| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Sjöquist, Emma S., et al.
(författare)
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Physical Activity Coaching of Patients with Rheumatoid Arthritis in Everyday Practice : A Long-term Follow-up
- 2011
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Ingår i: Musculoskeletal Care. - Chichester : John Wiley & Sons. - 1478-2189 .- 1557-0681. ; 9:2, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the long-term effects on perceived general health, disease activity, pain, activity limitation and cognitive behavioural factors of a one-year coaching programme performed in ordinary physical therapy practice to promote the adoption of health-enhancing physical activity in patients with early rheumatoid arthritis (RA).METHODS: A total of 228 patients with early RA, from 10 rheumatology clinics in Sweden, were randomly assigned to an intervention group (IG; n = 94) or a control group (CG; n = 134). The IG was coached by physical therapists during the first year to adopt health-enhancing levels of physical activity (30 minutes/day, moderately intensive, ≥ 4 days/week). No coaching was given during the subsequent year between post-intervention and follow-up. Follow-up assessment consisted of a postal questionnaire on physical activity and of visual analogue scales for ratings of general health perception and pain. The Health Assessment Questionnaire Disability Index (HAQ) and the Disease Activity Score in 28 joints (DAS 28) were collected at regular medical check-ups.RESULTS: Sixty-five (69%) participants in the IG and 92 (69%) in the CG completed the entire study period by filling in the follow-up questionnaire on physical activity two years after baseline. The intervention seemed to lack any significant influence on long-term outcome. However, different patterns of change in physical activity behaviour were observed in the two groups.CONCLUSIONS: No long-term improvement in perceived general health or other outcomes were found in the follow-up. This may partly be because the intervention lacked several important behavioural elements for physical activity maintenance. Copyright © 2011 John Wiley & Sons, Ltd.
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| 3. |
- Andersson, Irene, 1978, et al.
(författare)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 4. |
- Björkelund, Cecilia, 1948, et al.
(författare)
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Clinical effectiveness of care managers in collaborative care for patients with depression in Swedish primary health care: a pragmatic cluster randomized controlled trial
- 2018
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Ingår i: Bmc Family Practice. - : Springer Science and Business Media LLC. - 1471-2296. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression is one of the leading causes of disability and affects 10-15% of the population. The majority of people with depressive symptoms seek care and are treated in primary care. Evidence internationally for high quality care supports collaborative care with a care manager. Our aim was to study clinical effectiveness of a care manager intervention in management of primary care patients with depression in Sweden. Methods: In a pragmatic cluster randomized controlled trial 23 primary care centers (PCCs), urban and rural, included patients aged >= 18 years with a new (< 1 month) depression diagnosis. Intervention consisted of Care management including continuous contact between care manager and patient, a structured management plan, and behavioral activation, altogether around 6-7 contacts over 12 weeks. Control condition was care as usual (CAU). Outcome measures: Depression symptoms (measured by Mongomery-Asberg depression score-self (MADRS-S) and BDI-II), quality of life (QoL) (EQ-5D), return to work and sick leave, service satisfaction, and antidepressant medication. Data were analyzed with the intention-to-treat principle. Results: One hundred ninety two patients with depression at PCCs with care managers were allocated to the intervention group, and 184 patients at control PCCs were allocated to the control group. Mean depression score measured by MADRS-S was 2.17 lower in the intervention vs. the control group (95% CI [0.56; 3.79], p = 0.009) at 3 months and 2.27 lower (95% CI [0.59; 3.95], p = 0.008) at 6 months; corresponding BDI-II scores were 1.96 lower (95% CI [-0.19; 4.11], p = 0.07) in the intervention vs. control group at 6 months. Remission was significantly higher in the intervention group at 6 months (61% vs. 47%, p = 0.006). QoL showed a steeper increase in the intervention group at 3 months (p = 0.01). During the first 3 months, return to work was significantly higher in the intervention vs. the control group. Patients in the intervention group were more consistently on antidepressant medication than patients in the control group. Conclusions: Care managers for depression treatment have positive effects on depression course, return to work, remission frequency, antidepressant frequency, and quality of life compared to usual care and is valued by the patients.
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| 5. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 6. |
- Brusini, Irene, et al.
(författare)
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Changes in brain architecture are consistent with altered fear processing in domestic rabbits
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:28, s. 7380-7385
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Tidskriftsartikel (refereegranskat)abstract
- The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.
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| 7. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 8. |
- Jarvius, Malin, et al.
(författare)
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In situ detection of phosphorylated platelet-derived growth factor receptor beta using a generalized proximity ligation method
- 2007
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 6:9, s. 1500-1509
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Tidskriftsartikel (refereegranskat)abstract
- Improved methods are needed for in situ characterization of post-translational modifications in cell lines and tissues. For example, it is desirable to monitor the phosphorylation status of individual receptor tyrosine kinases in samples from human tumors treated with inhibitors to evaluate therapeutic responses. Unfortunately the leading methods for observing the dynamics of tissue post-translational modifications in situ, immunohistochemistry and immunofluorescence, exhibit limited sensitivity and selectivity. Proximity ligation assay is a novel method that offers improved selectivity through the requirement of dual recognition and increased sensitivity by including DNA amplification as a component of detection of the target molecule. Here we therefore established a generalized in situ proximity ligation assay to investigate phosphorylation of platelet-derived growth factor receptor β (PDGFRβ) in cells stimulated with platelet-derived growth factor BB. Antibodies specific for immunoglobulins from different species, modified by attachment of DNA strands, were used as secondary proximity probes together with a pair of primary antibodies from the corresponding species. Dual recognition of receptors and phosphorylated sites by the primary antibodies in combination with the secondary proximity probes was used to generate circular DNA strands; this was followed by signal amplification by replicating the DNA circles via rolling circle amplification. We detected tyrosine phosphorylated PDGFRβ in human embryonic kidney cells stably overexpressing human influenza hemagglutinin-tagged human PDGFRβ in porcine aortic endothelial cells transfected with the β-receptor, but not in cells transfected with the α-receptor, and also in immortalized human foreskin fibroblasts, BJ hTert, endogenously expressing the PDGFRβ. We furthermore visualized tyrosine phosphorylated PDGFRβ in tissue sections from fresh frozen human scar tissue undergoing wound healing. The method should be of great value to study signal transduction, screen for effects of pharmacological agents, and enhance the diagnostic potential in histopathology.
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| 9. |
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| 10. |
- Lundstedt, Ann-Charlotte, et al.
(författare)
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Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection.
- 2007
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 195:8, s. 1227-1234
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Tidskriftsartikel (refereegranskat)abstract
- Background. Urinary tract infections (UTIs) are important causes of morbidity and death. The present study investigated whether genetic factors influence susceptibility to acute pyelonephritis (APN). CXCR1 expression was investigated as a factor predisposing to APN, because low CXCR1 expression has been associated with disease susceptibility in mice and disease-prone children. Methods. The families of APN-prone children (n=130) and of age-matched control subjects without UTI (n=101) were studied. Three- generation pedigrees of UTI-associated morbidity were established by means of structured interviews of the families. CXCR1 expression was quantified by flow cytometric analysis of peripheral blood neutrophils obtained from family members and control subjects. Results. APN was significantly more common in the family members of the APN-prone children (20 [15%] of 130 family members) than in the relatives of the control subjects (3 [3%] of 101 family members) (P <.002). Acute cystitis, in contrast, occurred with equal frequency in both groups (19%; P=1.0). Some families included many affected individuals, consistent with a dominant pattern of inheritance, whereas other families showed a recessive pattern of disease susceptibility. CXCR1 expression was significantly lower in the APN-prone children and in their relatives than in pediatric and adult control subjects (P < .0001). Conclusions. Our results suggest that susceptibility to APN is inherited and that low CXCR1 expression might predispose to disease.
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