| 1. |
- Carmona-Gutierrez, D., et al.
(författare)
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Guidelines and recommendations on yeast cell death nomenclature
- 2018
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Ingår i: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 5:1, s. 4-31
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Forskningsöversikt (refereegranskat)abstract
- Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.
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| 2. |
- Gullström, Charlie
(författare)
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High-fidelity Mock-up Report : Public deliverable D.2.4 from COMPEIT, EU FP7 project
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- COMPEIT is a 3-year EU 7th framework project and focuses on a web-based system for highly interactive, personalised, shared media experiences by developing technologies that A) enrich social connections, B) improve the feeling of being together in one shared space and C) enhance collaboration whilst being separated in time or space. COMPEIT takes the view that Internet-based distribution will transform traditional broadcasting towards higher levels of interactivity and integration with virtual and augmented reality, enabled by advanced web technologies and the proliferation of tangible devices. The project addresses Quality of Experience as a key variable in the experience of media production and consumption systems.A first mock-up of the COMPEIT system has been put together. It illustrates technical components from WP 4 (Mediated Presence Components); services from WP 5 (New Media Services); and D3.2 Initial System Specification. It informs further research towards D3.4 First Prototype.
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| 3. |
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| 4. |
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| 5. |
- Toft, N, et al.
(författare)
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Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 32, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.Leukemia advance online publication, 22 September 2017; doi:10.1038/leu.2017.265.
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| 6. |
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| 7. |
- Anthony, Kenneth R. N., et al.
(författare)
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Operationalizing resilience for adaptive coral reef management under global environmental change
- 2015
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 21:1, s. 48-61
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Forskningsöversikt (refereegranskat)abstract
- Cumulative pressures from global climate and ocean change combined with multiple regional and local-scale stressors pose fundamental challenges to coral reef managers worldwide. Understanding how cumulative stressors affect coral reef vulnerability is critical for successful reef conservation now and in the future. In this review, we present the case that strategically managing for increased ecological resilience (capacity for stress resistance and recovery) can reduce coral reef vulnerability (risk of net decline) up to a point. Specifically, we propose an operational framework for identifying effective management levers to enhance resilience and support management decisions that reduce reef vulnerability. Building on a system understanding of biological and ecological processes that drive resilience of coral reefs in different environmental and socio-economic settings, we present an Adaptive Resilience-Based management (ARBM) framework and suggest a set of guidelines for how and where resilience can be enhanced via management interventions. We argue that press-type stressors (pollution, sedimentation, overfishing, ocean warming and acidification) are key threats to coral reef resilience by affecting processes underpinning resistance and recovery, while pulse-type (acute) stressors (e.g. storms, bleaching events, crown-of-thorns starfish outbreaks) increase the demand for resilience. We apply the framework to a set of example problems for Caribbean and Indo-Pacific reefs. A combined strategy of active risk reduction and resilience support is needed, informed by key management objectives, knowledge of reef ecosystem processes and consideration of environmental and social drivers. As climate change and ocean acidification erode the resilience and increase the vulnerability of coral reefs globally, successful adaptive management of coral reefs will become increasingly difficult. Given limited resources, on-the-ground solutions are likely to focus increasingly on actions that support resilience at finer spatial scales, and that are tightly linked to ecosystem goods and services.
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| 8. |
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| 9. |
- Eekers, Danielle B. P., et al.
(författare)
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The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology
- 2018
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Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 128:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (Cr) and magnetic resonance (MR) imaging. Methods: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. Results: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). Conclusion: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at w.cancerdata.c and will be updated whenever required.
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| 10. |
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| 11. |
- Fornes, R., et al.
(författare)
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The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.
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| 12. |
- Hessels, Roy S., et al.
(författare)
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Is the eye-movement field confused about fixations and saccades? : A survey among 124 researchers
- 2018
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Ingår i: Royal Society Open Science. - : The Royal Society. - 2054-5703. ; 5:8, s. 1-23
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Tidskriftsartikel (refereegranskat)abstract
- Eye movements have been extensively studied in a wide range of research fields. While new methods such as mobile eye tracking and eye tracking in virtual/augmented realities are emerging quickly, the eye-movement terminology has scarcely been revised. We assert that this may cause confusion about two of the main concepts: fixations and saccades. In this study, we assessed the definitions of fixations and saccades held in the eye-movement field, by surveying 124 eye-movement researchers. These eye-movement researchers held a variety of definitions of fixations and saccades, of which the breadth seems even wider than what is reported in the literature. Moreover, these definitions did not seem to be related to researcher background or experience. We urge researchers to make their definitions more explicit by specifying all the relevant components of the eye movement under investigation: (i) the oculomotor component: e.g. whether the eye moves slow or fast; (ii) the functional component: what purposes does the eye movement (or lack thereof) serve; (iii) the coordinate system used: relative to what does the eye move; (iv) the computational definition: how is the event represented in the eye-tracker signal. This should enable eye-movement researchers from different fields to have a discussion without misunderstandings.
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| 13. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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Asymmetric Inheritance of Aggregated Proteins and Age Reset in Yeast Are Regulated by Vac17-Dependent Vacuolar Functions
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 16:3, s. 826-838
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Tidskriftsartikel (refereegranskat)abstract
- Age can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae, we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan. The link between damage asymmetry and vesicle trafficking can be explained by a direct interaction between aggregates and vesicles. We also show that the protein disaggregase Hsp104 interacts physically with endocytic vesicle-associated proteins, such as the dynamin-like protein, Vps1, which was also shown to be required for Vac17-dependent sequestration of protein aggregates. These data demonstrate that two physiognomies of aging-reduced endocytosis and protein aggregation-are interconnected and regulated by Vac17.
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| 14. |
- Hoffman, Tove, et al.
(författare)
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Alkhurma Hemorrhagic Fever Virus RNA in Hyalomma rufipes Ticks Infesting Migratory Birds, Europe and Asia Minor
- 2018
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Ingår i: Emerging Infectious Diseases. - Atlanta, United States : U.S. Department of Health and Human Services * Centers for Disease Control and Prevention. - 1080-6040 .- 1080-6059. ; 24:5, s. 879-882
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Tidskriftsartikel (refereegranskat)abstract
- Alkhurma hemorrhagic fever virus RNA was detected in immature Hyalomma rufipes ticks infesting northward migratory birds caught in the North Mediterranean Basin. This finding suggests a role for birds in the ecology of the Alkhurma hemorrhagic fever virus and a potential mechanism for dissemination to novel regions. Increased surveillance is warranted.
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| 15. |
- Hooge, Ignace T.C., et al.
(författare)
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Do pupil-based binocular video eye trackers reliably measure vergence?
- 2019
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Ingår i: Vision Research. - : Elsevier BV. - 0042-6989. ; 156, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- A binocular eye tracker needs to be accurate to enable the determination of vergence, distance to the binocular fixation point and fixation disparity. These measures are useful in e.g. the research fields of visual perception, binocular control in reading and attention in 3D. Are binocular pupil-based video eye trackers accurate enough to produce meaningful binocular measures? Recent research revealed potentially large idiosyncratic systematic errors due to pupil-size changes. With a top of the line eye tracker (SR Research EyeLink 1000 plus), we investigated whether the pupil-size artefact in the separate eyes may cause the eye tracker to report apparent vergence when the eyeballs do not rotate. Participants were asked to fixate a target at a distance of 77 cm for 160 s. We evoked pupil-size changes by varying the light intensity. With increasing pupil size, horizontal vergence reported by the eye tracker decreased in most subjects, up to two degrees. However, this was not due to a rotation of the eyeballs, as identified from the absence of systematic movement in the corneal reflection (CR) signals. From this, we conclude that binocular pupil-CR or pupil-only video eye trackers using the dark pupil technique are not accurate enough to be used to determine vergence, distance to the binocular fixation point and fixation disparity.
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| 16. |
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| 17. |
- Jendle, Johan, 1963-, et al.
(författare)
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Effects on repetitive 24-hour ambulatory blood pressure in type 2 diabetic subjects randomized to liraglutide or glimepiride treatment both in combination with metformin : A randomized open parallel-group study
- 2018
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Ingår i: Journal of the American Society of Hypertension. - : Elsevier. - 1933-1711 .- 1878-7436. ; 12:5, s. 346-355
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Tidskriftsartikel (refereegranskat)abstract
- In this post hoc study, we aimed to investigate liraglutide treatment on repetitive 24-hour blood pressure (BP) in patients with type II diabetes. Sixty-two individuals with type II diabetes (45 males) were randomized to 1.8 mg liraglutide once daily or 4 mg glimepiride together with 1 g metformin twice daily. Ambulatory 24-hour systolic and diastolic blood pressure (sBP/dBP) was repetitively measured at baseline, 2 weeks, and 18 weeks. Outcomes were evaluated as treatment change from baseline, 2 weeks, and 18 weeks. Baseline clinical characteristics of liraglutide (n = 33) and glimepiride (n = 29) groups were well matched. No statistically significant difference in 24-hour sBP/dBP between three time periods and groups was observed. There was no treatment change for 24-hour sBP at week 2 or after week 18. There was a transient treatment change in 24-hour dBP in the liraglutide group at week 2 (3.2 ± 5.4 vs. -1.2 ± 4.5 mm Hg, P < .01). A treatment change in 24-hour heart rate at week 2 (4.9 ± 6.8 vs. 1.0 ± 6.0 bpm, P = .03) and at week 18 (5.9 ± 7.8 vs. 0.2 ± 6.3 bpm, P < .01) was observed in the liraglutide group. In conclusion, liraglutide treatment did not lower BP. However, a small diurnal variation in dBP without affecting BP variability or nocturnal BP dipping was observed.
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| 18. |
- Lindner, Philip, et al.
(författare)
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Who seeks ICBT for depression and how do they get there? : effects of recruitment source on patient demographics and clinical characteristics
- 2015
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Ingår i: Internet Interventions. - : Elsevier. - 2214-7829. ; 2:2, s. 221-225
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Tidskriftsartikel (refereegranskat)abstract
- Studies on internet-administered cognitive behavior therapy (ICBT) frequently use several different sources of recruitment, yet no study has investigated whether different recruitment sources produce different clinical and demographic profiles among participants. Using data from a large sample (n = 982) seeking ICBT for depression, we compared these characteristics on the basis of self-reported recruitment source. Recruitment sources that imply more active treatment-seeking behaviors (Google searches, viewing postings on mental health websites) presented more severe depression and anxiety than those recruited through more passive sources of information (newspaper advertisements, referrals by friends and family). In addition, a number of demographic differences between groups were found. These findings have important implications for ICBT research projects and clinical programs who employ open recruitment procedures and multi-modal recruitment strategies, and who wish to recruit representative samples or target specific subgroups. Replications in other countries will however be required to establish cross-cultural patterns.
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| 19. |
- Lopes, A. M., et al.
(författare)
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Host-Specific Glycans Are Correlated with Susceptibility to Infection by Lagoviruses, but Not with Their Virulence
- 2018
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Ingår i: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 92:4
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Tidskriftsartikel (refereegranskat)abstract
- Rabbit hemorrhagic disease virus (RHDV) and European brown hare syndrome virus (EBHSV) are two lagoviruses from the family Caliciviridae that cause fatal diseases in two leporid genera, Oryctolagus and Lepus, respectively. In the last few years, several examples of host jumps of lagoviruses among leporids were recorded. In addition, a new pathogenic genotype of RHDV emerged, and many nonpathogenic strains of lagoviruses have been described. The molecular mechanisms behind host shifts and the emergence of virulence are unknown. Since RHDV uses glycans of the histo-blood group antigen type as attachment factors to initiate infection, we studied if glycan specificities of the new pathogenic RHDV genotype, nonpathogenic lagoviruses, and EBHSV potentially play a role in determining the host range and virulence of lagoviruses. We observed binding to A, B, or H antigens of the histo-blood group family for all strains known to primarily infect European rabbits (Oryctolagus cuniculus), which have recently been classified as GI strains. However, we could not explain the emergence of virulence, since similar glycan specificities were found in several pathogenic and nonpathogenic strains. In contrast, EBHSV, recently classified as GII. 1, bound to terminal beta -linked N-acetylglucosamine residues of O-glycans. Expression of these attachment factors in the upper respiratory and digestive tracts in three lagomorph species (Oryctolagus cuniculus, Lepus europaeus, and Sylvilagus floridanus) showed species-specific patterns regarding susceptibility to infection by these viruses, indicating that species-specific glycan expression is likely a major contributor to lagovirus host specificity and range. IMPORTANCE Lagoviruses constitute a genus of the family Caliciviridae comprising highly pathogenic viruses, RHDV and EBHSV, that infect rabbits and hares, respectively. Recently, nonpathogenic strains were discovered and new pathogenic strains have emerged. In addition, host jumps between lagomorphs have been observed. The mechanisms responsible for the emergence of pathogenicity and host species range are unknown. Previous studies showed that RHDV strains attach to glycans expressed in the upper respiratory and digestive tracts of rabbits, the likely portals of virus entry. Here, we studied the glycan-binding properties of novel pathogenic and nonpathogenic strains looking for a link between glycan binding and virulence or between glycan specificity and host range. We found that glycan binding did not correlate with virulence. However, expression of glycan motifs in the upper respiratory and digestive tracts of lagomorphs revealed species-specific patterns associated with the host ranges of the virus strains, suggesting that glycan diversity contributes to lagovirus host ranges.
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| 20. |
- Muller-Deile, J., et al.
(författare)
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Identification of cell and disease specific microRNAs in glomerular pathologies
- 2019
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Ingår i: Journal of Cellular and Molecular Medicine. - : Wiley. - 1582-1838 .- 1582-4934. ; 23:6, s. 3927-3939
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression in physiological processes as well as in diseases. Currently miRs are already used to find novel mechanisms involved in diseases and in the future, they might serve as diagnostic markers. To identify miRs that play a role in glomerular diseases urinary miR-screenings are a frequently used tool. However, miRs that are detected in the urine might simply be filtered from the blood stream and could have been produced anywhere in the body, so they might be completely unrelated to the diseases. We performed a combined miR-screening in pooled urine samples from patients with different glomerular diseases as well as in cultured human podocytes, human mesangial cells, human glomerular endothelial cells and human tubular cells. The miR-screening in renal cells was done in untreated conditions and after stimulation with TGF-beta. A merge of the detected regulated miRs led us to identify disease-specific, cell type-specific and cell stress-induced miRs. Most miRs were down-regulated following the stimulation with TGF-beta in all cell types. Up-regulation of miRs after TGF-beta was cell type-specific for most miRs. Furthermore, urinary miRs from patients with different glomerular diseases could be assigned to the different renal cell types. Most miRs were specifically regulated in one disease. Only miR-155 was up-regulated in all disease urines compared to control and therefore seems to be rather unspecific. In conclusion, a combined urinary and cell miR-screening can improve the interpretation of screening results. These data are useful to identify novel miRs potentially involved in glomerular diseases.
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| 21. |
- Muller-Deile, J., et al.
(författare)
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Overexpression of preeclampsia induced microRNA-26a-5p leads to proteinuria in zebrafish
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- So far the pathomechanism of preeclampsia in pregnancy is focussed on increased circulating levels of soluble fms-like tyrosin kinase-1 (sFLT-1) that neutralizes glomerular VEGF-A expression and prevents its signaling at the glomerular endothelium. As a result of changed glomerular VEGF-A levels endotheliosis and podocyte foot process effacement are typical morphological features of preeclampsia. Recently, microRNA-26a-5p (miR-26a-5p) was described to be also upregulated in the preeclamptic placenta. We found that miR-26a-5p targets VEGF-A expression by means of PIK3C2a in cultured human podocytes and that miR-26a-5p overexpression in zebrafish causes proteinuria, edema, glomerular endotheliosis and podocyte foot process effacement. Interestingly, recombinant zebrafish Vegf-Aa protein could rescue glomerular changes induced by miR-26a-5p. In a small pilot study, preeclamptic patients with podocyte damage identified by podocyturia, expressed significantly more urinary miR-26a-5p compared to healthy controls. Thus, functional and ultrastructural glomerular changes after miR-26a-5p overexpression can resemble the findings seen in preeclampsia and indicate a potential pathophysiological role of miR-26a-5p in addition to sFLT-1 in this disease.
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| 22. |
- Muller-Deile, J., et al.
(författare)
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Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases
- 2017
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 92:4, s. 836-849
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.
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| 23. |
- Nguyen, Duong T., et al.
(författare)
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Humanizing Miniature Hearts through 4-Flow Cannulation Perfusion Decellularization and Recellularization
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.
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| 24. |
- Nyström, Markus B. T., et al.
(författare)
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Behavioral activation versus physical activity via the internet : A randomized controlled trial
- 2017
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 215, s. 85-93, s. 396-396
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Tidskriftsartikel (refereegranskat)abstract
- Background: A major problem today is that only about fifty percent of those affected by depressionseeks help. One way to reach more sufferers would be by offering easily accessible internet based treatments. The purpose of this study was to compare/evaluate four therapist supported internet administered treatments.Method/results: Two hundred eighty six participants were included. The treatment period lasted twelve weeks, consisting of the following treatments: 1) physical activity without treatment rational, 2) physical activity with treatment rational, 3) behavioral activation without treatment rational and 4) behavioral activation with treatment rational. All groups (including a control-group) showed a significant decrease in depressive symptoms. When the treatment groups were pooled and compared to the control group, there were significant differences from pretest to posttest (Hedges gav treatment =1.01, control group =0.47). This held true also when each of the four treatment groups was compared to the control group, with one exception: Physical activity without treatment rationale.Limitations: The differences between how many modules the participants completed could indicate that there are other factors than the treatments that caused the symptom reduction, however, the dose-response analysis did not detect any significant differences on account of modules completed.Conclusions: The results support the positive effects of internet administered treatments for depression, and highlights the importance of psychoeducation, which tends to affect both the treatment outcome and the probability of remaining in treatment. These aspects need to be considered when developing and conducting new treatments for depression, since they would increase the likelihood of positive treatment outcomes.
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| 25. |
- Nyström, Markus B. T., et al.
(författare)
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Shame and interpersonal sensitivity : Gender differences and the association between internalized shame coping strategies and interpersonal sensitivity
- 2018
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Ingår i: Bulletin of the Menninger Clinic. - : Guilford Publications. - 0025-9284 .- 1943-2828. ; 82:2, s. 137-155
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigated gender differences in interpersonal sensitivity and internalized shame coping strategies in 252 undergraduate students. To measure interpersonal sensitivity and shame coping strategies, the self-assessment forms Interpersonal Sensitivity Measure and Compass of Shame Scale were used. The analyses revealed that compared to men, women display interpersonal sensitivity to a higher degree, and they use internalized shame coping strategies to a greater extent. The results also showed that interpersonal sensitivity is highly correlated with shame coping strategies. However, in contrast to earlier research, no gender difference was found, and gender did not significantly mediate the association between interpersonal sensitivity and internalized shame coping. These results could aid clinicians and researchers in promoting, designing, delivering, and evaluating treatments for patients with, for example, depression, anxiety, and interpersonal and/or relational problems.
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| 26. |
- Nyström, Markus B. T., 1973-
(författare)
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Treating depression with activation
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to evaluate and compare four therapist-supported Internet-administered treatments for depression. Three studies were conducted. The first was a systematic review to determine the most effective mode and dose of physical activity (PA) for treating major depressive disorders (MDDs), and to suggest guidelines and recommendations for clinicians. These recommendations included that the PA needs to be individually customized, performed for at least 30 minutes, preferably under supervision, and with a frequency of at least three times per week to be effective for treating MDDs. Recommendations, however, must be viewed in light of the relatively few studies that match the inclusion criteria. The second study aimed to empirically evaluate and compare the effect of four therapist-supported Internet-administered treatments for mild to moderate depression. Two of the treatments were based on PA and two on behavioural activation (BA). One PA group was provided with a rationale; whereas, the other was not. The treatment in one BA group was based on Lewinsohn’s model and the other on Martell’s model. Results showed that all groups (including the control group) significantly reduced their depressive symptoms. Group comparisons revealed that three of the four treatment groups (all except the PA group that did not receive a rationale) had a significantly greater symptom reduction than the control group. This suggests that some sort of rationale is important for symptom reduction. The third study aimed to examine if a relapse prevention program would affect symptom change during a 24-month follow-up. We also examined if symptom change during the acute phase (AP) treatment period predicted symptom change during the follow-up period. A third and final aim was to examine if the number of symptoms post-AP treatment predicted symptom change during the follow-up period. The initial analysis indicated that the introduction of a relapse prevention program did not affect symptom change during follow-up. The symptom change during AP treatment did predict symptom change during follow-up for three of the four treatment groups (all except one of the BA groups). The number of symptoms post-AP treatment, however, did not predict symptom change during follow-up for any of the treatment groups. The main conclusion from this thesis is that PA seems to be effective for treating and preventing depressive symptoms. PA with a rationale is more effective than without one, and an understanding of the person’s situation is important for a treatment outcome. If a symptom change can be achieved during the acute phase, the likelihood for symptom change during the follow-up increases.
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| 27. |
- Nyström, Markus B. T., 1973-, et al.
(författare)
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Treating Major Depression with Physical Activity : A Systematic Overview with Recommendations
- 2015
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Ingår i: Cognitive Behaviour Therapy. - : Informa UK Limited. - 1650-6073 .- 1651-2316. ; 44:4, s. 341-352
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this systematic overview was to determine the most effective mode and dose of physical activity (PA) for treating major depressive disorder (MDD), and to suggest guidelines and recommendations for clinicians. The selection process consisted of a comprehensive search that was conducted up until April 2014 in the following databases: PsycINFO, Medline, PubMed and Scopus. The inclusion criteria were: (1) a randomized controlled trial (RCT) design, (2) complete description of intensity, duration and frequency of the PA, (3) the participants had to be diagnosed with MDD according to Diagnostic Statistical Manual 4 th edition (DSM-IV) or International Classification of Disease tenth Revision (ICD-10) criteria (4) if the controls received any treatment, it had to be specified, (5) published after 1990, (6) consist of aerobic or anaerobic treatment PA, and (7) not be a pilotor preliminary study. A quality assessment of each study was conducted independently by two reviewers; this stringent selection process resulted in 12 reviewed studies. Conclusion: individually customized PA, for at least 30 minutes, preferably performed under supervision and with a frequency of at least three times per week is recommended when treating MDD. These recommendations must be viewed in light of the relatively few studies matching the inclusion criteria.
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| 28. |
- Nyström, Magda, 1984, et al.
(författare)
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Extracting extensional properties through excess pressure drop estimation in axisymmetric contraction and expansion flows for constant shear viscosity, extension strain-hardening fluids
- 2016
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Ingår i: Rheologica Acta. - : Springer Science and Business Media LLC. - 1435-1528 .- 0035-4511. ; 55:5, s. 373-396
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Tidskriftsartikel (refereegranskat)abstract
- In this study, hyperbolic contraction-expansion flow (HCF) devices have been investigated with the specific aim of devising new experimental measuring systems for extensional rheological properties. To this end, a hyperbolic contraction-expansion configuration has been designed to minimize the influence of shear in the flow. Experiments have been conducted using well-characterized model fluids, alongside simulations using a viscoelastic White-Metzner/FENE-CR model and finite element/finite volume analysis. Here, the application of appropriate rheological models to reproduce quantitative pressure drop predictions for constant shear viscosity fluids has been investigated, in order to extract the relevant extensional properties for the various test fluids in question. Accordingly, experimental evaluation of the hyperbolic contraction-expansion configuration has shown rising corrected pressure drops with increasing elastic behaviour (D e=0 similar to 16), evidence which has been corroborated through numerical prediction. Moreover, theoretical to predicted solution correspondence has been established between extensional viscosity and first normal stress difference. This leads to a practical means to measure extensional viscosity for elastic fluids, obtained through the derived pressure drop data in these HCF devices.
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| 29. |
- Nyström, Magda, 1984, et al.
(författare)
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Hyperbolic contraction measuring systems for extensional flow
- 2017
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Ingår i: Mechanics of Time-Dependent Materials. - : Springer Science and Business Media LLC. - 1385-2000 .- 1573-2738. ; 21:3, s. 455-479
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Tidskriftsartikel (refereegranskat)abstract
- In this paper an experimental method for extensional measurements on medium viscosity fluids in contraction flow is evaluated through numerical simulations and experimental measurements. This measuring technique measures the pressure drop over a hyperbolic contraction, caused by fluid extension and fluid shear, where the extensional component is assumed to dominate. The present evaluative work advances our previous studies on this experimental method by introducing several contraction ratios and addressing different constitutive models of varying shear and extensional response. The constitutive models included are those of the constant viscosity Oldroyd-B and FENE-CR models, and the shear-thinning LPTT model. Examining the results, the impact of shear and first normal stress difference on the measured pressure drop are studied through numerical pressure drop predictions. In addition, stream function patterns are investigated to detect vortex development and influence of contraction ratio. The numerical predictions are further related to experimental measurements for the flow through a 15:1 contraction ratio with three different test fluids. The measured pressure drops are observed to exhibit the same trends as predicted in the numerical simulations, offering close correlation and tight predictive windows for experimental data capture. This result has demonstrated that the hyperbolic contraction flow is well able to detect such elastic fluid properties and that this is matched by numerical predictions in evaluation of their flow response. The hyperbolical contraction flow technique is commended for its distinct benefits: it is straightforward and simple to perform, the Hencky strain can be set by changing contraction ratio, non-homogeneous fluids can be tested, and one can directly determine the degree of elastic fluid behaviour. Based on matching of viscometric extensional viscosity response for FENE-CR and LPTT models, a decline is predicted in pressure drop for the shear-thinning LPTT model. This would indicate a modest impact of shear in the flow since such a pressure drop decline is relatively small. It is particularly noteworthy that the increase in pressure drop gathered from the experimental measurements is relatively high despite the low Deborah number range explored.
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| 30. |
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| 31. |
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| 32. |
- Olafsdottir, Arndis, 1978, et al.
(författare)
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Excess risk of lower extremity amputations in people with type 1 diabetes compared with the general population: Amputations and type 1 diabetes
- 2019
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Ingår i: BMJ Open Diabetes Research and Care. - : BMJ. - 2052-4897. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective This study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control, and renal complications. Research design and methods We analyzed data from people with type 1 DM from the Swedish National Diabetes Register without prior amputation from January 1998 to December 2013. Each person (n=36 872) was randomly matched with five controls by sex, age, and county (n=184 360) from the population without diabetes. All were followed until first amputation, death or end of follow-up. Results The overall adjusted HR for all amputation was 40.1 (95% CI 32.8 to 49.1) for type 1 DM versus controls. HR increased with longer diabetes duration. The incidence of amputation/1000 patient-years was 3.18 (95% CI 2.99 to 3.38) for type 1 DM and 0.07 (95% CI 0.05 to 0.08) for controls. The incidence decreased from 1998-2001 (3.09, 95% CI 2.56 to 3.62) to 2011-2013 (2.64, 95% CI 2.31 to 2.98). The HR for major amputations was lower than for minor amputations and decreased over the time period (p=0.0045). Worsening in glycemic control among patients with diabetes led to increased risk for amputation with an HR of 1.80 (95% CI 1.72 to 1.88) per 10 mmol/mol (1%) increase in hemoglobin A1c. Conclusions Although the absolute risk of amputation is relatively low, the overall excess risk was 40 times that of controls. Excess risk was substantially lower for those with good glycemic control and without renal complications, but excess risk still existed and is greatest for minor amputations. © 2019 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 33. |
- Persson, Frederik, et al.
(författare)
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Different patterns of second-line treatment in type 2 diabetes after metformin monotherapy in Denmark, Finland, Norway and Sweden (D360 Nordic) : A multinational observational study.
- 2018
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Ingår i: Endocrinology, diabetes & metabolism. - : Wiley. - 2398-9238. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The understanding of second-line use of glucose-lowering drugs (GLDs) in the general population with type 2 diabetes (T2D) treatment is important as recent results have shown cardiovascular benefits with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). Our aim was to describe second-line GLD treatment patterns in four Nordic countries.Methods: All T2D patients treated with GLD between 2006 and 2015 were identified in prescribed drug registries in Denmark, Finland, Norway and Sweden, and linked with National Patient and Cause of Death Registries. Second-line treatment was defined as a prescription of a second GLD class following ≥6 months of metformin monotherapy. Index was the date of first dispense of the second-line drug.Results: A rapid uptake of newer GLDs (GLP-1RA, DPP-4i and SGLT-2i) over the 10-year observation period was seen in Denmark, Finland and Norway, while slower in Sweden. In 2015, 33,880 (3.1%) of 1,078,692 T2D patients initiated second-line treatment, and newer GLDs were more commonly used in Finland (92%), Norway (71%) and Denmark (70%) vs Sweden (44%). In 2015, the use of older GLDs (insulin and sulphonylureas) was 7-fold greater in Sweden compared to Finland (49% vs 7%), and 1.6-fold greater compared with Denmark and Norway (49% vs 30% and 29%, respectively).Conclusions: Despite comparable demography and healthcare systems in four neighbouring countries, surprisingly large differences in second-line use of newer GLDs were found. With recent evidence of potential cardiovascular benefits with newer GLDs, such differences may have an important impact on cardiovascular outcomes.
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| 34. |
- Psonka-Antonczyk, Katarzyna M., et al.
(författare)
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Nanoscale Structure and Spectroscopic Probing of A beta 1-40 Fibril Bundle Formation
- 2016
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Ingår i: Frontiers in Chemistry. - : Frontiers Research Foundation. - 2296-2646. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid plaques composed of fibrillar Amyloid-beta (A beta) are hallmarks of Alzheimers disease. However, A beta fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated A beta fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the A beta fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the A beta 1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (empty set similar to 2.5 nm) into higher order bundled structures (empty set similar to 5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated A beta plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.
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| 35. |
- Sator, Lea, et al.
(författare)
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Overdiagnosis of COPD in Subjects With Unobstructed Spirometry A BOLD Analysis
- 2019
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Ingår i: Chest. - : Elsevier BV. - 0012-3692 .- 1931-3543. ; 156:2, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012.METHODS: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7).RESULTS: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication.CONCLUSIONS: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.
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| 36. |
- Sj?lin, G., et al.
(författare)
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The Long-Term Outcome of Treatment for Graves' Hyperthyroidism
- 2019
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 29:11, s. 1545-1557
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Tidskriftsartikel (refereegranskat)abstract
- Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine (I-131), or surgery for Graves' hyperthyroidism is well described. However, there are a few reports on the long-term total outcome of each treatment modality regarding how many require levothyroxine supplementation, the need of thyroid ablation, or the individual patient's estimation of their recovery. Methods: We conducted a pragmatic trial to determine the effectiveness and adverse outcome in a patient cohort newly diagnosed with Graves' hyperthyroidism between 2003 and 2005 (n = 2430). The patients were invited to participate in a longitudinal study spanning 8 +/- 0.9 years (mean +/- standard deviation) after diagnosis. We were able to follow 1186 (60%) patients who had been treated with ATD, I-131, or surgery. We determined the mode of treatment, remission rate, recurrence, quality of life, demographic data, comorbidities, and lifestyle factors through questionnaires and a review of the individual's medical history records. Results: At follow-up, the remission rate after first-line treatment choice with ATD was 45.3% (351/774), with I-131 therapy 81.5% (324/264), and with surgery 96.3% (52/54). Among those patients who had a second course of ATD, 29.4% achieved remission (vs. the 45.3% after the first course of ATD). The total number of patients who had undergone ablative treatment was 64.3% (763/1186), of whom 23% (278/1186) had received surgery, 43% (505/1186) had received I-131 therapy, including 2% (20/1186) who had received both surgery and I-131. Patients who received ATD as first-line treatment and possibly additional ATD had 49.7% risk (385/774) of having undergone ablative treatment at follow-up. Levothyroxine replacement was needed in 23% (81/351) of the initially ATD treated in remission, in 77.3% (204/264) of the I-131 treated, and in 96.2% (50/52) of the surgically treated patients. Taken together after 6-10 years, and all treatment considered, normal thyroid hormone status without thyroxine supplementation was only achieved in 35.7% (423/1186) of all patients and in only 40.3% of those initially treated with ATD. The proportion of patients that did not feel fully recovered at follow-up was 25.3%. Conclusion: A patient selecting ATD therapy as the initial approach in the treatment of Graves' hyperthyroidism should be informed that they have only a 50.3% chance of ultimately avoiding ablative treatment and only a 40% chance of eventually being euthyroid without thyroid medication. Surprisingly, 1 in 4 patients did not feel fully recovered after 6-10 years. The treatment for Graves' hyperthyroidism, thus, has unexpected long-term consequences for many patients.
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| 37. |
- Stukenborg, J. -B., et al.
(författare)
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Spermatogonial quantity in human prepubertal testicular tissue collected for fertility preservation prior to potentially sterilizing therapy
- 2018
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Ingår i: Human Reproduction. - : Oxford University Press. - 0268-1161 .- 1460-2350. ; 33:9, s. 1677-1683
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Does chemotherapy exposure (with or without alkylating agents) or primary diagnosis affect spermatogonial quantity in human prepubertal testicular tissue? SUMMARY ANSWER: Spermatogonial quantity is significantly reduced in testes of prepubertal boys treated with alkylating agent therapies or with hydroxyurea for sickle cell disease. WHAT IS KNOWN ALREADY: Cryopreservation of spermatogonial stem cells, followed by transplantation into the testis after treatment, is a proposed clinical option for fertility restoration in children. The key clinical consideration behind this approach is a sufficient quantity of healthy cryopreserved spermatogonia. However, since most boys with malignancies start therapy with agents that are not potentially sterilizing, they will have already received some chemotherapy before testicular tissue cryopreservation is considered. STUDY DESIGN, SIZE, DURATION: We examined histological sections of prepubertal testicular tissue to elucidate whether chemotherapy exposure or primary diagnosis affects spermatogonial quantity. Quantity of spermatogonia per transverse tubular cross-section (S/T) was assessed in relation to treatment characteristics and normative reference values in histological sections of paraffin embedded testicular tissue samples collected from 32 consecutive boy patients (aged 6.3 +/- 3.8 [mean +/- SD] years) between 2014 and 2017, as part of the NORDFERTIL study, and in 14 control samples (from boys aged 5.6 +/- 5.0 [mean +/- SD] years) from an internal biobank. PARTICIPANTS/MATERIALS, SETTING, METHODS: Prepubertal boys in Sweden, Finland and Iceland who were facing treatments associated with a very high risk of infertility, were offered the experimental procedure of testicular cryopreservation. Exclusion criteria were testicular volumes > 10 ml and high bleeding or infection risk. There were 18 patients with a diagnosis of malignancy and 14 patients a nonmalignant diagnosis. While 20 patients had the testicular biopsy performed 1-45 days after chemotherapy, 12 patients had not received any chemotherapy. In addition, 14 testicular tissue samples of patients with no reported testicular pathology, obtained from the internal biobank of the Department of Pathology at Karolinska University Hospital, were included as control samples in addition to reference values obtained from a recently published meta-analysis. The quantity of spermatogonia was assessed by both morphological and immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The main finding was a significant reduction in spermatogonial cell counts in boys treated with alkylating agents or with hydroxyurea for sickle cell disease. The mean S/T values in boys exposed to alkylating agents (0.2 +/- 0.3, n = 6) or in boys with sickle cell disease and exposed to hydroxyurea (0.3 +/- 0.6, n = 6) were significantly lower (P = 0.003 and P = 0.008, respectively) than in a group exposed to non-alkylating agents or in biobank control samples (1.7 +/- 1.0, n = 8 and 4.1 +/- 4.6, n = 14, respectively). The mean S/T values of the testicular tissue samples included in the biobank control group and the patient group exposed to nonalkylating agents were within recently published normative reference values. LIMITATIONS, REASONS FOR CAUTION: Normal testicular tissue samples included in this study were obtained from the internal biobank of Karolinska University Hospital. Samples were considered normal and included in the study if no testicular pathology was reported in the analysed samples. However, detailed information regarding previous medical treatments and testicular volumes of patients included in this biobank were not available. WIDER IMPLICATIONS OF THE FINDINGS: This study summarizes, for the first time, spermatogonial quantity in a prepubertal patient cohort just before and after potentially sterilizing treatments. Boys facing cancer and cytotoxic therapies are regarded as the major group who will benefit from novel fertility preservation techniques. There are no previous reports correlating spermatogonial quantity to cumulative exposure to alkylating agents and anthracyclines (non-alkylating agents) and no information about the timing of cytotoxic exposures among this particular patient cohort. For prepubertal boys in whom fertility preservation is indicated, testicular tissue should be obtained before initiation of chemotherapy with alkylating agents, whilst for those with sickle cell disease and treated with hydroxyurea, this approach to fertility preservation may not be feasible. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from The Swedish Childhood Cancer Foundation (PR2016-0124; TJ2016-0093; PR2015-0073, TJ2015-0046) (J.-B.S. and K.J.), the Jane and Dan Olssons Foundation (2016-33) (J.-B.S.), the Finnish Cancer Society (K.J.), the Foundation for Paediatric Research (J.-B.S.), Kronprinsessan Lovisas Forening For Barnasjukvard/Stiftelsen Axel Tielmans Minnesfond, Samariten Foundation (J.-B.S.), the Vare Foundation for Paediatric Cancer Research (K.J.) and the Swedish Research Council (2012-6352) (O.S.). R.T.M. was supported by a Wellcome Trust Fellowship (09822). J.P.A.-L. and M.K. were supported by the ITN Marie Curie program 'Growsperm' (EU-FP7-PEOPLE-2013-ITN 603568). The authors declare no conflicts of interest.
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| 38. |
- Wadensten, T., et al.
(författare)
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A Smartphone app For Self-Management of Urgency and Mixed Urinary Incontinence : a Randomized Controlled Trial
- 2019
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Ingår i: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 38, s. S361-S363
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hypothesis / aims of study: Urgency (UUI) and mixed (MUI) urinary incontinence are common clinical problems. They account for almost half of all cases of urinary incontinence (UI) in women [1], and have a potentially large impact on quality of life. Nonetheless, many women are reluctant to seek treatment, sometimes due to UI being a stigmatized condition. The recommended first-line treatment for UUI and MUI is pelvic floor muscle training (PFMT) and lifestyle advice [2], with bladder training as a valuable complement to the treatment. Previous studies have shown that a smartphone app was an effective form of self-management for women with stress urinary incontinence (SUI), both in terms of treatment efficacy [3] and cost-effectiveness. On-going studies show promising results of the app once it was made freely available for download, and a further study of the user experience of the app found that the app provided an appreciated and satisfactory experience. In this study, we aimed to evaluate whether a new smartphone app for the self-management of UUI and MUI in women was effective, in comparison to app-based information only. Study design, materials and methods: Between April 2017 and March 2018, women were consecutively recruited to this randomized controlled trial (RCT) via a screening questionnaire on the homepage of the research project. The trial has been Clinical Trials registered. The inclusion criteria were as follows: woman (gender self-stated and sex assigned at birth), ≥18 years, UUI or MUI with ≥2 leakages/week and ≥12 months of symptom duration. Pregnant women or women who used another PFMT app or anti-muscarinic drugs were not eligible to participate in the study. In order to identify and redirect cases that were better suited to receive usual care, an algorithm was developed by a team of professionals with both clinical and scientific experience from fields such as urogynecology, general practice, urology and incontinence care. The algorithm included questions on the person’s history of cancer in the pelvic region, diabetes, and neurological symptoms and diseases, as well as questions on certain alarm symptoms (e.g. painful urges, dysuria, haematuria, metrorrhagia, recurring urinary tract infections, bladder-emptying difficulties and pyelonephritis). The presence of any alarm symptom led to the respondent being classified as not eligible for the study and instead recommended to contact their usual medical care provider. Women who passed the screening questionnaire and submitted an email address received information about the study, and were asked to fill in an Informed Consent form, a two-day bladder diary and a baseline questionnaire which included the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF), which provides a validated UI symptom score (range 0 - 21 points) with questions on frequency, amount and overall impact. Respondents were then contacted by telephone for an interview during which the symptom-based diagnosis of UUI or MUI was determined, and questions about alarm symptoms and UI symptoms were asked to ensure that the respondent was truly eligible for the study. Throughout the study, there was no face-to-face contact between the research group and the participants, only communication by email and telephone. The participants were randomized 1:1 to the two groups using sealed opaque envelopes prepared by an independent administrator who generated the randomization plan via the online randomization tool at http://www.randomization.com. Women randomized to the intervention group received access to the Treatment App, a smartphone app built on four themes: PFMT; bladder training; psychological education; and lifestyle information (Figure 1). The PFMT and bladder training parts of the app included 11-step and 7-step training programmes, respectively, in addition to information on pelvic floor anatomy and bladder physiology. The psychological education contained information on psychological topics related to UI, and three optional exercises. The Treatment App also offered an option to set three different times for reminder notifications, as well as an automated feedback function. In addition, the app included individual advice based on information from questionnaires and the bladder diary. The advice was generated via a pre-designed template and offered guidance to the most relevant parts of the app for each user. The control group received access to the Information App, a very limited version of the app, containing only brief information on the different topics and no training programmes or other features. Three months after randomization, the participants were asked to fill in a follow-up questionnaire and another bladder diary. In this abstract we present the results of the analysis of the primary outcome measure, the ICIQ-UI SF, measured at baseline and follow-up. Analyses of secondary outcomes, including incontinence episode frequency, are currently on-going and will be presented at a later date. Sample size calculation: Based on the findings of previous studies, improvements in the ICIQ-UI SF of 2.5 points in the Treatment App group and 0.9 points in the Information App group were assumed. To detect this difference with 80% power, 2-side test and a significance of 0.05, a sample size of 49 women was needed in each group. To allow for a dropout rate of 20%, each group needed to include 60 participants, and we therefore aimed to recruit 120 women in total. Statistical analysis: We performed Intention to Treat analysis by using a linear mixed model to estimate the difference between the groups in the ICIQ-UI SF at follow-up. A paired t-test was used for within-groups comparisons of the mean ICIQ-UI SF scores at baseline and follow-up. Results: 123 women were randomized to receive the Treatment App (n=60) or the Information App (n=63). The groups did not differ significantly in baseline measures (e.g. age, BMI, education level) nor in the mean ICIQ-UI SF scores. The mean age was 58.30 (SD 9.55) years and the mean BMI was 26.17 (SD 4.47) kg/m². The symptom-based diagnosis of MUI was more common (n=88) than that of UUI (n=35), and this distribution was equal across the two groups. The majority of women had moderate (n=73), severe (n=43) or very severe (n=4) incontinence, based on the ICIQ-UI SF scores. Two women, both in the Treatment App group, were lost to follow-up. Participants in both groups improved with regard to the mean ICIQ-UI SF score at follow-up (Treatment App group -4.67 (-5.65 to -3.69, 95% CI, p <0.001) and Information App group -1.64 (-2.31 to -0.96, 95% CI, p <0.001)). The improvement was significantly larger in the Treatment App group (p = 0.001) (Figure 2). Interpretation of results: Self-management of UUI or MUI using a mobile app led to highly significant improvements in incontinence symptoms with a significant difference compared to a control group. Thus the findings in this study show that the use of an app that includes treatment with PFMT, bladder training, psychological education and lifestyle advice was effective for women with UUI or MUI. Concluding message: Previous studies have shown that a smartphone app is an effective, easily accessible and appreciated first-line treatment option for women with SUI. The findings in the current study indicate that, provided that certain alarm symptoms or risk factors are not present, a smartphone app may be a useful addition to first-line treatment options for women with UUI or MUI who are interested in eHealth self-management.
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| 39. |
- Wadensten, T., et al.
(författare)
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Development and Use of an algorithm For Identifying Women With Urgency Or Mixed Urinary Incontinence Suitable For E-Health Treatment
- 2018
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Ingår i: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 37:S5, s. S72-S74
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hypothesis / aims of study One of the challenges in health care today is providing affordable care for those in need, and identifying a reasonable level of care for care-seekers. Many women with urinary incontinence might be reluctant to seek care for various reasons. Recent reviews propose lifestyle advice, pelvic floor muscle training (PFMT) and, in some cases, behavioural changes as first-line treatment for urgency (UUI) and mixed (MUI) urinary incontinence in women (1). Treatment via a smartphone app containing lifestyle advice and PFMT has been shown to be effective for, and appreciated by, women with stress urinary incontinence (SUI) (2). A smartphone app could also be a way to make treatment available to more women with UUI and MUI. The traditional recommendation of an extensive examination, on the other hand, has been described as a potential barrier to offering diagnosis and treatment to women with those conditions (3). The results of one study support the use of an algorithm combined with dipstick urinalysis for diagnosing women with urgency-predominant incontinence suitable for pharmacological treatment (3). The first aim of this study was to develop and use an extensive algorithm intended for women with UUI or MUI, to identify those with symptoms that would motivate a physical examination within usual care. The algorithm was intended for women interested in treatment via a smartphone app. To our knowledge, this is the first attempt to identify this target group in this way. The second aim was to estimate the proportion of the people interested that might be suitable for smartphone app treatment, based on the algorithm. Study design, materials and methods This report is part of a larger RCT study aimed at evaluating smartphone app treatment for women with UUI and MUI. As part of the preparations for the RCT study, a team of experienced general practitioners (GP), a Specialist Continence nurse, a urologist and a urogynecologist together developed an algorithm with questions regarding symptoms for which an examination would be judged important within usual care. The team included both researchers and clinicians. The RCT study was approved by a regional ethics board and registered in the Clinical Trials register. Recruitment was carried out via conventional methods (press releases, information to midwives, advertisements in media) as well as via Facebook advertisements. The advertisements directed interested people to the homepage of the research project, where additional information about the study and a link to a web-based screening questionnaire was provided. The screening questionnaire included questions on inclusion criteria and some background information, before presenting the questions related to the algorithm (figure 1). People who did not meet the inclusion criteria (woman, ≥18 years, ≥2 leakages/week, ≥12 month symptom duration, urgency or mixed urinary incontinence), or those who were pregnant or used another PFMT app or antimuscarinic drugs could not proceed further with the questionnaire. If a respondent gave a positive answer on any symptom from the algorithm, she was excluded and recommended to contact her normal health care provider for further assessment. Any respondent who passed the screening questionnaire in full was asked to provide her email address and thereafter received an informed consent form and a bladder diary to complete. Once these were returned, the respondent received another questionnaire and was thereafter contacted via telephone by a Specialist Continence nurse or GP. The purpose of this telephone interview was to give the diagnosis and to verify the answers to the algorithm questions. Results Following a year of meetings and discussions in the research team, a final algorithm was decided via consensus, based on previous literature on the subject as well as clinical experience. The symptoms and conditions included in the algorithm were painful urges; pyelonephritis; three or more urinary tract infections (UTI) in the last 12 months; dysuria (burning upon urination); visible haematuria; non-investigated bladder emptying difficulties; metrorrhagia; cancer in the pelvic area, bladder or bowels; decreased mobility or sensibility in the legs or pelvic area; previous stroke; neurological disease and diabetes (figure 1). The algorithm was used in the web-based screening questionnaire as described above. Out of 765 women with UUI or MUI with ≥2 leakages/week and ≥12 month duration, 523 were identified as eligible to be offered e-health treatment after exclusions. The 238 women who were excluded for symptoms in the algorithm were automatically advised to contact their normal health care provider for further assessment (figure 1). A further four women left the questionnaire before completion of all questions and were therefore not included. Of the 523 eligible women, 142 women chose to complete all the successive steps and were interviewed via telephone. In the interviews, nine women presented algorithm-related symptoms. In five cases, those symptoms were neurological (i.e. a diffuse sense of numbness in regions of the lower limbs), one woman, aged 51, also had painful urges. Another woman, aged 45, had painful urges as her only symptom. One woman, aged 64, reported having recurring visible haematuria and dysuria three months prior to the interview and had earlier been examined with cystoscopy. Another woman, aged 70, had current dysuria and was being treated for a UTI. One woman had metrorrhagia and was being investigated in usual care. All of these cases were discussed with an experienced GP and/or urogynecologist and were excluded and redirected to their normal health care provider as an extra precaution. Interpretation of results It is possible to develop an algorithm as described above via consensus within a team of experienced clinicians and researchers. Approximately two-thirds of women with UUI or MUI with ≥2 leakages/week and ≥12 month duration who are interested in an e-health intervention might be suited to this kind of treatment. An algorithm such as the one described here might be one way to identify suitable women and redirect those who should contact usual care for an assessment of specific symptoms. However, we do not know whether the respondents who were redirected to usual care had already been examined for these symptoms and/or had relevant underlying pathology. Nonetheless, our view was that the occurrence of any of the other symptoms should motivate precaution, and was a reason for the patient to contact their normal health care provider. Concluding message An algorithm such as the one described here might both help the patient (or health care personnel) to choose a reasonable level of care, and possibly also identify women who had not previously considered seeking care for certain symptoms. In the long term an algorithm might help lessen the burden of ordinary health care providers by directing interested and eligible women to suitable e-health options. We are currently evaluating the efficacy of an app treatment for women with UUI/MUI, both in the short and long term. The results will include information from registers regarding diagnosis and care for relevant conditions.
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- Zhao, Lin-Ling, 1957, et al.
(författare)
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A genome-wide imaging-based screening to identify genes involved in synphilin-1 inclusion formation in Saccharomyces cerevisiae
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Synphilin-1 is a major component of Parkinson's disease (PD) inclusion bodies implicated in PD pathogenesis. However, the machinery controlling synphilin-1 inclusion formation remains unclear. Here, we investigated synphilin-1 inclusion formation using a systematic genome-wide, high-content imaging based screening approach (HCI) in the yeast Saccharomyces cerevisiae. By combining with a secondary screening for mutants showing significant changes on fluorescence signal intensity, we filtered out hits that significantly decreased the expression level of synphilin-1. We found 133 yeast genes that didn't affect synphilin-1 expression but that were required for the formation of synphilin-1 inclusions. Functional enrichment and physical interaction network analysis revealed these genes to encode for functions involved in cytoskeleton organization, histone modification, sister chromatid segregation, glycolipid biosynthetic process, DNA repair and replication. All hits were confirmed by conventional microscopy. Complementation assays were performed with a selected group of mutants, results indicated that the observed phenotypic changes in synphilin-1 inclusion formation were directly caused by the loss of corresponding genes of the deletion mutants. Further growth assays of these mutants showed a significant synthetic sick effect upon synphilin-1 expression, which supports the hypothesis that matured inclusions represent an end stage of several events meant to protect cells against the synphilin-1 cytotoxicity.
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