| 1. |
- Aits, Sonja, et al.
(författare)
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HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:5, s. 1008-1019
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
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| 2. |
- Brest, Patrick, et al.
(författare)
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Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.
- 2007
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Ingår i: Cancer Research. - 1538-7445. ; 67:23, s. 11327-11334
-
Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.
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| 3. |
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| 4. |
- Fischer, Hans, et al.
(författare)
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Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4.
- 2007
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Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 9:5, s. 1239-1251
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal Toll-like receptors (TLRs) respond to pathogens, but remain inert to the indigenous flora, suggesting that the TLRs can receive pathogen-specific signals. For example, TLR4 signalling is activated in CD14-negative epithelial cells by P-fimbriated, uropathogenic Escherichia coli, but not by lipopolysaccharide. The fimbriae use glycosphingolipids as recognition receptors and there is release of ceramide, which is the membrane-anchoring domain of the receptors. In this study, ceramide was identified as a TLR4 agonist and as a putative signalling intermediate between the glycosphingolipid recognition receptors and TLR4. Exogenous ceramide activated a TLR4-dependent epithelial cell response, as shown by exposing stably transfected TLR4-positive or -negative human embryonal kidney cells to C2 and C6 ceramide. A similar, TLR4-dependent response occurred after deliberate release of endogenous long-chained ceramide with sphingomyelinase. Microbial ligands with glycosphingolipid specificity (P fimbriae or the B subunit of Shiga toxin) were shown to increase the levels of ceramide and to trigger a TLR4-dependent response in epithelial cells. The results show that ceramide activates TLR4 signalling and suggest that this mechanism might allow pathogens to elicit mucosal TLR4 responses by perturbing sphingolipid receptors for virulence ligands like P fimbriae.
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| 5. |
- Ahmadi, Zainab, et al.
(författare)
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Smoking and home oxygen therapy : a review and consensus statement from a multidisciplinary Swedish taskforce
- 2024
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Ingår i: European Respiratory Review. - : European Respiratory Society. - 0905-9180 .- 1600-0617. ; 33:171
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Forskningsöversikt (refereegranskat)abstract
- Background: Home oxygen therapy (HOT) improves survival in patients with hypoxaemic chronic respiratory disease. Most patients evaluated for HOT are former or active smokers. Oxygen accelerates combustion and smoking may increase the risk of burn injuries and fire hazards; therefore, it is considered a contraindication for HOT in many countries. However, there is variability in the practices and policies regarding this matter. This multidisciplinary Swedish taskforce aimed to review the potential benefits and risks of smoking in relation to HOT, including medical, practical, legal and ethical considerations.Methods: The taskforce of the Swedish Respiratory Society comprises 15 members across respiratory medicine, nursing, medical law and ethics. HOT effectiveness and adverse risks related to smoking, as well as practical, legal and ethical considerations, were reviewed, resulting in five general questions and four PICO (population–intervention–comparator–outcome) questions. The strength of each recommendation was rated according to the GRADE (grading of recommendation assessment, development and evaluation) methodology.Results: General questions about the practical, legal and ethical aspects of HOT were discussed and summarised in the document. The PICO questions resulted in recommendations about assessment, management and follow-up of smoking when considering HOT, if HOT should be offered to people that meet the eligibility criteria but who continue to smoke, if a specific length of time of smoking cessation should be considered before assessing eligibility for HOT, and identification of areas for further research.Conclusions: Multiple factors need to be considered in the benefit/risk evaluation of HOT in active smokers. A systematic approach is suggested to guide healthcare professionals in evaluating HOT in relation to smoking.
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| 6. |
- Andersson, Eva-Lotta, 1966-
(författare)
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Kön och ansvar i sjukförsäkringen : En studie av utredningstexter 1944 - 2006
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent decades, the welfare state has changed as a result of various market adaptations and privatisations. The state’s responsibility for the provision of welfare has diminished and responsibility has been shifted onto the market, the family and civil society.The aim of this thesis is to examine how shifting the responsibility for sickness insurance between the state, the market and the family interacts with ideas and beliefs about gender, and what the consequences are for the eligibility to receive sickness benefit insurance of those who are insured. The material consists of governmental inquiries into the Swedish sickness insurance system from 1944 to 2006, the texts of which have been analysed using discourse analysis.The study shows that the division of responsibility studied in the texts, in various ways, worked to create a hierarchy and to maintain the separation between different categories, and thus has contributed to create gender-defined positions. The design of the sickness insurance system is shaped by gender-defined interpretative frameworks.In the texts I study how divisions of responsibility is characterised by ideas and beliefs about gender. The first period is dominated by an interpretive framework in which the man is the provider and the woman is provided for. These ideas and beliefs about gender characterise the division of responsibility, and those who are insured are separated into gender-defined groups by the way in which responsibility for different parts of the insurance system are divided between the state, the market and the family. As a result, gender-defined status positions are created, with men as policy holders and women as beneficiaries.The second period is dominated by an interpretive framework based on equality of treatment. It is characterised by ideas that both men and women contribute to supporting the household through paid work. Differentiation between the sexes decreases as women, to a much greater extent, positioned as wage-earners, while those who work in the home become increasingly marginalised as they are perceived as old-fashioned.In the third period, economic interpretive frameworks and concepts relating to insurability come, increasingly, to the fore. Differentiation increases as the responsibility is shifted to the market and the individual. The roles of beneficiary and the policy holder return, although the division is not as clearly defined by gender as it was in the first period.
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| 7. |
- Annerback, Eva-Maria, et al.
(författare)
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Child physical abuse and concurrence of other types of child abuse in Sweden : Associations with health and risk behaviors
- 2012
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Ingår i: International Journal of Child Abuse & Neglect. - : Elsevier BV. - 0145-2134 .- 1873-7757. ; 36:7-8, s. 585-595
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the associations between child physical abuse executed by a parent or caretaker and self-rated health problems/risk-taking behaviors among teenagers. Further to evaluate concurrence of other types of abuse and how these alone and in addition to child physical abuse were associated with bad health status and risk-taking behaviors.Methods: A population-based survey was carried out in 2008 among all the pupils in 2 different grades (15 respectively 17 years old) in Sodermanland County, Sweden (n = 7,262). The response rate was 81.8%. The pupils were asked among other things about their exposure to child physical abuse, exposure to parental intimate violence, bullying, and exposure to being forced to engage in sexual acts. Adjusted analyses were conducted to estimate associations between exposure and ill-health/risk-taking behaviors.Results: Child physical abuse was associated with poor health and risk-taking behaviors with adjusted odds ratios (OR) ranging from 1.6 to 6.2. The associations were stronger when the pupils reported repeated abuse with OR ranging from 2.0 to 13.2. Also experiencing parental intimate partner violence, bullying and being forced to engage in sexual acts was associated with poor health and risk-taking behaviors with the same graded relationship to repeated abuse. Finally there was a cumulative effect of multiple abuse in the form of being exposed to child physical abuse plus other types of abuse and the associations increased with the number of concurrent abuse.Conclusions: This study provides strong indications that child abuse is a serious public health problem based on the clear links seen between abuse and poor health and behavioral problems. Consistent with other studies showing a graded relationship between experiences of abuse and poor health/risk-taking behaviors our study shows poorer outcomes for repeated and multiple abuse. Thus, our study calls for improvement of methods of comprehensive assessments, interventions and treatment in all settings where professionals meet young people.
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| 8. |
- Borgquist, Ola, et al.
(författare)
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Micro- and macromechanical effects on the wound bed of negative pressure wound therapy using gauze and foam.
- 2010
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Ingår i: Annals of Plastic Surgery. - 1536-3708. ; 64:6, s. 789-793
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Tidskriftsartikel (refereegranskat)abstract
- Negative pressure wound therapy (NPWT) results in 2 types of tissue deformation, macrodeformation (ie, wound contraction) and microdeformation (ie, the interaction of tissue and dressing on a microscopic level). These effects have been delineated for one type of wound filler, foam, but not for gauze. The mechanical deformation initiates a signaling cascade which ultimately leads to wound healing. The aim of the present study was to examine the effect of gauze and foam on macro- and microdeformation during treatment with negative pressure. An in vivo porcine peripheral wound model was used. NPWT was applied for 72 hours at 0, -75, and -125 mm Hg, using either foam or gauze as wound filler. The mechanical effects of NPWT were examined by measuring the wound surface area reduction and by histologic analysis of the wound bed tissue. Similar degrees of wound contraction (macrodeformation) were seen during NPWT regardless if foam or gauze was used. After negative pressure had been discontinued, the wound stayed contracted. There was no difference in wound contraction between -75 and -125 mm Hg. Biopsies of the wound bed revealed a repeating pattern of wound surface undulations and small tissue blebs ("tissue mushrooms") were pulled into the pores of the foam dressing and the spaces between the threads in the gauze dressing (microdeformation). This pattern was obvious in wounds treated both with foam and gauze, at atmospheric pressure (0 mm Hg) as well as at subatmospheric pressures (-75 and -125 mm Hg). The degrees of micro- and macrodeformation of the wound bed are similar after NPWT regardless if foam or gauze is used as wound filler.
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| 9. |
- Düringer, Caroline, et al.
(författare)
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HAMLET; a novel tool to identify apoptotic pathways in tumor cells.
- 2005
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Ingår i: Application of apoptosis to cancer treatment.. - Berlin/Heidelberg : Springer-Verlag. - 9781402033032 ; , s. 223-245
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Tumor cells often carry mutations in genes that control cell survival, and become resistant to signals that trigger cell death. Yet, some cell death pathways remain intact in tumor cells. If identified, these pathways might be exploited to selectively remove tumor cells. HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex derived from human milk that activates cell death programs in tumor cells but not in healthy differentiated cells. We use HAMLET as a tool to identify apoptosis and apoptosis-like cell death mechanisms in tumor cells and to understand if these mechanisms differ between tumor and healthy cells. HAMLET interacts with the cell surface, translocates into the cytoplasm and accumulates in cell nuclei, where it disrupts the chromatin. Recent in vivo studies have shown that HAMLET maintains the tumoricidal activity in glioblastoma, papilloma and bladder cancer models, with no significant side effects. The results suggest that HAMLET should be explored as a new therapeutic agent with selectivity for the tumor and with little toxicity for adjacent healthy tissue. Such therapies are a much-needed complement to conventional treatments, to reduce the side effects and improve the selectivity.
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| 10. |
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| 11. |
- Fischer, Walter, et al.
(författare)
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Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.
- 2004
-
Ingår i: Cancer Research. - 1538-7445. ; 64:6, s. 2105-2112
-
Tidskriftsartikel (refereegranskat)abstract
- Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human α-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from α-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and α-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all α-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm3). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.
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| 12. |
- Frick, Inga-Maria, et al.
(författare)
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Uptake and intracellular transportation of a bacterial surface protein in lymphoid cells.
- 2002
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 44:4, s. 917-934
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Tidskriftsartikel (refereegranskat)abstract
- Some strains of the human pathogen Streptococcus pyogenes express a surface protein called protein H, which is released from the streptococcal surface by a cysteine proteinase produced by the bacteria. Here, we find that soluble protein H binds to the surface of lymphocytes and granulocytes, and that the molecule is taken up by lymphocytes and transported to the perinuclear region. The translocation over the cell membrane is rapid, and the uptake and intracellular transportation is not dependent on actin polymerization. Protein H could be immunoprecipitated from cell extracts and nuclear preparations of lymphocytes, and analysis of molecular interactions between pro-tein H and proteins of different cellular compart-ments demonstrated a binding to nucleophosmin/ B23, a protein known to shuttle between the cytoplasm and the nucleus, and to the nuclear proteins SET and hnRNP A2/B1. Nucleophosmin/B23 was co-immunoprecipitated with protein H from cell and nuclear extracts, and binding experiments, including kinetic analyses, suggest that protein H dissociating from nucleophosmin/B23 complexes in the perinuclear region or in the nucleus binds to proteins SET and hnRNP A2/B1. Finally, the uptake and intracellular transportation of protein H was found to result in a cytostatic effect on B and T lymphocytes.
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| 13. |
- Gesslein, Bodil, et al.
(författare)
-
Mitogen-activated protein kinases in the porcine retinal arteries and neuroretina following retinal ischemia-reperfusion.
- 2010
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Ingår i: Molecular Vision. - 1090-0535. ; 16, s. 392-407
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of the present study was to examine changes in the expression of intracellular signal-transduction pathways, specifically mitogen-activated protein kinases, following retinal ischemia-reperfusion. METHODS: Retinal ischemia was induced by elevating the intraocular pressure in porcine eyes, followed by 5, 12, or 20 h of reperfusion. The results were compared to those of the sham- operated fellow eye. The retinal arteries and neuroretina were isolated separately and examined. Tissue morphology and DNA fragmentation were studied using histology. Extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, c-junNH(2)-terminal kinases (JNK), and c-jun protein and mRNA expression were examined using immunofluorescence staining, western blot, and real-time PCR techniques. RESULTS: Pyknotic cell nuclei, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and glial fibrillary acidic protein mRNA expression were increased in ischemia, suggesting injury. Phosphorylated ERK1/2 protein levels were increased in the neuroretina following ischemia, while mRNA levels were unaltered. p38 protein and mRNA levels were not affected by ischemia. Immunofluorescence staining for phosphorylated p38 was especially intense in the retinal blood vessels, while only weak in the neuroretina. Phosphorylated JNK protein and mRNA were slightly decreased in ischemia. Phosphorylated c-jun protein and mRNA levels were higher in the neuroretina after ischemia-reperfusion. CONCLUSIONS: Retinal ischemia-reperfusion alters expression of mitogen-activated protein kinases, particularly ERK1/2, in the neuroretina and retinal arteries. The development of pharmacological treatment targeting these intracellular transduction pathways may prevent injury to the eye following retinal circulatory failure.
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| 14. |
- Gesslein, Bodil, et al.
(författare)
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Protein kinase C in porcine retinal arteries and neuroretina following retinal ischemia-reperfusion.
- 2009
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Ingår i: Molecular Vision. - 1090-0535. ; 15:Apr 13, s. 737-746
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Identification of the intracellular signal-transduction pathways activated in retinal ischemia may be important in revealing novel pharmacological targets. To date, most studies have focused on identifying neuroprotective agents. The retinal blood vessels are key organs in circulatory failure, and this study was therefore designed to examine the retinal vasculature separately from the neuroretina. METHODS: Retinal ischemia was induced by elevating the intraocular pressure in porcine eyes, followed by 5, 12, or 20 h of reperfusion. Protein kinase C (PKC)alpha, PKCbeta1, and PKCbeta2 mRNA levels, and protein expression were determined using real-time PCR, western blot, and immunofluorescence staining techniques. RESULTS: The retinal arteries could easily be dissected free and studied separately from the neuroretina in this porcine model. The PKCalpha, PKCbeta1, and PKCbeta2 mRNA levels tended to be lower in ischemia-reperfused than in sham-operated eyes in both the retinal arteries and the neuroretina. This was most prominent after 5 h, and less pronounced after 12 h and 20 h of reperfusion. Likewise, the protein levels of PKCalpha, PKCbeta1, and PKCbeta2 were slightly lower following ischemia-reperfusion when compared to sham-operated eyes. PKCalpha, PKCbeta1, and PKCbeta2 immunostaining were observed in bipolar cells of the neuroretina and in endothelial cells, and to a low extent in the smooth muscle layer, of the retinal arteries. CONCLUSIONS: Retinal ischemia followed by reperfusion results in lower levels of PKC in both the neuroretina and retinal arteries. New targets for pharmacological treatment may be found by studying the retinal vasculature so as to identify the intracellular signal-transduction pathways involved in the development of injury following retinal circulatory failure.
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| 15. |
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| 16. |
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| 17. |
- Gustafsson, Ewa, 1955, et al.
(författare)
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The use of information technology among young adults--experience, attitudes and health beliefs
- 2003
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Ingår i: Appl Ergon. - : Pergamon. - 0003-6870 .- 1872-9126. ; 34:6, s. 565-70
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to explore attitudes, coherence and health beliefs among young adults, related to their use and experience of information technology (IT). A qualitative approach was used and the data were collected through individual thematised interviews with 25 young IT users, aged 18-24. The interviews were analysed in line with the grounded theory method with a constructivist approach. The main findings were the young adults' experience of the two sides of being social, efficient and independent here and now. They described almost unlimited opportunities in connection with IT, but they also had misgivings, and perceived risks regarding IT use. Feelings of freedom and being efficient were countered by feelings of restrictions on living space and of intangibility. Knowledge concerning these attitudes, coherence and health beliefs can be considered when designing epidemiological and ergonomic studies aimed at risk identification.
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| 18. |
- Gustafsson, Lotta
(författare)
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Blytak
- 1999
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Skriften som riktar sig till både hantverkare och antikvarier vill sprida kunskap om de få kvarvarande blytakens kulturhistoriska betydelse och ge råd kring tillsyn och reparation. Projektets fallstudie har utförts på Övraby kyrka i Skåne.
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| 19. |
- Gustafsson, Lotta
(författare)
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Bröstmjölk mot cancerceller
- 2007
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Ingår i: Illustrerad Vetenskap. - 0281-9341.
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 20. |
- Gustafsson, Lotta, et al.
(författare)
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Changes in proteasome structure and function caused by HAMLET in tumor cells.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded protein-lipid complex, which is internalized by tumor cells and triggers cell death. METHODOLOGY/PRINCIPAL FINDINGS: HAMLET bound directly to isolated 20S proteasomes in vitro and in tumor cells significant co-localization of HAMLET and 20S proteasomes was detected by confocal microscopy. This interaction was confirmed by co-immunoprecipitation from extracts of HAMLET-treated tumor cells. HAMLET resisted in vitro degradation by proteasomal enzymes and degradation by intact 20S proteasomes was slow compared to fatty acid-free, partially unfolded alpha-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (beta1 and beta5) and structural subunits (alpha2, alpha3, alpha6 and beta3). Proteasome inhibition was confirmed in extracts from HAMLET-treated cells and there were indications of proteasome fragmentation in HAMLET-treated cells. CONCLUSIONS/SIGNIFICANCE: The results suggest that internalized HAMLET is targeted to 20S proteasomes, that the complex resists degradation, inhibits proteasome activity and perturbs proteasome structure. We speculate that perturbations of proteasome structure might contribute to the cytotoxic effects of unfolded protein complexes that invade host cells.
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| 21. |
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| 22. |
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| 23. |
- Gustafsson, Lotta
(författare)
-
HAMLET - In vivo effects and mechanisms of tumor-cell death
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells), a molecular complex derived from human milk, is an interesting new tool in cancer research since it induces programmed cell death in tumor cells while leaving normal, differentiated cells unharmed. The in vivo effects of HAMLET were studied in a rat xenograft model of human glioblastoma. HAMLET reduced the tumor volume and delayed the onset of pressure symptoms. Programmed cell death was induced in the tumor, but not in the adjacent normal brain tissue. In non-grafted rats, HAMLET spread throughout the infused brain hemisphere and no significant toxic side-effects were recorded. The therapeutic effects of HAMLET were investigated further in a placebo-controlled study of patients with skin papillomas. Local application of HAMLET for a three-week period reduced the volume of the papillomas by >75% in all the patients and in 96% of the papillomas as compared with 21% in the placebo-control group. No adverse reactions were reported and there was no difference in outcome for immunosuppressed patients. A mechanism of tumor-cell death was suggested, one that relates to the partially unfolded state of HAMLET. Massive amounts of HAMLET gained entry into the tumor cells, it interacted with the proteasomes and caused a stress response due to the overload of partially unfolded protein. HAMLET activated the proteasomes in the cytoplasm, but degradation was delayed and fragmentation of the proteasomes was triggered instead. HAMLET and proteasomes translocated to the tumor cell nuclei, where chromatin homeostasis was disrupted. HAMLET-induced tumor-cell death was partially prevented by blocking proteasome activity, supporting the role of proteasomes in cell death. HAMLET represents a new approach to cancer therapy, having therapeutic effects in vivo and targeting cell death pathways that are susceptible for activation in tumor cells, thus circumventing the roadblocks that prevent cell death in many tumor cells.
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| 24. |
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| 25. |
- Gustafsson, Lotta, et al.
(författare)
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HAMLET kills tumor cells by apoptosis: Structure, cellular mechanisms, and therapy
- 2005
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Ingår i: Journal of Nutrition. - 1541-6100. ; 135:5, s. 1299-1303
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Tidskriftsartikel (refereegranskat)abstract
- New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human a-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, α-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.
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| 26. |
- Gustafsson, Lotta, 1958-
(författare)
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Medeltidskyrkan i Uppland : restaurering och rumslig förnyelse under 1900-talet
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this work is to illuminate the history of restoration in 20th century Sweden by studying restorations of medieval Uppland churches, in the hope of highlighting the debate and conflicts surrounding the ideologies forming the framework of church restorations and identifying the crucial considerations. It is an attempt to depicting church restorations with the focus of attention on the function of the church interior, but also on ways of achieving a credible design appropriate to the present. Theological and liturgical issues and their connection with usability constitute an important background. The study takes as its starting point the architect’s mission as the person in charge of the restoration project. The heritage conservation aspects and issues of principle concerning preservation are present as a basic precondition of every restoration assignment.The study demonstrates the complexity of the design of the various church interiors. The 20th century restorations have been concerned with modernisation, with questions of materials and with the character of the church interiors, but they have also hinged on individual architects and their differing attitudes towards preservation and new design, and on the relation between restoration and spatial renewal. This study encompasses the whole of the 20th century, but with special emphasis on the period between about 1920 and 1980. First of all a general count was taken of all major restorations in the province of Uppland. Their time-related character prompted a division of the 20th century into four periods, and one church from each period was chosen for closer study. The four churches chosen were Tensta, Skånela, Knivsta and Orkesta. More examples were then used to illustrate the complexity of the restorations. Studies of the church buildings, in the in-depth studies and in supplementary examples from the province as a whole, were then viewed in relation to overarching issues concerning restoration tradition, values and viewpoints held by the heritage conservation authorities, parochial needs for changes to the church interiors, but also discussions concerning the functional and artistic design of new churches and how those discussions were reflected in the historic churches.
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| 27. |
- Gustafsson, Lotta, 1958-
(författare)
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Mörby slottsruin i Uppland
- 1997
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Ingår i: Kulturmiljövård. - Stockholm : Riksantikvarieämbetet. - 1100-4800. ; :3, s. 53-56
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Gustafsson, Lotta
(författare)
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Spån, puts och solbänk : Förändringar i uppländska medeltidskyrkor under 1900-talet
- 2002
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Varför ser vissa medeltidskyrkor så övertygande ålderdomliga ut, medan andra genast upplevs som nutida? Vilken betydelse har materialval, ytskikt och utformning av detaljer för upplevelsen av en gammal byggnad? Denna skrift försöker ge svar på dessa frågor. Den riktar sig främst till förvaltare, projektörer, antikvarier och naturligtvis till hantverkare som utför det byggnadsvårdande arbetet. Författaren, Lotta Gustafsson, är arkitekt med projektering och forskning som huvudsakligt arbetsområde.
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| 32. |
- Gustafsson, Lotta, et al.
(författare)
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Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid
- 2004
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 350:26, s. 2663-2672
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We studied the effect on skin papillomas of topical application of a complex of α-lactalbumin and oleic acid (often referred to as human α-lactalbumin made lethal to tumor cells [HAMLET]) to establish proof of the principle that α-lactalbumin-oleic acid kills transformed cells but not healthy, differentiated cells. METHODS: Forty patients with cutaneous papillomas that were resistant to conventional treatment were enrolled in a randomized, placebo-controlled, double-blind study, in which α-lactalbumin-oleic acid or saline placebo was applied daily for three weeks and the change in the volume of each lesion was recorded. After this first phase of the study, 34 patients participated in the second phase, an open-label trial of a three-week course of α-lactalbumin-oleic acid. Approximately two years after the end of the open-label phase of the study, 38 of the original 40 patients were examined, and long-term follow-up data were obtained. RESULTS: In the first phase of the study, the lesion volume was reduced by 75 percent or more in all 20 patients in the α-lactalbumin-oleic acid group, and in 88 of 92 papillomas; in the placebo group, a similar effect was evident in only 3 of 20 patients (15 of 74 papillomas) (P<0.001). After the patients in the initial placebo group had been treated with α-lactalbumin-oleic acid in the second phase of the study, a median reduction of 82 percent in lesion volume was observed. At follow-up two years after the end of the second phase, all lesions had completely resolved in 83 percent of the patients treated with α-lactalbumin-oleic acid, and the time to resolution was shorter in the group originally assigned to receive a-lactalbumin-oleic acid than among patients originally in the placebo group (2.4 vs. 9.9 months; P<0.01). No adverse reactions were reported, and there was no difference in the outcomes of treatment between immunocompetent and immunosuppressed patients. CONCLUSIONS: Treatment with topical α-lactalbumin-oleic acid has a beneficial and lasting effect on skin papillomas.
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| 33. |
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| 34. |
- Gustafsson, Lotta, et al.
(författare)
-
Utan sömn ingen fart
- 2008
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Ingår i: TEMPO - Om fart och det föränderliga. - 9789170610608
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Bokkapitel (populärvet., debatt m.m.)
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| 35. |
- Gustafsson, Sofia S., et al.
(författare)
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Quantification of interactions between drug leads and serum proteins by use of "binding efficiency"
- 2011
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 409:2, s. 163-175
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Tidskriftsartikel (refereegranskat)abstract
- To develop efficient and reliable methods for prediction of serum protein binding of drug leads, the kinetic characteristics for the interactions between selected compounds and human serum albumin and α(1)-acid glycoprotein have been explored using a surface plasmon resonance biosensor. Conventional methods for quantification of interactions (i.e., using rate constants or affinities determined on the basis of a reasonable mechanistic model) were applicable for only a few of the compounds. The affinity of a primary interaction and the contribution of lower affinity secondary interactions could be estimated for some compounds, but the affinity of many compounds could not be quantified by either of these methods. To have a quantification method that could be used for all compounds, independent of affinity and complexity of interaction mechanisms, the concept of "binding efficiency," analogous to "catalytic efficiency" used for enzymes, was developed. It allowed the quantification of the binding of compounds interacting with weak affinity and for which saturation is not reached within a concentration range where the compound is soluble or when the influence of interactions with secondary sites makes interpretations difficult. In addition, compounds with large fractional binding can be identified by this strategy and simply quantified relative to reference compounds. This approach will enable ranking and identification of structure-activity relationships of compounds with respect to their serum protein binding profile.
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| 36. |
- Hallberg, Sven-Erik, et al.
(författare)
-
Anti-Skid Treatment Tests with Glucose, Fructose and Unrefined Sugar
- 2007
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Konferensbidrag (refereegranskat)abstract
- Over the past ten years, salt consumption for de-icing treatment on Swedish roads has been halved from approximately 400,000 tons to some 200,000 tons per year. This is largely a result of preventive measures with salt solution, which entails significantly smaller salt doses than in the case of dry and moistened salt. The purpose of the investigation has been to conduct tests with a salt solution in combination with glucose/fructose/refined sugar in order to determine whether a certain amount of the salt solution can be replaced by a product containing these substances and the kind of technical and environmental effects the mixture would have. The introductory trials, which were performed on an airport landing strip 2004/2005 gave experience of value, regarding friction coefficients etc, to continued testing. Field tests have been carried out the winter season 2005/2006. The fact that salt will continue to play an important role in anti-freeze treatment is borne out by the testing. The investigation has shown that it is possible to use a mixture of the salt solution that is today used for anti-freeze treatment together with a glucose/fructose product and maintain safety friction conditions. Exactly how large the sugar solution is and its concentration should be further studied through continued airfield trials and as well as on a section of road used by traffic. The results from the recent season as using mixtures of 75% salt and 25% sugar as well as trials on 50/50 base, looks promising. The sugar part of the solution can not melt ice but delay freezing. The product should be looked upon as a complement to salt as it leads to a lower freezing-point of the solution. Friction measurements Cost The analysis does not contain any form of financial evaluation in year one as to the cost of the solution or the value of reduced salt attack on the vehicle fleet. Since the mixtures have been produced manually and on a small scale, practical handling of the mixtures on a larger scale is included in the investigation in the winter season 2005/2006. The products environmental impact on corrosion, concrete, animal life and plant life have been studied. Oxygen is consumed in the breakdown of glucose/fructose/unrefined sugar. The breaking down of glucose/fructose/unrifined sugar by micro-organisms is influenced by the presence of toxic substances such as metals and salts and should be studied both in the field and in the laboratory. Furthermore, the oxygen consumption in recipients should be studied.
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| 37. |
- Hallgren, Oskar, et al.
(författare)
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Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2008
-
Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
-
Forskningsöversikt (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.
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| 38. |
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| 39. |
- Håkansson, Gisela, et al.
(författare)
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Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia
- 2010
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Ingår i: Journal of Ocular Biology, Diseases, and Informatics. - : Springer Science and Business Media LLC. - 1936-8445. ; 3:1, s. 20-29
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Tidskriftsartikel (refereegranskat)abstract
- Retinal ischemia arises from circulatory failure. As the retinal blood vessels are key organs in circulatory failure, our aim was to study the retinal vasculature separately from the neuroretina to elucidate the role of hypoxia-inducible factor (HIF) 1α and 1β and vascular endothelial growth factor (VEGF) in retinal ischemia. Retinal ischemia was induced in porcine eyes by applying an intraocular pressure, followed by 12 h of reperfusion. HIF-1α mRNA expression was not affected by ischemia, while immunofluorescence staining was higher after ischemia in the neuroretina. HIF-1β immu-noreactivity and mRNA expression were unaffected. VEGF protein levels in the vitreous humor and VEGF staining in the neuroretina were more pronounced in eyes subjected to ischemia than in the sham eyes. VEGF may be activated downstream of HIF-1 and is known to stimulate retinal neovascularization, which causes sight-threatening complications. These results emphasize the need for pharmacological treatment to block the HIF and VEGF signaling pathways in retinal ischemia.
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| 40. |
- Jonsson, Frida, et al.
(författare)
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Life Course Pathways of Adversities Linking Adolescent Socioeconomic Circumstances and Functional Somatic Symptoms in Mid-Adulthood : A Path Analysis Study
- 2016
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other potential pathways are few. Following a chain of risk life course model, this prospective study seeks to examine whether pathways of occupational class as well as material and social adversities across the life course link socioeconomic disadvantage in adolescent to functional somatic symptoms in mid-adulthood. Applying path analysis, a multiple mediator model was assessed using prospective data collected during 26 years through the Northern Swedish Cohort. The sample contained 987 individuals residing in the municipality of Lulea, Sweden, who participated in questionnaire surveys at age 16, 21, 30 and 42. Socioeconomic conditions (high/low) in adolescence (age 16) were operationalized using the occupation of the parents, while occupational class in adulthood (manual/nonmanual) was measured using the participant's own occupation at age 21 and 30. The adversity measurements were constructed as separate age specific parcels at age 21 and 30. Social adversity included items pertaining to stressful life events that could potentially harm salient relationships, while material adversity was operationalized using items concerning unfavorable financial and material circumstances. Functional somatic symptoms at age 42 was a summary measure of self-reported physical symptoms, palpitation and sleeping difficulties that had occurred during the last 12 months. An association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = 0.068) which was partially explained by people's own occupational class at age 21 and then material as well as social adversity at age 30 was revealed. Rather than proposing a direct and independent health effect of the socioeconomic conditions of the family, the present study suggests that growing up in an unfavorable socioeconomic environment might be a source for a chain of adverse material and social living situations, which in turn affects adult health.
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| 41. |
- Jonsson, F., et al.
(författare)
-
Paths of adversity linking adolescent socioeconomic conditions to adult functional somatic symptoms
- 2016
-
Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 26:Suppl 1, s. 227-227
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Tidskriftsartikel (refereegranskat)abstract
- Background: While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other pathways are few. Following a chain of risk life course model, this study examine if the socioeconomic conditions of the family contributes to an adverse social and material environment across life ultimately affecting functional somatic symptoms in adulthood.Methods: Mediation was examined using path analysis on prospective data from a sample of 987 individuals residing in Luleå, Sweden in 1981 and who answered surveys at age 16, 21, 30 and 42. Early socioeconomic conditions was assessed at age 16 by using the parents occupation. The participant’s own occupation was measured at age 21 and 30. At age 21 and 30, social adversity comprised of items pertaining to stressful life events, while material adversity included items of unfavorable economic conditions. Functional somatic symptoms was examined at age 42 as a summary of self-reported physical symptoms, palpitation and sleeping difficulties occurring during the last 12 months.Results: The results suggested that the association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = .068) could be explained by two plausible pathways. Through own class at age 21 and then through material (B = .064, 95% CI = .004 – .123) and social adversity (B = .067, 95% CI = .019 – .114) at age 30.Conclusions: Growing up in an unfavorable socioeconomic setting might be a source for later adversities, and these might largely explain the effects of early disadvantage on later health. Thus, improved social and financial living conditions for people from poor backgrounds could avert adult stress-related health problems.Key messages:Chains of life events may be central to understand socioeconomic health effectsBreaking life course chains might avert adult health effects of early disadvantage
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| 42. |
- Kindstedt, Jonas, et al.
(författare)
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Exploring medication-related hospital admissions and their association with cognitive impairment among acutely admitted older people
- 2023
-
Ingår i: Research in Social and Administrative Pharmacy. - : Elsevier. - 1551-7411 .- 1934-8150. ; 19:7, s. 1048-1053
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Medication-related hospital admissions (MRAs) are common among older people. Persons with cognitive impairment are especially vulnerable to adverse drug effects. At the same time, increased home health care and social support could theoretically prevent medication-related problems. This study aims to estimate the proportion of MRAs and explore their relationship with cognitive impairment in a population of acutely admitted older people.Methods: This cross-sectional study comprised 300 individuals aged 75 years or older admitted to an acute medical ward. Two assessors identified possibly MRAs using the Assessment Tool for Hospital Admissions Related to Medications 10 (AT-HARM10). Screening for cognitive impairment was performed during ward stay using a 4-item test related to time orientation. Prevalence odds ratios between cognitive test scores and MRAs were analysed through logistic regression.Results: Using AT-HARM10, 108 out of 300 admissions (36%) were classified as possibly MRAs by both assessors. Moreover, MRAs were least common among patients with the lowest cognitive test scores. There was an association regarding MRAs when the lowest test score was treated as a cut-off and compared against a reference category comprising all other scores (OR, 0.31 [95% CI 0.10–0.93]; p = 0.037) in a logistic regression model adjusted for cohabitation and home health care.Conclusion: Approximately one-third of the hospital admissions among acutely admitted older people were considered at least possibly medication-related. Hence, there is still a great need to manage medication-related problems and reduce MRAs in this vulnerable population. Using a 4-item instrument to screen for cognitive impairment, there was a negative association between MRA and lowest cognitive test score. Further exploration of the relationship between MRAs and cognitive impairment may indicate appropriate components and target populations for interventions that aims to reduce the risk of MRA.
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| 43. |
- Kindstedt, Jonas, et al.
(författare)
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Investigating the effect of clinical pharmacist intervention in transitions of care on drug-related hospital readmissions among the elderly : study protocol for a randomised controlled trial
- 2020
-
Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 10:4
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Drug-related problems (DRPs) are a major cause of unplanned hospital admissions among elderly people, and transitions of care have been emphasised as a key area for improving patient safety. We have designed a complex clinical pharmacist intervention that targets people >= 75 years of age undergoing transitions of care from hospital to home and primary care. The main objective is to investigate if the intervention can reduce the risk of unplanned drug-related readmission within the first 180 days after the person is discharged from hospital.Methods and analysis: This is a randomised, controlled, superiority trial with two parallel arms. A total of 700 people >= 75 years will be assigned to either intervention or routine care (control). The intervention, which aims to find and manage DRPs, is initiated within a week of the person being discharged from hospital and combines repeated medical chart reviews, phone interviews and in some cases medication reviews. People in both study arms may have been the subject of a medication review during their ward stay. As the primary outcome, we will measure time until unplanned drug-related readmission within 180 days of leaving hospital and use log rank tests and Cox proportional hazard models to analyse differences between the groups. Further investigations of subgroup effects and adjustments of the regression models will be based on heart failure and cognitive impairment as prognostic factors.Ethics and dissemination: The study has been approved by the Regional Ethical Review Board in Umea (registration numbers 2017-69-31M, 2018-83-32M and 2018-254-32M). We intend to publish the results with open access in international peer-reviewed journals and present our findings at international conferences. The trial is expected to result in more than one published article and form part of two PhD theses.
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| 44. |
- Kindstedt, Jonas, 1986-
(författare)
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Medication-related problems and psychotropic drug use in vulnerable older populations : a focus on acute hospital admissions and cognitive impairment
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The ageing process involves several physiological changes that affect both pharmacodynamics and pharmacokinetics and that, in combination with a heavier disease burden and more extensive use of medicines, put older people at higher risk of medication-related problems and associated clinical outcomes. The older population is often treated as a homogenous group, when in fact there are factors that render certain individuals more vulnerable to adverse drug effects and other types of medication-related problems. Older people encountered in the acute medical care setting and/or individuals with varying degrees of cognitive impairment are especially vulnerable in that context. The overall aim of this thesis was to describe and understand medication use in certain vulnerable subgroups of older people, which in turn might identify suitable target populations in which medication-related problems can be prevented or managed through interventions or similar efforts.Paper I presented, in the form of a study protocol, a clinical pharmacist intervention intended to reduce the risk of medication-related readmission to hospital among people aged 75 years or older during transitions of care. Based on 300 participants from the intervention study, approximately 50% had been readmitted to hospital within 180 days of being discharged from the hospital. Both heart failure and cognitive impairment, the latter identified through a four-item test, were predictors of early readmission. Altogether, the study population seems relevant for the purpose of the intervention; whether the intervention model is effective remains to be determined.Based on the same sample of study participants, paper II found that approximately one third of the 300 index hospital admissions were possibly medication related. Moreover, possibly medication-related hospital admissions were negatively associated with the fewest positive/correct answers on the four-item screening tool for cognitive impairment, which suggests that those clinical events might be less prevalent among people with cognitive impairment when exploring the association cross-sectionally. Both papers III and IV were registry-based studies, and their overall objective can be summarized as to describe psychotropic drug use and associated factors among older people with major neurocognitive disorder (NCD). Paper III focused on differences between major NCD subtypes, whereas paper IV compared people with major NCD against matched references from the total older population. In brief, overall psychotropic drug use was notably higher among people with major NCD, although generally in line with national treatment guidelines in terms of individual drugs of choice. The use of hypnotic drugs was also extensive in the reference group, and deprescribing efforts seem warranted, although longitudinal studies that focus on long-term use could provide a better picture of the potential problem. Nursing home stay was also positively associated with psychotropic drug use for all classes of psychotropic drugs, and the difference was most prominent for antipsychotic drugs. In that context, over 1,200 people in the reference population, most of them nursing home residents, had filled prescriptions for antipsychotic drugs, a figure indicating that the management of neuropsychiatric symptoms might also be an issue among older people who, due to various circumstances, have not been examined and diagnosed with neurocognitive disorders. Regarding major NCD subtypes, individuals with Lewy body dementia had, except for antidementia drugs, higher odds of psychotropic drug use than did those with Alzheimer’s disease. For example, the odds of antipsychotic drug use were more than twice as high, which is a worrying figure given that people with Lewy body dementia are extremely sensitive to the adverse effects of those specific drugs.In conclusion, this thesis illustrates the heterogeneity of demographics and drug use among older people and indicates that certain types of medication-related problems may be more relevant in certain older subpopulations. Medicines appear to be involved in many hospital admissions of older people, and the acute medical setting and subsequent care transitions are likely an important focus of pharmaceutical interventions. However, psychotropic drugs are probably not a major issue in that specific context. Efforts to reduce psychotropic drug use are likely more relevant to people with major NCD, especially in the nursing home setting. Antipsychotic drug exposure among persons with Lewy body dementia could be one such focus, especially since there are other better-balanced pharmacological treatment options for these individuals in terms of efficacy and safety profile.
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| 45. |
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| 46. |
- Kindstedt, Jonas, 1986-, et al.
(författare)
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The impact of nursing home residency on psychotropic drug use in major neurocognitive disorder : a nationwide comparison
- 2023
-
Ingår i: International Journal of Geriatric Psychiatry. - : John Wiley & Sons. - 0885-6230 .- 1099-1166. ; 38:11
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Psychotropic drugs are utilized against neuropsychiatric symptoms among people with major neurocognitive disorder (NCD) despite well-documented risks, and older people in nursing homes are expected to be more frequently exposed to those medicines. This study compared psychotropic drug use and associated factors between older people with major NCD and matched references.Methods: This cross-sectional study included individuals from three national registries in Sweden. References were randomly matched 1:1 by age and sex from the Swedish Total Population Register. Drug use was defined as at least one prescription fill from 1 July to 31 December 2019 and presented as proportion of drug users. In addition, ORs regarding psychotropic drug use and associated factors use were analysed using generalized estimating equations.Results: There were 102,419 complete matching pairs alive on 31 December 2019. The proportions of psychotropic drug users were 59% in the population of people with major NCD and 28% in the reference group. Moreover, there was a substantial number of individuals in nursing homes who had been treated with antipsychotics but who, for unknown reasons, had not been diagnosed with major NCD. Psychotropic drug use was positively associated with both major NCD and nursing home residency. The difference in drug use in relation to major NCD was more pronounced among people living in ordinary homes.Conclusion: Despite well-documented risks in people with cognitive impairment, psychotropic drug use was overall high and positively associated with both major NCD and nursing home residency. Taken together, interventions to better target neuropsychiatric symptoms in older people are warranted. Hypnotic drug use among older people in general as well as antipsychotic drug exposure among older people in nursing homes appear to be two important focus areas.
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| 47. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 48. |
- Kreuger, A., et al.
(författare)
-
[Acute lymphatic leukemia in Swedish children 1968-2001. The marked improvement of the survival can be ascribed to successful treatment]
- 2004
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Ingår i: Lakartidningen. - 0023-7205. ; 101:48
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Tidskriftsartikel (refereegranskat)abstract
- This is a survey of acute lymphoblastic leukemia (ALL) in Swedish children from 1968 to 2001. The survival has increased from a few per cent to more than 80 per cent of children with ALL in these national complete patient materials. Changes in diagnosis and treatment are discussed as well as the importance of supportive care. The favorable results can almost certainly be ascribed to continuous cooperation between the Swedish pediatric departments, the Swedish Child Leukemia Group and international working groups.
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| 49. |
- Kreuger, Anders, et al.
(författare)
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Akut lymfatisk leukemi hos barn i Sverige 19682001. Markant förbättring av överlevnaden tack vare framgångsrik behandling
- 2004
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Ingår i: Läkartidningen. - 0023-7205. ; 101:48, s. 3890-3898
-
Tidskriftsartikel (refereegranskat)abstract
- This is a survey of acute lymphoblastic leukemia (ALL) in Swedish children from 1968 to 2001. The survival has increased from a few per cent to more than 80 per cent of children with ALL in these national complete patient materials. Changes in diagnosis and treatment are discussed as well as the importance of supportive care. The favorable results can almost certainly be ascribed to continuous cooperation between the Swedish pediatric departments, the Swedish Child Leukemia Group and international working groups.
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| 50. |
- Lie, S. O., et al.
(författare)
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Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials
- 2005
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 19:12, s. 2090-100
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Tidskriftsartikel (refereegranskat)abstract
- In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.
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