| 1. |
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| 2. |
- Strakova, A., et al.
(författare)
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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.
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| 3. |
- Coccolini, F., et al.
(författare)
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Aortic balloon occlusion (REBOA) in pelvic ring injuries: preliminary results of the ABO Trauma Registry
- 2020
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Ingår i: Updates in Surgery. - : Springer Science and Business Media LLC. - 2038-131X .- 2038-3312. ; 2020:72, s. 527-536
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Tidskriftsartikel (refereegranskat)abstract
- EndoVascular and Hybrid Trauma Management (EVTM) has been recently introduced in the treatment of severe pelvic ring injuries. This multimodal method of hemorrhage management counts on several strategies such as the REBOA (resuscitative endovascular balloon occlusion of the aorta). Few data exist on the use of REBOA in patients with a severely injured pelvic ring. The ABO (aortic balloon occlusion) Trauma Registry is designed to capture data for all trauma patients in hemorrhagic shock where management includes REBOA placement. Among all patients included in the ABO registry, 72 patients presented with severe pelvic injuries and were the population under exam. 66.7% were male. Mean and median ISS were respectively 43 and 41 (SD ± 13). Isolated pelvic injuries were observed in 12 patients (16.7%). Blunt trauma occurred in 68 patients (94.4%), penetrating in 2 (2.8%) and combined in 2 (2.8%). Type of injury: fall from height in 15 patients (23.1%), traffic accident in 49 patients (75.4%), and unspecified impact in 1 patient (1.5%). Femoral access was gained pre-hospital in 1 patient, in emergency room in 43, in operating room in 12 and in angio-suite in 16. REBOA was positioned in zone 1 in 59 patients (81,9%), in zone 2 in 1 (1,4%) and in zone 3 in 12 (16,7%). Aortic occlusion was partial/periodical in 35 patients (48,6%) and total occlusion in 37 patients (51,4%). REBOA associated morbidity rate: 11.1%. Overall mortality rate was 54.2% and early mortality rate (≤ 24h) was 44.4%. In the univariate analysis, factors related to early mortality (≤ 24h) are lower pH values (p = 0.03), higher base deficit (p = 0.021), longer INR (p = 0.012), minor increase in systolic blood pressure after the REBOA inflation (p = 0.03) and total aortic occlusion (p = 0.008). None of these values resulted significant in the multivariate analysis. In severe hemodynamically unstable pelvic trauma management, REBOA is a viable option when utilized in experienced centers as a bridge to other treatments; its use might be, however, accompanied with severe-to-lethal complications. © 2020, Italian Society of Surgery (SIC).
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| 4. |
- Hilbert-Carius, Peter, et al.
(författare)
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Pre-hospital CPR and early REBOA in trauma patients-results from the ABOTrauma Registry
- 2020
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Ingår i: World Journal of Emergency Surgery. - : Springer Science and Business Media LLC. - 1749-7922. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Author(s). Background: Severely injured trauma patients suffering from traumatic cardiac arrest (TCA) and requiring cardiopulmonary resuscitation (CPR) rarely survive. The role of resuscitative endovascular balloon occlusion of the aorta (REBOA) performed early after hospital admission in patients with TCA is not well-defined. As the use of REBOA increases, there is great interest in knowing if there is a survival benefit related to the early use of REBOA after TCA. Using data from the ABOTrauma Registry, we aimed to study the role of REBOA used early after hospital admission in trauma patients who required pre-hospital CPR. Methods: Retrospective and prospective data on the use of REBOA were collected from the ABOTrauma Registry from 11 centers in seven countries globally between 2014 and 2019. In all patients with pre-hospital TCA, the predicted probability of survival, calculated with the Revised Injury Severity Classification II (RISC II), was compared with the observed survival rate. Results: Of 213 patients in the ABOTrauma Registry, 26 patients (12.2%) who had received pre-hospital CPR were identified. The median (range) Injury Severity Score (ISS) was 45.5 (25-75). Fourteen patients (54%) had been admitted to the hospital with ongoing CPR. Nine patients (35%) died within the first 24 h, while seventeen patients (65%) survived post 24 h. The survival rate to hospital discharge was 27% (n = 7). The predicted mortality using the RISC II was 0.977 (25 out of 26). The observed mortality (19 out of 26) was significantly lower than the predicted mortality (p = 0.049). Patients not responding to REBOA were more likely to die. Only one (10%) out of 10 non-responders survived. The survival rate in the 16 patients responding to REBOA was 37.5% (n = 6). REBOA with a median (range) duration of 45 (8-70) minutes significantly increases blood pressure from the median (range) 56.5 (0-147) to 90 (0-200) mmHg. Conclusions: Mortality in patients suffering from TCA and receiving REBOA early after hospital admission is significantly lower than predicted by the RISC II. REBOA may improve survival after TCA. The use of REBOA in these patients should be further investigated.
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| 5. |
- Hilbert-Carius, Peter, et al.
(författare)
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Successfully REBOA performance: does medical specialty matter? International data from the ABOTrauma Registry
- 2020
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Ingår i: World Journal of Emergency Surgery. - : Springer Science and Business Media LLC. - 1749-7922. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2020, The Author(s). Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive procedure being increasingly utilized to prevent patients with non-compressible torso hemorrhage from exsanguination. The increased use of REBOA is giving rise to discussion about “Who is and who should be performing it?” Methods: Data from the international ABO (aortic balloon occlusion) Trauma Registry from between November 2014 and April 2020 were analyzed concerning the question: By who, how, and where is REBOA being performed? The registry collects retrospective and prospective data concerning use of REBOA in trauma patients. Results: During the study period, 259 patients had been recorded in the registry, 72.5% (n = 188) were males with a median (range) age of 46 (10-96) years. REBOA was performed in the ER in 50.5%, in the OR in 41.5%, and in the angiography suite in 8% of patients. In 54% of the patients REBOA was performed by surgeons (trauma surgeons 28%, vascular surgeons 22%, general surgeons 4%) and in 46% of the patients by non-surgeons (emergency physicians 31%, radiologists 9.5%, anesthetists 5.5%). Common femoral artery (CFA) access was achieved by use of external anatomic landmarks and palpation alone in 119 patients (51%), by cutdown in 57 patients (24%), using ultrasound in 49 patients (21%), and by fluoroscopy in 9 patients (4%). Significant differences between surgeons and non-surgeons were found regarding patient’s age, injury severity, access methods, place where REBOA was performed, location patients were taken to from the emergency room, and mortality. Conclusion: A substantial number of both surgical and non-surgical medical disciplines are successfully performing REBOA to an almost equal extent. Surgical cutdown is used less frequently as access to the CFA compared with reports in older literature and puncture by use of external anatomic landmarks and palpation alone is used with a high rate of success. Instead of discussing “Who should be performing REBOA?” future research should focus on “Which patient benefits most from REBOA?”
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| 9. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 13. |
- Bergquist, Jonas, et al.
(författare)
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Capillary electrophoresis with laser-induced fluorescence detection : a sensitive method for monitoring extracellular concentrations of amino acids in the periaqueductal grey matter.
- 1996
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270 .- 1872-678X. ; 65:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The use of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) for the analysis of microdialysate samples from the periaqueductal grey matter (PAG) of freely moving rats is described. By employing 3-(4-carboxybenzoyl)-2-quinoline-carboxaldehyde (CBQCA) as a derivatization agent, we simultaneously monitored the concentrations of 8 amino acids (arginine, glutamine, valine, gamma-amino-n-butyric acid (GABA), alanine, glycine, glutamate, and aspartate), with nanomolar and subnanomolar detection limits. Two of the amino acids (GABA and glutamate) were analysed in parallel by conventional high-performance liquid chromatography (HPLC) in order to directly compare the two analytical methods. Other CE methods for analysis of microdialysate have been previously described, and this improved method offers greater sensitivity, ease of use, and the possibility to monitor several amino acids simultaneously. By using this technique together with an optimised form of microdialysis technique, the tiny sample consumption and the improved detection limits permit the detection of fast and transient transmitter changes.
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| 22. |
- Sundberg, T., et al.
(författare)
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Opposite Drug Prescription and Cost Trajectories following Integrative and Conventional Care for Pain - A Case-Control Study
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Pharmacotherapy may have a limited role in long-term pain management. Comparative trajectories of drug prescriptions and costs, two quality-of-care indicators for pain conditions, are largely unknown subsequent to conventional or integrative care (IC) management. The objectives of this study were to compare prescribed defined daily doses (DDD) and cost of first line drugs for pain patients referred to conventional or anthroposophic IC in Stockholm County, Sweden. Methods: In this retrospective high quality registry case-control study, IC and conventional care patients were identified through inpatient care registries and matched on pain diagnosis (ICD-10: M79), age, gender and socio-demographics. National drug registry data was used to investigate changes in DDD and costs from 90/180 days before, to 90/180 days after, index visits to IC and conventional care. The primary selected drug category was analgesics, complemented by musculo-skeletal system drugs (e.g. anti-inflammatories, muscle relaxants) and psycholeptics (e.g. hypnotics, sedatives). Results: After index care visits, conventional care pain patients (n = 1050) compared to IC patients (n = 213), were prescribed significantly more analgesics. The average (95% CI) group difference was 15.2 (6.0 to 24.3), p = 0.001, DDD/patient after 90 days; and 21.5 (7.4 to 35.6), p = 0.003, DDD/patient after 180 days. The cost of the prescribed and sold analgesics was significantly higher for conventional care after 90 days: euro/patient 10.7 (1.3 to 20.0), p = 0.025. Changes in drug prescription and costs for the other drug categories were not significantly different between groups. Conclusions: Drug prescriptions and costs of analgesics increased following conventional care and decreased following IC, indicating potentially fewer adverse drug events and beneficial societal cost savings with IC.
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| 23. |
- Sundberg, T, et al.
(författare)
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The Art of Integrating in Practical Care
- 2010
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Ingår i: FORSCHENDE KOMPLEMENTARMEDIZIN. - 1021-7096. ; 17:1, s. 35-36
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 24. |
- Sundberg, T., et al.
(författare)
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Usage and cost of first-line drugs for patients referred to inpatient anthroposophic integrative care or inpatient conventional care for stress-related mental disorders-a register based study
- 2015
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Ingår i: Bmc Complementary and Alternative Medicine. - : Springer Science and Business Media LLC. - 1472-6882. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Stress-related mental disorders (SRMD) are common and costly. Rehabilitation strategies, including pharmacotherapy, may be complicated to evaluate. Previous research has indicated increased quality of life and self-rated health for SRMD patients that receive a combination of conventional and complementary therapies, i.e. integrative care. The aim of this retrospective registry study was to explore and contrast the prescription of first-line drugs for SRMD patients referred to hospital inpatient anthroposophic integrative care (AIC) or inpatient conventional care (CC). Methods: SRMD patients that had received AIC or CC were identified through high-quality inpatient registry data from Stockholm County Council and matched by available background characteristics including diagnosis (ICD-10: F43), age, gender and socio-economics. General disease load was estimated by analysis of ICD-10 chapter data. The Swedish Prescribed Drug Register was then used to investigate purchased defined daily doses (DDD) and cost of drugs from 90-days before/after, and 180-days before/after, the first visits (index) to AIC and CC respectively. First-line drug categories were Anatomical Therapeutic Chemical classification codes N05A (antipsychotics), N05B (anxiolytics), N05C (hypnotics and sedatives) and N06A (antidepressants). Results: There were no statistically significant differences between the AIC (n = 161) and the CC (n = 1571) cohorts in terms of background characteristics and the overall disease loads were similar between the groups the preceding year. At baseline, the prescription of first-line anxiolytics and antidepressants were not statistically different between groups whereas the prescription of antipsychotics and hypnotics/sedatives were lower for the AIC cohort. The overall change in drug prescriptions and costs during the investigated periods, both for the 90-days before/after and for the 180-days before/after the index visit, showed a general decrease within the AIC cohort with significantly less prescribed anxiolytics and hypnotics/sedatives. During the same time periods there was a general increase in prescriptions and costs of first-line drugs within the CC cohort. The overall disease loads were generally stable within both cohorts over time, except that the CC cohort had increased visits registered with an ICD-10 F-chapter diagnosis the year after index. Conclusions: The results suggests that there may be different drug utilization patterns for SRMD patients referred to AIC or CC. Different management strategies between AIC and CC providers, different SRMD disease severities and different preferences of patients referred to AIC and CC are hypothetical differentiating factors that may influence drug outcomes over time. Additional studies including prospective and randomized clinical trials are warranted to determine if there is a causal link between inpatient AIC and reduced drug utilization.
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| 25. |
- Sundberg, T, et al.
(författare)
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Using hospital data and routines to estimate costs and effects of integrative care programmes for chronic pain and stress disorders--a feasibility study
- 2014
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Ingår i: Forschende Komplementarmedizin (2006). - : S. Karger AG. - 1661-4127. ; 21:3, s. 164-170
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background: </i></b>Evidence of cost and effects for comprehensive hospital-based integrative care (IC) is scarce. The aim of this study was to explore the feasibility of using local hospital data and routines to estimate costs and effects of anthroposophic IC programmes for chronic pain and stress disorders in Sweden. <b><i>Methods: </i></b>Retrospective analysis of one IC hospital's local administrative registry data. Main outcomes embraced patient demographics, programme duration and costs, patients' health status (EQ-5D index, 0-1) and self-rated health (EQ-5D VAS, 0-100), from hospital admittance to discharge. The use of postal questionnares for collecting follow-up data after hospital discharge was assessed. <b><i>Results: </i></b>The IC pain programme had 461 records, all with complete data on costs and duration: average programme cost, EUR 5,925 (95% CI 5,780-6,070), and duration, 17.8 (SD 4.7) days. The IC stress programme had 263 records, all with complete cost and duration data: programme cost, EUR 5,494 (95%CI 5,318-5,671); duration 18.0 (SD 4.7) days. From admittance to discharge, health status improved by 0.23 (95% CI 0.19-0.27) in the pain, and by 0.16 (95% CI 0.12-0.20) in the stress programme. Improvements in self-rated health were 20 (95% CI 18-22), and 21 (95% CI 18-23), respectively. There was a general decrease in questionnaire response rate after hospital discharge, whereby 27-32% of respondents had completed data after 9 months. <b><i>Conclusions: </i></b>It was feasible to use hospital registry data to estimate costs and show positive effects of anthroposophic IC programmes for pain and stress disorders in Sweden. Clinical implications and the need for long-term follow-up are discussed.
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| 26. |
- Abrams, AL, et al.
(författare)
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Legislative landscape for traditional health practitioners in Southern African development community countries: a scoping review
- 2020
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:1, s. e029958-
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Tidskriftsartikel (refereegranskat)abstract
- Globally, contemporary legislation surrounding traditional health practitioners (THPs) is limited. This is also true for the member states of the Southern African Development Community (SADC). The main aim of this study is to map and review THP-related legislation among SADC countries. In order to limit the scope of the review, the emphasis is on defining THPs in terms of legal documents.MethodsThis scoping review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews methods. Two independent reviewers reviewed applicable legal definitions of THPs by searching the Southern African Legal Information Institute (SAFLII) database in April 2018 for legislation and bills. To identify additional legislation applicable in countries not listed on SAFLII and/or further relevant SADC legislation, the search engines, Google and PubMed, were used in August 2018 and results were reviewed by two independent reviewers. Full texts of available policy and legal documents were screened to identify policies and legislation relating to the regulation of THPs. Legislation was deemed relevant if it was a draft of or promulgated legislation relating to THPs.ResultsFour of 14 Southern African countries have legislation relating to THPs. Three countries, namely South Africa, Namibia and Zimbabwe, have acknowledged the roles and importance of THPs in healthcare delivery by creating a council to register and formalise practices, although they have not operationalised nor registered and defined THPs. In contrast, Tanzania has established a definition couched in terms that acknowledge the context-specific and situational knowledge of THPs, while also outlining methods and the importance of local recognition. Tanzanian legislation; thus, provides a definition of THP that specifically operationalises THPs, whereas legislation in South Africa, Namibia and Zimbabwe allocates the power to a council to decide or recognise who a THP is; this council can prescribe procedures to be followed for the registration of a THP.ConclusionsThis review highlights the differences and similarities between the various policies and legislation pertaining to THPs in SADC countries. Legislation regarding THPs is available in four of the 14 SADC countries. While South Africa, Tanzania, Namibia and Zimbabwe have legislation that provides guidance as to THP recognition, registration and practices, THPs continue to be loosely defined in most of these countries. Not having an exact definition for THPs may hamper the promotion and inclusion of THPs in national health systems, but it may also be something that is unavoidable given the tensions between lived practices and rigid legalistic frameworks.
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| 27. |
- Airosa, F, et al.
(författare)
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Tactile Massage as Part of the Caring Act: A Qualitative Study in Short-Term Emergency Wards
- 2016
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Ingår i: Journal of holistic nursing : official journal of the American Holistic Nurses' Association. - : SAGE Publications. - 1552-5724. ; 34:1, s. 13-23
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Tidskriftsartikel (refereegranskat)abstract
- Aims and Objectives: The aim of this study was to illuminate the nursing staff’s lived experiences and meaning in giving tactile massage (TM) while caring for patients in short-term emergency ward. Method: Data were collected through individual qualitative interviews with six nurses and eight assistant nurses working with TM in short-term emergency wards in two hospitals in Sweden. The narratives were analyzed using a phenomenological hermeneutical method. Findings: Nurses experienced providing TM to patients as a present awareness in connection with compassion for the patient. TM provided the nurses with a tool to ease patient suffering and pain. Three dimensions were found where touch became a tool of doing, was an aware presence as a mindful being, and was embodied in a human-to-human connection with a changed caregiver. Conclusion: Given the current high-tech health care system with overcrowded units and a shortage of nursing staff, TM could be included as a caring tool to improve the caring in caregiving, allowing nurses to act in aware presence by touch to encourage health and well-being for both the patient and themselves.
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| 28. |
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| 32. |
- Bergbrede, T., et al.
(författare)
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An Adaptable High-Throughput Technology Enabling the Identification of Specific Transcription Modulators
- 2017
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Ingår i: Slas Discovery. - : Elsevier BV. - 2472-5552. ; 22:4, s. 378-386
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria harbor the oxidative phosphorylation (OXPHOS) system, which under aerobic conditions produces the bulk of cellular adenosine triphosphate (ATP). The mitochondrial genome encodes key components of the OXPHOS system, and it is transcribed by the mitochondrial RNA polymerase, POLRMT. The levels of mitochondrial transcription correlate with the respiratory activity of the cell. Therefore, compounds that can increase or decrease mitochondrial gene transcription may be useful for fine-tuning metabolism and could be used to treat metabolic diseases or certain forms of cancer. We here report the establishment of a novel high-throughput assay technology that has allowed us to screen a library of 430,000 diverse compounds for effects on mitochondrial transcription in vitro. Following secondary screens facilitated by the same assay principle, we identified 55 compounds that efficiently and selectively inhibit mitochondrial transcription and that are active also in cell culture. Our method is easily adaptable to other RNA or DNA polymerases and varying spectroscopic detection technologies.
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| 33. |
- Berggård, T, et al.
(författare)
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Prothrombin, albumin and immunoglobulin A form covalent complexes with alpha1-microglobulin in human plasma
- 1997
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 245:3, s. 83-676
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Tidskriftsartikel (refereegranskat)abstract
- Molecules containing the 33-kDa plasma protein alpha1-microglobulin were isolated from human plasma by anti-(alpha1-microglobulin) affinity chromatography. Five major bands could be seen after electrophoretic separation of the alpha1-microglobulin-containing proteins under native conditions. Immunoblotting demonstrated alpha1-microglobulin in all five bands. Two of these have been described previously: free alpha1-microglobulin and alpha1-microglobulin complexed with IgA (IgA x alpha1-microglobulin). The other three bands were identified as prothrombin alpha1-microglobulin, albumin x alpha1-microglobulin and dimeric alpha1-microglobulin. Prothrombin x alpha1-microglobulin were 1:2 and 1:1 complexes which carried approximately 1% of total alpha1-microglobulin, had molecular masses of about 145 kDa and 110 kDa upon SDS/PAGE and dissociated completely to free alpha1-microglobulin and prothrombin (72 kDa) when reducing agents were added, suggesting that the complexes were stabilized by disulfide bonds. The alpha1-microglobulin molecules did not inhibit cleavage of prothrombin by factor Xa and were bound to the peptides which were released upon activation of prothrombin. Albumin x alpha1-microglobulin, corresponding to 7% of total plasma alpha1-microglobulin, was a mixture between 1:1 and 1:2 complexes, with masses upon SDS/PAGE of approximately 100 kDa and 135 kDa, respectively. Both these complexes dissociated only partially to free alpha1-microglobulin and albumin when reducing agents were added. The albumin x alpha1-microglobulin complexes carried a yellow-brown chromophore similar to free alpha1-microglobulin. The complex-binding to alpha1-microglobulin did not block the fatty-acid-binding ability of albumin. The plasma concentrations of albumin x alpha1-microglobulin and prothrombin x alpha1-microglobulin were estimated to 5.2 mg/l and 1.1 mg/l, respectively.
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| 34. |
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| 35. |
- Bonekamp, N. A., et al.
(författare)
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Small-molecule inhibitors of human mitochondrial DNA transcription
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588, s. 712-716
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Tidskriftsartikel (refereegranskat)abstract
- Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system(1-6). The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.
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| 36. |
- Bratic, A., et al.
(författare)
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Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Replication errors are the main cause of mitochondrial DNA (mtDNA) mutations and a compelling approach to decrease mutation levels would therefore be to increase the fidelity of the catalytic subunit (POLγA) of the mtDNA polymerase. Here we genomically engineer the tamas locus, encoding fly POLγA, and introduce alleles expressing exonuclease- (exo-) and polymerase-deficient (pol-) POLγA versions. The exo- mutant leads to accumulation of point mutations and linear deletions of mtDNA, whereas pol- mutants cause mtDNA depletion. The mutant tamas alleles are developmentally lethal but can complement each other in trans resulting in viable flies with clonally expanded mtDNA mutations. Reconstitution of human mtDNA replication in vitro confirms that replication is a highly dynamic process where POLγA goes on and off the template to allow complementation during proofreading and elongation. The created fly models are valuable tools to study germ line transmission of mtDNA and the pathophysiology of POLγA mutation disease. © 2015 Macmillan Publishers Limited. All rights reserved.
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| 38. |
- Brunes, A., et al.
(författare)
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Use and underuse of mobility aids in individuals with visual impairment: a cross-sectional study of a Norwegian sample
- 2022
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Ingår i: Disability and Rehabilitation: Assistive Technology. - : Informa UK Limited. - 1748-3107 .- 1748-3115.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the use and underuse of mobility aids in individuals with visual impairment. Methods: A telephone survey including a probability sample of 736 adults who were members of the Norwegian Association of the Blind and Sighted (response rate: 61%). The interviews took place between January and May 2017, collecting information about access, use, underuse and training in five types of mobility aids (white cane, guide dog, GPS, door-to-door transport and sighted guide). For each mobility aid, we obtained data for underuse defined as non-use despite expecting benefits of use in terms of increased mobility or safety. Participants also answered questions about loneliness (Three-Item Loneliness Scale) and life satisfaction (Cantril's Ladder of Life Satisfaction). Results: Of the participants, 69% reported using at least one type of mobility aid. Use of specific aids ranged from 12% for the GPS to 52% for door-to-door transport. Estimates of underuse ranged between 14% for door-to-door transport and 28% for GPS. Underuse was not related to lack of resources, as many non-users expecting benefits had access to mobility aids and had undergone training in its use. For example, 81% of non-users of the white cane had access to a cane. In post hoc analyses, non-users who expected benefits from use had lower life satisfaction compared with users. Conclusions: Many individuals with visual impairment do not use mobility aids. Strategies that help visually impaired individuals overcome barriers to the use of mobility aids may improve their sense of safety, mobility and quality of life.
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- Chuc, NTK, et al.
(författare)
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Management of childhood acute respiratory infections at private pharmacies in Vietnam
- 2001
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Ingår i: The Annals of pharmacotherapy. - : SAGE Publications. - 1060-0280 .- 1542-6270. ; 35:10, s. 1283-1288
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the knowledge and practice among private pharmacy staff in Hanoi regarding case management of mild acute respiratory infection (ARI) in children. METHODS: Sixty private pharmacies in Hanoi were randomly selected. Knowledge was assessed through interviews with pharmacy staff using a questionnaire; practice was assessed through the Simulated Client Method. RESULTS: In the questionnaire, 20% of the pharmacy staff stated that they would dispense antibiotics. In practice, 83% of the pharmacies dispensed antibiotics. Only 36% of the cases were handled according to guidelines. In the questionnaire, 81% of interviewees stated that antibiotics are not effective in short therapeutic courses. In practice, 48% of the antibiotics were dispensed in courses less than five days. Traditional herbal medicines were dispensed in 41% of the encounters. In the questionnaire, 53% of the pharmacy staff stated that they would ask the patient about difficulty of breathing. In practice, questions related to difficulty of breathing were asked in less than 10% of the encounters. CONCLUSIONS: Dispensing of antibiotics for mild ARI was common practice among private pharmacies, and there was a significant difference between knowledge and practice. Interventions are needed to improve pharmacy practice in Hanoi.
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- Del Dotto, V., et al.
(författare)
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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
- 2020
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:1, s. 108-125
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Tidskriftsartikel (refereegranskat)abstract
- Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.
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- Dzhigaev, D., et al.
(författare)
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Bragg coherent x-ray diffractive imaging of a single indium phosphide nanowire
- 2016
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Ingår i: Journal of Optics. - : IOP Publishing. - 2040-8978 .- 2040-8986. ; 18:6
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Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional (3D) Bragg coherent x-ray diffractive imaging (CXDI) with a nanofocused beam was applied to quantitatively map the internal strain field of a single indium phosphide nanowire. The quantitative values of the strain were obtained by pre-characterization of the beam profile with transmission ptychography on a test sample. Our measurements revealed the 3D strain distribution in a region of 150 nm below the catalyst Au particle. We observed a slight gradient of the strain in the range of 0.6% along the [111] growth direction of the nanowire. We also determined the spatial resolution in our measurements to be about 10 nm in the direction perpendicular to the facets of the nanowire. The CXDI measurements were compared with the finite element method simulations and show a good agreement with our experimental results. The proposed approach can become an effective tool for in operando studies of the nanowires.
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| 47. |
- Erdinc, Direnis, et al.
(författare)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
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Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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