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- Björkman, Kristoffer, et al.
(författare)
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Clinical course of patients with single large-scale mtDNA deletions and childhood onset anemia
- 2022
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Ingår i: 14th European Paediatric Neurology Society Congress, Glasgow, UK (ISBN 978-3-00-072065-9).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To add to our knowledge of the clinical spectrum of patients with single large-scale mitochondrial DNA (mtDNA) deletion and childhood onset anemia. Methods: Retrospective collection of clinical data from medical records for patients, both living and deceased, with a single large-scale mtDNA deletion from seven mitochondrial disease centers in five countries. Statistical analysis with descriptive methods and Kaplan-Meier survival analysis. Results: Seventeen patients matching the genetic criterium and with anemia onset before six years of age. Exocrine pancreatic insufficiency was only seen in five patients in this group. Multiple organs were involved in all patients, with the most common non-hematologic ones being skeletal muscle, central nervous system, endocrine, eyes, gastrointestinal system, kidneys, hearing, liver and heart. Psychomotor retardation was seen in ten patients, hearing impairment in nine patients, failure to thrive in eight patients. Eight later developed Kearns-Sayre syndrome. Eleven patients were deceased, with a median age at death of 7.5 years. Conclusions: The classically described phenotype of patients with large-scale mtDNA deletions and early onset anemia is Pearson marrow-pancreas syndrome, characterized by sideroblastic anemia and exocrine pancreas dysfunction. Only a minority of our patients fulfill the original criteria of Pearson syndrome though. Involvement of other organs than the pancreas is more common. The clinical course vary, but multi-system impact is the rule and life-expectancy is low. Early onset anemia in patients with large-scale mtDNA deletions is most frequently not associated with exocrine pancreas dysfunction. Better knowledge of the phenotype is helpful for diagnosis and more accurate prognosis.
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| 2. |
- 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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| 3. |
- Decker, Ralph, 1968, et al.
(författare)
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Case report of a girl with secondary amenorrhea associated with aurantiasis cutis
- 2016
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Ingår i: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: --- Aurantiasis cutis is a condition of yellowish or golden skin discoloration that can result from eating excessive amounts of foods containing carotene leading to hypercarotenemia(1), described causing secondary amenorrhea(2). Objective & hypothesis: --- Hypercarotenemia can cause secondary amenorrhea without overconsumption of excessive quantities of carotene. Results: --- Laboratory tests showed a ß-Carotene level more than the 2-fold above the upper reference level. Hyperbilirubinemia could be excluded. Hypogonadotropic hypogonadism was not present. There was no evidence for adrenal dysfunction. Liver function tests were normal. Material/ Methods: --- A 16-year-old girl presented to our endocrine outpatient clinic with a 2-year history of varying yellow discoloration of her skin and secondary amenorrhea. The findings of the general physical examination were normal, but there was a marked yellow discoloration of the palms, soles, and nasolabial folds. A dietary history revealed a low carotene diet, but also a low carbohydrate diet. BMI was 19.9 kg/m² (-0.2 SDS) without signs of anorexia. Discussion: --- In this girl we observed hypercarotenemia associated with secondary nonhypothalamic amenorrhea in absence of excess external intake of carotenes. This suggests an intrinsic reason due to a polymorphism(3) in ß-carotene 15,15'-monooxygenase (BCO)(4), an enzyme breaking down carotenes to vitamin A(5). Phenotype-genotype association studies are needed to confirm this hypothesis. Conclusion: --- Secondary non-hypothalamic amenorrhea can be associated with hypercarotenemia. References: --- 1. Tanikawa K, Seta K, Machii A, Itoh S 1961 [Aurantiasis cutis due to overeating of dried laver (nori): a case report]. Jpn J Med Sci Biol 50:414-419 2. Kemmann E, Pasquale SA, Skaf R 1983 Amenorrhea associated with carotenemia. JAMA 249:926-929 3. Leung WC, Hessel S, Meplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G 2009 Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15'-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB j 23:1041-1053 4. Frumar AM, Meldrum DR, Judd HL 1979 Hypercarotenemia in hypothalamic amenorrhea. Fertil Steril 32:261-264 5. Lindqvist A, Andersson S 2002 Biochemical properties of purified recombinant human beta-carotene 15,15'-monooxygenase. J Biol Chem 277:23942-23948
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| 7. |
- Tsiartas, Panos, et al.
(författare)
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P–459 Ex vivo perfusion of whole ewe ovaries with follicular maturation for up to seven days: towards the development of an alternative fertility preservation method
- 2021
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Ingår i: Human Reproduction Vol 36 Issue Supplement 1. - : Oxford University Press (OUP). - 0268-1161.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Study question To develop an alternative fertility preservation method for young female cancer patients based on an ex vivo perfusion of whole ovaries serving as a platform for future ovarian stimulation studies. Summary answer It is possible to maintain viable follicles and to retrieve oocytes after ex vivo perfusion of ewe ovaries for up to 7 days. What is known already Some progress has been made in terms of follicular growth and the isolation of mature oocytes in vitro. However, full development, from early follicular stages to a viable offspring, has only been described in rodent models. The complex events controlling follicular expansion and the long time required for folliculogenesis and oocyte maturity in large mammalian species creating challenges and limitations for in vitro studies. Ex vivo perfusion of a whole ovary could potentially be a solution by exploiting the intact ovarian architecture to support folliculogenesis and oocyte maturation. Study design, size, duration Thirty-one ewe ovaries were divided into 4 groups and ex vivo perfused in a bioreactor. Group 1 (n = 14) perfusion for 48 hours with no hormone supplementation; Group 2 (n = 4) perfusion 96–101 hours with follicle stimulating hormone (FSH); Group 3 (n = 3) perfusion 120–168 hours with human menopausal gonadotropin (hMG); Group 4 (n = 10) perfusion 72–144 hours with hMG. Participants/materials, setting, methods Ewe ovaries from sexually mature ewes were ex vivo perfused in a bioreactor under normothermic conditions for up to 7 days (max total 168 hours). Histomorphological, immunohistochemical, hormonal and biochemical analyses were performed to assess ovarian structure and viability after cold ischemia and after perfusion which was subsequently compared to control ovaries. Main results and the role of chance The perfused ovaries in group 2 and 3 showed no significant differences in follicular density, viability and oocyte quality after ischemia and perfusion compared to control ovaries. Estradiol and progesterone levels did not increase during the perfusion. The perfused ovaries in group 1 and 4 showed a significant decrease in the ovarian reserve and oocyte quality. In total, 16 GV-MI oocytes were retrieved from groups 3 and 4. Limitations, reasons for caution 1. Ovaries were retrieved from ewes of unknown cycle and reproductive history. 2. The perfusion medium was changed after 24 hours from perfusion start to remove detrimental metabolites and this could affect the measured concentrations of hormones and metabolites in the perfusion medium. Wider implications of the findings: These results pave the way to propose ex vivo perfusion as a good platform for fertility preservation studies on whole mammalian and human ovaries to retrieve fully mature oocytes. Trial registration number Not applicable
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| 9. |
- Andersson, Elin, et al.
(författare)
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Quantification of chondroitin sulfates and hyaluronan in synovial fluid using high performance liquid chromatography
- 2022
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 30:Suppl 1, s. 106-106
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Konferensbidrag (refereegranskat)abstract
- Purpose: Extracellular proteins such as aggrecan may be primed with specific glycan-patterns which result in their degradation, and hence may play a role in the pathogenesis of osteoarthritis (OA). To be able to use glycans as molecular biomarkers, the method of analysis of these molecules needs to be validated. The primary aim of this study was to validate quantitative high performance liquid chromatography (HPLC) of chondroitin sulfate (CS) and hyaluronan (HA) in synovial fluid samples. The secondary aim was to examine the glycan-pattern in different subject groups, and the correlation between age and the concentration of specific glycans.Methods: OA (n=25, age=36-86 years, 40% women) and recent knee injury patients (0-5 days from injury; n=13, age=36-64 years, 46% women) were selected from a cross-sectional convenience cohort. Individual synovial fluid samples, a synovial fluid pool (SF-control; n=7) and a CS quality control sample (CS-QC; Sigma #C2905) were digested with chondroitinase ABC overnight. Samples and glycan standards (CS [n=8] and HA [n=1] standards from Iduron) were labelled with 2-aminoacridone (AMAC) and analyzed using a quantitative HPLC assay. Aggrecan from synovial fluid samples (n=6) was purified using density centrifugation (D1 mini-prep). Sulfated glycosaminoglycans (sGAG) were quantified using Alcian blue precipitation. Since the CS, HA and sGAG data were not normally distributed, non-parametric analyses for group comparisons were done. P-values less than 0.05 were considered statistically significant.Results: Synovial fluid samples were digested with varying concentrations of chondroitinase ABC and analyzed with the HPLC assay; 5 mU chondroitinase ABC per μg sGAG gave the highest CS- and HA-signals and were chosen for the rest of the study (data not shown).The CS profiles in synovial fluid and on aggrecan purified from corresponding synovial fluids were assessed from six knee injury patients. Of the six CS-markers that were detected, uronic acid (UA)-N-acetylgalactosamine (GalNAc) was only present in aggrecan samples, while UA2S-GalNAc and UA2S-GalNAc6S were found only in the synovial fluids. Similar proportions of UA-GalNAc4S and UA-GalNAc6S were found in synovial fluids and aggrecan samples (Figure 1), and these CS-glycans accounted for 95% of all glycans in the SF-control sample (Table 1).The technical performance of CS- and HA-markers using HPLC-assay were evaluated (Table 1). Of the nine markers, five were present in the majority of the synovial fluid samples (N=20-38) and included in the investigation of the technical performance. The mean intra coefficient of variation (CV) for the synovial fluid samples was between 1.2 and 12.9%. For the SF-control sample, the mean intra CV was 3.3-12.1% and the inter CV was 11.0-18.5%. For the CS-QC sample, the mean intra CV was 2.5-9.5% and the mean inter CV was 3.3-31.7%. For the glycan standards, the mean intra CV was 0.2-7.0%. With dilution of the SF-control sample up to 1:10, the dilution recovery rate for the five CS- and HA-markers was mainly between 75 and 125%.The synovial fluid concentration of biomarkers UA-GalNAc6S and UA2s-GalNAc6s and sGAG were approximately 2 to 3 times higher for the recent injury group compared to the age-matched OA group, while the HA levels were 3.7 times lower for the recent injury group (data not shown). No difference in biomarker concentrations were found between the sexes in any of the patient groups (data not shown). For correlation assessments, the two patient groups were merged (total N=38, assessment N = between 20 and 38). Synovial fluid concentrations of HA and UA-GalNAc4S,6S correlated positively with age (rS=0.420 and 0.532, respectively) while UA-GalNAc6S and sGAG correlated negatively with age (rS=-0.333 and -0.528, respectively). HA correlated negatively with UA-GalNAc6S (rS=-0.462) and sGAG (rS=-0.472) and positively with UA-GalNAc4S,6S (rS=0.868).Conclusions: The technical performance of the HPLC-assay indicates that the method is suitable for analyzing CS and HA markers in synovial fluid samples. Our results suggest that: the vast majority of CS in synovial fluid derives from aggrecan, the glycan pattern differs between OA and knee injured subjects and that the concentrations of some of the CS-markers seem to be associated with HA and age.
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| 10. |
- Gupta, Anindya, et al.
(författare)
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Convolutional neural networks for false positive reduction of automatically detected cilia in low magnification TEM images
- 2017
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Ingår i: Image Analysis. - Cham : Springer. - 9783319591254 ; , s. 407-418
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Konferensbidrag (refereegranskat)abstract
- Automated detection of cilia in low magnification transmission electron microscopy images is a central task in the quest to relieve the pathologists in the manual, time consuming and subjective diagnostic procedure. However, automation of the process, specifically in low magnification, is challenging due to the similar characteristics of non-cilia candidates. In this paper, a convolutional neural network classifier is proposed to further reduce the false positives detected by a previously presented template matching method. Adding the proposed convolutional neural network increases the area under Precision-Recall curve from 0.42 to 0.71, and significantly reduces the number of false positive objects.
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