000, and the preschool incidences of both Alper's syndrome and infantile mitochondrial myopathy with cytochrome C oxidase deficiency were 1 out of 51,000. The point prevalence January 1, 1999) of mitochondrial encephalomyopathies in children under 16 years of age was 1 out of 21,000. The median survival for patients with infantile onset was until 12 years of age. We identified 4 cases with mitochondrial DNA point mutations, 2 cases with mitochondrial DNA deletions, and 2 cases with nuclear mutations in the SURF1 gene. We conclude that mitochondrial encephalomyopathies are relatively common neurometabolic disorders in childhood.

Age of Onset↗

PubMed2000

Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene.

We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy. The disorder has previously been described in a family with an "autosomal dominant myopathy, with joint contractures, ophthalmoplegia, and rimmed vacuoles." Linkage analysis and radiation hybrid mapping showed that the gene locus (Human Genome Map locus name: IBM3) is situated in a 2-Mb region of chromosome 17p13, where also a cluster of MyHC genes is located. These include the genes encoding embryonic, IIa, IIx/d, IIb, perinatal, and extraocular MyHCs. Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal. This observation prompted us to investigate the MyHC-IIa gene, since MyHC-IIa is the major isoform in type 2A fibers. The complete genomic sequence for this gene was deduced by using an "in silico" strategy. The gene, found to consist of 38 exons, was subjected to a complete mutation scan in patients and controls. We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region. By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family.

Adult↗

PubMed2000

Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy.

We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15-18 nm in diameter. Except for the absence of significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions are present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this family with h-IBM.

Adolescent↗

PubMed2000

Weaning from mechanical support in a patient with acute heart failure and multiple sclerosis.

We describe a 19-year-old woman developing acute left ventricular heart failure during her first exacerbation of multiple sclerosis. Histopathologic examination of myocardial tissue showed extensive myocytolysis. A left ventricular assist device was implanted. Three months later the cardiac function was restored and the left ventricular assist device was explanted. After 1 year the patient still remains well and her cardiac function is normal.

Acute Disease↗

PubMed2000

Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes.

Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.

Adenosine Triphosphate↗

PubMed2000

Fatal dilated cardiomyopathy associated with a mitochondrial DNA deletion.

A 27-year-old man was admitted to hospital because of severe cardiac failure. Investigation revealed dilated cardiomyopathy with a left ventricular ejection fraction of 15-20%. During adolescence the patient had been investigated for growth retardation and he also had progressive external ophthalmoplegia. There had been no symptoms of cardiac disease until 2 weeks before admittance. An endomyocardial biopsy showed cardiomyocytes deficient in cytochrome c oxidase (COX) in a mosaic pattern. A skeletal muscle biopsy showed mitochondrial myopathy with COX-deficient ragged-red fibers. Molecular genetic analysis revealed a heteroplasmic, 3.8-kb, mitochondrial DNA (mtDNA) deletion in heart and muscle. PCR-based quantification of the proportion of mtDNA with deletion showed 47% mutated mtDNA in the myocardial biopsy and 68% in muscle. In spite of treatment, the condition deteriorated and the patient died 5 days after admittance. This case demonstrates that mtDNA deletions may occasionally be the cause of severe dilated cardiomyopathy, and that morphological and molecular genetic diagnosis may be obtained by endomyocardial biopsy.

Adult↗

PubMed1999

Autosomal dominant progressive external ophthalmoplegia: distribution of multiple mitochondrial DNA deletions.

OBJECTIVE: To relate signs and symptoms to morphologic changes and presence of multiple mitochondrial DNA (mtDNA) deletions in a patient with autosomal dominant progressive external ophthalmoplegia (adPEO) and mitochondrial myopathy. BACKGROUND: An etiologic association between the somatic multiple mtDNA deletions in adPEO and clinical manifestations other than the myopathy has so far not been demonstrated. METHODS: The authors investigated a patient with adPEO and multiorgan system manifestations including levodopa-responsive parkinsonism. She died at age 61 years of pancreatic carcinoma. Autopsy tissue specimens were investigated for morphologic alterations and occurrence of mtDNA deletions by Southern blot and long-extension PCR analyses. RESULTS: The patient had carcinoma of the pancreas with metastases to liver, lymph nodes, and bone marrow. The brain revealed slight gliosis of the gray and white matter and degeneration of the substantia nigra. The myocardium showed focal areas with loss and atrophy of myocytes and fibrosis. Analysis of mtDNA revealed multiple deletions in different regions of the brain, skeletal muscle, and myocardium. Twenty-five different mtDNA deletions were identified. Most of these were flanked by large direct-sequence repeats. Six identical deletions were found in muscle and brain. CONCLUSIONS: These findings indicate that somatic multiple mtDNA deletions are associated with degenerative tissue changes and clinical manifestations in adPEO.

Antiparkinson Agents↗

PubMed1999

A novel heteroplasmic point mutation in the mitochondrial tRNA(Lys) gene in a sporadic case of mitochondrial encephalomyopathy: de novo mutation and no transmission to the offspring.

We have identified a new mutation in the tRNA(Lys) gene of mtDNA, in a 49-year-old patient with mitochondrial encephalomyopathy. The mutation is a heteroplasmic G-->A transition at position 8328, which affects the anticodon stem loop at a conserved site. The mutation was neither found in 100 controls nor in the maternal relatives of the patient. The level of mutated mtDNA was 57% in muscle, 13% in fibroblasts, and 10% in lymphocytes. Histochemistry of muscle tissue revealed cytochrome c oxidase-deficient fibers with abnormal accumulation of mitochondria. Biochemistry of muscle mitochondria showed slight cytochrome c oxidase deficiency. The mean ratio of mutant mtDNA to normal mtDNA in cytochrome c oxidase-positive muscle fibers was 59%, whereas a mean ratio of 95% was found in cytochrome c oxidase-negative fibers. The difference between cytochrome c oxidase-positive and cytochrome c oxidase-negative fibers was highly significant (P < 0.001). The mutation was not found in muscle or lymphocytes of the mother and daughter of the proband. This is the first report of a de novo point mutation in the tRNA(Lys) gene in an individual expressing disease and the first report of lack of transmission of the mutation to the offspring of a patient expressing a mitochondrial encephalomyopathy caused by a point mutation in mtDNA.

Base Sequence↗

PubMed1999

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q.

Twenty-one members of a Swedish family suffering from myopathy and cardiomyopathy underwent neurological and cardiological investigations. Medical charts of 2 affected deceased patients were reviewed. Twelve patients had myopathy. The distribution of weakness was axial in mildly affected, axial and predominantly distal in moderately affected, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy revealed granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic right ventribular cardiomyopathy. Nonsustained ventribular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of them had a pacemaker implanted because of atrioventricular block and sick sinus syndrome. Inheritance is autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. Linkage analysis of candidate chromosomal regions showed a maximum 2-point LOD score of 2.76 for marker locus D10S1752 on chromosome 10q. A multipoint peak LOD score of 3.06 between markers D10S605 and D10S215 suggests linkage to chromosome 10q22.3, and this region may harbor a genetic defect for myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopahty.

Adult↗

PubMed1999

Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.

Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation and may also have a role in ageing and acquired diseases of old age. We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, we have disrupted Tfam in heart and muscle. Mutant animals develop a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, atrioventricular heart conduction blocks and die at 2-4 weeks of age. This animal model reproduces biochemical, morphological and physiological features of the dilated cardiomyopathy of Kearns-Sayre syndrome. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.

Animals↗

PubMed1999

Rhabdomyolysis and acute renal failure associated with influenza virus type A.

Two patients with rhabdomyolysis-induced acute renal failure due to influenza A virus infection are presented. Both had influenza symptoms, with high fever and severe muscular pain leading to walking problems. In addition, they were dehydrated due to vomiting and diarrhoea. Both had evidence of an ongoing influenza infection according to serological tests. Muscle injury due to the viral infection gave rise to rhabdomyolysis with efflux of myoglobin from the muscles, causing renal failure. In conclusion, influenza A virus infection can cause rhabdomyolysis accompanied by reversible acute renal failure.

Acute Kidney Injury↗

PubMed1999

Dominant hereditary inclusion-body myopathy gene (IBM3) maps to chromosome region 17p13.1.

We recently described an autosomal dominant inclusion-body myopathy characterized by congenital joint contractures, external ophthalmoplegia, and predominantly proximal muscle weakness. A whole-genome scan, performed with 161 polymorphic markers and with DNA from 40 members of one family, indicated strong linkage for markers on chromosome 17p. After analyses with additional markers in the region and with DNA from eight additional family members, a maximum LOD score (Zmax) was detected for marker D17S1303 (Zmax=7.38; recombination fraction (theta)=0). Haplotype analyses showed that the locus (Genome Database locus name: IBM3) is flanked distally by marker D17S945 and proximally by marker D17S969. The positions of cytogenetically localized flanking markers suggest that the location of the IBM3 gene is in chromosome region 17p13.1. Radiation hybrid mapping showed that IBM3 is located in a 2-Mb chromosomal region and that the myosin heavy-chain (MHC) gene cluster, consisting of at least six genes, co-localizes to the same region. This localization raises the possibility that one of the MHC genes clustered in this region may be involved in this disorder.

Chromosome Mapping↗

PubMed1999

Inclusion body myositis.

Sporadic inclusion body myositis is a severely disabling muscle disease that mainly affects elderly individuals. The typical distribution of muscle weakness, poor response to immunosuppressive treatment, pathological accumulation of various proteins in vacuolated muscle fibres, inflammatory reaction and mitochondrial changes have all been subjects of recent research that has led to better understanding of the pathogenic events that leads to muscle degeneration and weakness.

Humans↗