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- Björkman, Kristoffer, et al.
(författare)
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Genotype-phenotype correlations in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1
- 2014
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Ingår i: Euromit 2014, 15-19 juni, Tampere, Finland.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To study genotype-phenotype correlations in genes encoding complex I electron input module subunits. Materials and methods: We studied five patients with isolated complex I deficiency, three with NDUFS1 mutations and two with NDUFV1 mutations. A literature review of all reported cases of mutations in the affected genes was performed. Results: The literature review revealed pathological mutations in NDUFS1 for 18 patients in 17 families and correspondingly in NDUFV1 for 26 patients in 19 families. Unpublished clinical data for our five patients were added. Our study showed quite variable clinical courses; death before two years of age was seen in 41% of patients while 18% were alive at seven years. There was a significant difference between the NDUFS1 and NDUFV1 groups for clinical onset and life-span. Mutations in NDUFS1 were linked to a worse clinical course with earlier onset and earlier death. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a worse clinical course than patients with NDUFV1 mutation. Identifying the mutations is of importance for accurate prognostic information and genetic counseling.
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| 4. |
- Vikingsson, Svante, 1983-
(författare)
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Development of new methodology for therapeutic drug monitoring of thiopurine treatment
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The three thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat several diseases, including inflammatory bowel disease (IBD). They are pro-drugs and are believed to act through the formation of thioguanine nucleotides (TGNs). Other important metabolites are the methylthioinosine nucleotides (meTINs). These metabolites are active in the white blood cells (WBCs).Most patients respond well to the thiopurine drugs but up to a third have to modify or discontinue their treatment due to adverse events or a lack of therapeutic effects. This could be caused by inter-patient variability in the metabolism of the drugs. Therapeutic drug monitoring (TDM) of thiopurine nucleotides in red blood cells (RBCs) is used to guide treatment. Current routine assays measure the nucleotides after hydrolysation to nucleic bases and are therefore unable to distinguish between mono-, di-, and triphosphates. Recently it was shown that these assays failed to predict the clinical outcome in about 40% of the patients. It has been suggested that measuring thioguanosine triphosphate (TGTP) (believed to be the most active of the TGNs) separately might increase the clinical value.An assay suitable for measuring thioguanosine mono- (TGMP) and diphosphate (TGDP) and TGTP, as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) separately in RBCs in clinical samples has been developed. In clinical studies of 82 IBD patients, we found no correlation between the thiopurine dose and metabolite levels in RBCs, thus illustrating the importance of metabolite measurements in the TDM of thiopurines.The TGN peak measured by the routine assay during TDM of patients treated with thiopurines consisted of TGTP and TGDP with a small contribution from TGMP. The meTIN also consisted of mono-, di- and triphosphates, but in different proportions, indicating differences in the formation. The inter-individual differences in nucleotide distribution were very small and a strong correlation between the different nucleotides and their respective sums was observed. As a consequence, measuring the mono-, di- and triphosphates separately was not beneficial in predicting remission, which was confirmed by the results from the clinical study.Further research into the metabolism and mode of action of thiopurine drugs is needed to understand the inter-patient variability in response and metabolite formation. An assay suitable for such studies, measuring TGNs and meTINs in cultured cells, has also been developed.
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| 5. |
- Alafuzoff, Irina
(författare)
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Alzheimerin tauti : (Alzheimer’s sjukdom)
- 2012. - 1
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Ingår i: Patologia. - Helsingfors : Duodecim. - 9789516561847 ; , s. 1029-1031
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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- Elfving, Karin, 1982-
(författare)
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Epidemiological and Bacteriological Aspects of Spotted Fever Rickettsioses in Humans, Vectors and Mammals in Sweden
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rickettsiae are obligate intracellular gram-negative bacteria transmitted by arthropod vectors. Rickettsiae sometimes cause disease in humans, typically with high fever, headache and occasionally an eschar.In Sweden, Rickettsia helvetica, belonging to the spotted fever group, is the only tick-transmitted rickettsia found free in nature. The pathogenic roll of R. helvetica has not been fully investigated, but it has been implicated in aneruptive fever and cardiac disease.This thesis describes parts of the transmission pathways of rickettsiae in Sweden. Rickettsia infection rates in ticks collected from birds were analysed, and the birds’ role as disseminators and reservoirs was studied. We found that more than one in ten ticks was infected with rickettsia bacteria, predominantly R. helvetica, and that migrating birds contribute not only to long-distance dispersion of bacteria, but also to an inflow of novel and potentially pathogenic rickettsia species, in this case R. monacensis and R. sp. strain Davousti-like species, into Sweden.Further, wild and domestic animals were found to have seroreactivity against R. helvetica, which shows that they are exposed and susceptible to rickettsia. Their role as reservoirs has not been determined, yet they may indirectly be involved in transmission of rickettsia to humans by infected ticks feeding on them.The seroreactivity in humans was also studied. Patients investigated for suspected Borrelioses and blood donors had detectable antibodies against Rickettsia spp., with the highest prevalence detected in the suspected Borreliosis group. This shows that humans in Sweden are exposed to and develop an immune response against rickettsia. The suspicion that R. helvetica may cause severe symptoms was verified by a patient with subacute meningitis where the bacterium was shown for the first time to cause an invasive infection with CNS involvement and where the bacterium was isolated from the patient’s cerebrospinal fluid.Growth characteristics and morphology of R. helvetica were studied to better understand invasiveness and virulence. The findings indicate that the invasiveness is comparable with other rickettsia, though R. helvetica seems to have a stable but slightly slower growth. Rickettsia helvetica is endemic in Sweden and therefore needs to be considered when investigating disease after a tick bite.
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