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- Luoma, Petri, et al.
(författare)
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Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study
- 2004
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Ingår i: Lancet. ; 364:9437, s. 875-82
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinson's disease. However, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the gene sequence of POLG in patients with progressive external ophthalmoplegia and their healthy relatives. METHODS: In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET). FINDINGS: We recorded mutations in POLG in members of all seven families. Clinical assessment showed significant cosegregation of parkinsonism with POLG mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron loss. Post-mortem examination in two individuals showed loss of pigmented neurons and pigment phagocytosis in substantia nigra without Lewy bodies. Furthermore, most women with progressive external ophthalmoplegia had early menopause-before age 35 years. The POLG gene defect resulted in secondary accumulation of mtDNA deletions in patients' tissues. INTERPRETATION: Dysfunction of mitochondrial POLG causes a severe progressive multisystem disorder including parkinsonism and premature menopause, which are not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG mutations in our families suggests that when defective, this gene can underlie mendelian transmission of parkinsonism. RELEVANCE TO PRACTICE: Awareness that mitochondrial POLG mutations can underlie parkinsonism is important for clinicians working in diagnosis of movement disorders, as well as for studies of the genetics of Parkinson's disease. Further, progressive external ophthalmoplegia with muscle weakness and neuropathy can mask symptoms of parkinsonism, and clinicians should pay special attention to detect and treat parkinsonism in those individuals.
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| 2. |
- Maddison, P, et al.
(författare)
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The rate and pattern of organ damage in late onset systemic lupus erythematosus
- 2002
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 29:5, s. 913-917
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To compare the extent and type of damage in patients with late onset and earlier onset Systemic lupus erythematosus (SLE) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Methods. A total of 86 SLE patients with disease onset after the age of 54 years were matched for center, sex, and ethnic origin with 155 SLE patients with disease onset before the age of 40 years. SDI scores were obtained at one year and 5 years after the diagnosis of SLE. Analysis was based on conditional logistic regression. Results. SDI scores were higher in the late onset group than in younger patients at both one [mean 0.7 (range 0-3) vs 0.3 (range 0-3). p < 0.001] and 5 years [mean 1.6 (range 0-8) vs 0.9 (range 0-7); p < 0.001] after diagnosis. There was also a difference in the pattern of organ damage. While damage to the skin, kidneys, and central nervous system occurred with similar frequency, late onset disease was characterized by significantly more cardiovascular (OR 14.13, p < 0.001). ocular (OR 9.38, p 0.001), and musculoskeletal (OR 2.68, p = 0.016) damage and malignancy (OR 7.04, 3 = 0.046). Conclusion. The occurrence of organ damage assessed by the SDI is greater in patients with late onset SLE than in younger patients and, by this criterion, lupus cannot be judged to be more benign in this age group. Also, the pattern of damage is different, but whether this reflects age per se or the effect of the disease in the elderly remains to be established.
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| 3. |
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| 4. |
- He, Yulong, et al.
(författare)
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Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis.
- 2004
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 64:11
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial progenitor cells have been shown to contribute to angiogenesis in various tumor models. Here, we have studied the relative contributions of bone marrow (BM)-derived endothelial progenitors and pre-existing lymphatic vessels to tumor lymphangiogenesis. We did not find significant incorporation of genetically marked BM-derived cells in lymphatic vessels during tumor- or vascular endothelial growth factor C-induced lymphangiogenesis. The degree of tumor lymphangiogenesis correlated with lymphatic vessel density in the peritumoral area, and despite tumor lymphangiogenesis, lymphatic metastasis failed to occur in gene-targeted vascular endothelial growth factor C(+/-) mice that have hypoplasia of the lymphatic network. Our data demonstrate that during tumor lymphangiogenesis and cancer cell dissemination via the lymphatics, the newly formed lymphatic vessels sprout from the pre-existing local lymphatic network with little if any incorporation of BM-derived endothelial progenitor cells.
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| 5. |
- Lehenkari, Petri, et al.
(författare)
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The effects of tamoxifen and toremifene on bone cells involve changes in plasma membrane ion conductance
- 2003
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 18:3, s. 473-481
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Tidskriftsartikel (refereegranskat)abstract
- Selective estrogen receptor modulators (SERMs), tamoxifen (Tam) and toremifene (Tor), are widely used in the treatment of breast cancer. In addition, they have been demonstrated to prevent estrogen deficiency-induced bone loss in postmenopausal women. These effects are thought to be caused by the interaction of the SERMs with the estrogen receptor, although SERMs have also been shown to conduct non-receptor-mediated effects such as rapid changes in membrane functions. We compared the effects of Tam, Tor, and 17β-estradiol (E2) on the viability of rat osteoclasts and osteoblasts. Both Tam and Tor were found to cause osteoclast apoptosis in in vitro cultures, which was reversed by E2. In addition, at higher concentration (10 μM), both SERMs had an estrogen receptor-independent effect, which involved interaction with the plasma membrane as demonstrated with UMR-108 osteosarcoma cells by Tam and Tor, but not E2. A leak of protons leading to changes in intracellular pH was shown both in medullary bone derived membrane vesicles and in intact cells. These effects were followed by a rapid loss of cell viability and subsequent cell lysis. Our results show that both Tam and Tor have an ionophoric effect on the plasma membranes of bone cells and that these SERMs differed in this ability: Tor induced rapid membrane depolarization only in the presence of high concentration of potassium. These non-receptor-mediated effects may be involved in therapeutic responses and explain some clinical side effects associated with the treatment of patients with these SERMs
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