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| 3. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 5. |
- Van Haute, L., et al.
(författare)
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
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| 6. |
- Vogel, G. F., et al.
(författare)
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Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants
- 2023
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 25:6
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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| 8. |
- Weismuller, T. J., et al.
(författare)
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Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
- 2017
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 152:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P <.001 and HR, 0.90; P =.03, respectively) and malignancy (HR, 0.68; P =.008 and HR, 0.77; P =.004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P <.001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P =.002 and HR, 0.68; P <.001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P <.001 and adjusted HR for women, 0.48; P =.003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P <.001) or no IBD (HR, 1.15; P =.002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
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| 9. |
- Allori, AC, et al.
(författare)
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A Standard Set of Outcome Measures for the Comprehensive Appraisal of Cleft Care
- 2017
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Ingår i: The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association. - : SAGE Publications. - 1545-1569. ; 54:5, s. 540-554
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Tidskriftsartikel (refereegranskat)abstract
- Care of the patient with cleft lip and/or palate remains complex. Prior attempts at aggregating data to study the effectiveness of specific interventions or overall treatment protocols have been hindered by a lack of data standards. There exists a critical need to better define the outcomes- particularly those that matter most to patients and their families-and to standardize the methods by which these outcomes will be measured. This report summarizes the recommendations of an international, multidisciplinary working group with regard to which outcomes a typical cleft team could track, how those outcomes could be measured and recorded, and what strategies may be employed to sustainably implement a system for prospective data collection. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of cleft care that intercenter comparisons can become possible. This is important for quality-improvement endeavors, comparative effectiveness research, and value-based health-care reform.
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| 10. |
- Lundström, M, et al.
(författare)
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Capsule complication during cataract surgery: Background, study design, and required additional care: Swedish Capsule Rupture Study Group report 1.
- 2009
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Ingår i: Journal of cataract and refractive surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0886-3350 .- 1873-4502. ; 35:10, s. 1679-1687
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To report the selection procedure of complicated and uneventful cataract extractions included in the Swedish Capsule RuptureStudy and to describe the additional care required after a capsule complication during cataract surgery. Setting: Ten ophthalmic surgery departments in Sweden. Methods: Consecutive cataract extractions with a reported capsule complication were selected from the national database. Surgical data and data from the matching ophthalmic records at the participating clinics were analyzed. Controls were selected as the first uneventful procedure in the database after each procedure with a complication. Results: Data on 655 cataract extractions were studied for evaluation of risks and additional care; a capsule complication occurred in 324 procedures and no complication in 331 procedures. Using these records, 369 patients were recruited for a follow-up examination of the outcomes 3 years after the original cataract extraction. The records showed a substantial increase in additional care after a capsule complication, including more visits after surgery, increased need for in-patient care, and a significantly greater percentage of reoperations than after the uneventful surgery. With additional care, the average cost of a procedure with a capsule complication was approximately double the cost of an uneventful cataract extraction. Conclusions: The combined study of the database and matching medical records showed a substantial increase in additional care after a capsule complication. Using the database allowed identification of a large number of capsule complication cases and uneventful cases, indicating that national databases are excellent sources of data for studying unusual complications.
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| 11. |
- Lundström, M, et al.
(författare)
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Cataract surgery and quality of life in patients with age related macular degeneration
- 2002
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Ingår i: British Journal of Ophthalmology. - : BMJ. - 0007-1161 .- 1468-2079. ; 86:12, s. 1330-1335
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Tidskriftsartikel (refereegranskat)abstract
- Background: The coexistence of cataract and age related macular degeneration (AMD) is not unusual, especially in the very elderly. The outcome of cataract surgery in these cases depends on the effect of AMD on vision. In this study the authors have compared the outcome of cataract patients with AMD to that of cataract patients with no vision threatening ocular comorbidity, and analysed possible predictors of good or poor outcome. Methods: An observational prospective study on consecutive cases operated for cataract during 1 month at six surgical departments affiliated to the Swedish National Cataract Register (NCR). Data were collected according to the protocol of NCR and subjects completed the Catquest questionnaire before and 6 months after surgery. 90 subjects with AMD were compared to 335 subjects with no sight threatening ocular comorbidity. Results: Difficulties in performing various daily life activities improved significantly for AMD subjects after surgery (p<0.001, Wilcoxon signed rank test). Satisfaction with vision also improved significantly after surgery (p<0.001, Wilcoxon signed rank test). Activity level and independence were unchanged. Subjects with no ocular comorbidity had a still better outcome. The most important variable related to a good self assessed functional outcome was postoperative visual acuity irrespective of the presence of AMD. AMD subjects scheduled for second eye surgery and AMD subjects dissatisfied with their vision before surgery had a poorer outcome. Conclusion: Subjects with various stages of dry AMD and cataract improved their self assessed visual function and satisfaction with vision significantly after cataract extraction.
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| 12. |
- Thorburn, Doko-Miles J., et al.
(författare)
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Origin matters : Using a local reference genome improves measures in population genomics
- 2023
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Ingår i: Molecular Ecology Resources. - : WILEY. - 1755-098X .- 1755-0998. ; 23:7, s. 1706-1723
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Tidskriftsartikel (refereegranskat)abstract
- Genome sequencing enables answering fundamental questions about the genetic basis of adaptation, population structure and epigenetic mechanisms. Yet, we usually need a suitable reference genome for mapping population-level resequencing data. In some model systems, multiple reference genomes are available, giving the challenging task of determining which reference genome best suits the data. Here, we compared the use of two different reference genomes for the three-spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigated the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference genomes impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e. p, Tajima's D and F-ST), window-based statistics using different references resulted in different outlier genes and enriched gene functions. A marker-based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference-genome-based population genomic analyses.
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| 14. |
- Wejde, G, et al.
(författare)
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Endophthalmitis following cataract surgery in Sweden: national prospective survey 1999-2001.
- 2005
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Ingår i: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 83, s. 7-10
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT. Purpose: To investigate the epidemiology of postoperative endophthalmitis (POE) following cataract surgery in Sweden during a 3-year period, using the framework of the Swedish National Cataract Register. Methods: Clinically presumed cases of POE were reported in a prospective survey involving all Swedish ophthalmic surgical units except one. Data on results of the intraocular culture and visual outcome after infection, as well as patient age and gender and various elements of the surgical procedure, were collected. Results: The nationwide incidence of POE was 0.0595%, representing 112 cases in 188 151 cataract operations. Gram-positive bacteria were the predominant aetiology, with an 84.6% share of culture-positive cases. A significantly decreased risk for POE was found for patients who had received prophylactic intracameral antibiotics (mainly cefuroxime) in comparison with those who had been treated with topical antibiotics only. Conclusions: The prevalence of POE after cataract surgery in Sweden is at the lower end of the spectrum of incidence currently reported in the developed world. The administration of intracameral antibiotics may have contributed to these results.
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