| 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. |
- 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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| 3. |
- Johansson, Anna, et al.
(författare)
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Perceptions of how sleep is influenced by rest, activity and health in patients with coronary heart disease : A phenomenographical study
- 2007
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Ingår i: Scandinavian Journal of Caring Sciences. - : Wiley. - 0283-9318 .- 1471-6712. ; 21:4, s. 467-475
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Tidskriftsartikel (refereegranskat)abstract
- A framework is needed for identifying internal and external factors essential for the nursing management of psychological supportive health care and education for patients' self-care in sleep. In order to generate more knowledge from the patient's perspective, the aim of this study was to describe how patients with coronary artery disease (CAD) perceive that their sleep is influenced by rest, activity and health in outpatient care. Qualitative interviews were performed with 33 outpatients. The data were analysed using a phenomenographic method. Three descriptive categories of the phenomenon were described: my lifestyle is reflected in my sleep behaviour, handling the practices around tiredness and sleep, and feelings of negative and positive efficacy. Feelings of tiredness, fatigue and sleepiness were different pre-sleep stages, but were also related to the patient's adaptation and recovery. Creating one's own personal time and feelings of efficacy gave an inner sense of strength which is indicated as being particularly important in managing stress and the demands of everyday life in a satisfactory manner. From a contextual, holistic perspective on health, it is important to identify the patient's needs, symptoms and intentional or unintentional self-care management strategies regarding sleep and lifestyle. To promote a positive health outcome it is essential to identify sleeplessness behaviour and perceived self-efficacy for self-care in sleep. © 2007 Nordic College of Caring Science.
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| 4. |
- Ahlquist, Eva-Maria, et al.
(författare)
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Montessoripedagogik* : En pedagogik för världens alla barn
- 2005
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Ingår i: Boken om pedagogerna. - : Liber, Stockholm. - 9147052309 ; , s. 148-169
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Bokkapitel (populärvet., debatt m.m.)abstract
- Boken är en aktuell och mångfacetterad beskrivning av vårt pedagogiska arv och dagens skolverklighet. Viktiga frågor som rör utbildningens innehåll, form och mål har fått en särskilt framträdande plats. Kapitlet presenterar Montessoripedagogikens filosofiska idé och gör nedslag i den praktiska tillämpningen från förskola till grundskolans senare år.
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| 5. |
- Ahlqvist, Eva-Maria, et al.
(författare)
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Allt ljus på Montessoripedagogiken
- 2007
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Ingår i: Sydsvenska Dagbladet. ; :2007-05-21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
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| 7. |
- Ahlsson, Fredrik, et al.
(författare)
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Females born large for gestational age have a doubled risk of giving birth to large for gestational age infants
- 2007
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 96:3, s. 358-362
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To analyse if females born large for gestational age (LGA) have an increased risk to give birth to LGA infants and to study anthropometric characteristics in macrosomic infants of females born LGA.Methods: The investigation was performed as an intergenerational retrospective study of women born between 1973 and 1983, who delivered their first infant between 1989 and 1999. Birth characteristics of 47 783 females, included in the Swedish Birth Register both as newborns and mothers were analysed. LGA was defined as >2 SD in either birth weight or length for gestational age. The infants were divided into three subgroups: born tall only, born heavy only and born both tall and heavy for gestational age. Multiple logistic and linear regression analyses were performed.Results: Females, born LGA with regard to length or weight, had a two-fold (adjusted OR 1.96, 95% Cl 1.54-2.48) increased risk to give birth to an LGA infant. Females, born LGA concerning weight only, had a 2.6 (adjusted OR 2.63, 95%, 1.85-3.75) fold increased risk of having an LGA offspring heavy only and no elevated risk of giving birth to an offspring that was tall only, compared to females born not LGA. In addition, maternal obesity was associated with a 2.5 (adjusted OR 2.56, 95%, 2.20-2.98) fold increased risk of having an LGA newborn, compared to mothers with normal weight.Conclusion: Females, born LGA, have an increased risk to give birth to LGA infants, compared to mothers born not LGA. Maternal overweight increases this risk even further.
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| 8. |
- Anderzén-Carlsson, Agneta, 1966-, et al.
(författare)
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Fear in children with cancer : observations at an outpatient visit
- 2008
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Ingår i: Journal of Child Health Care. - London : Sage. - 1367-4935 .- 1741-2889. ; 12:3, s. 191-208
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to describe interactions within the family and between them and professionals on a routine visit at a paediatric oncology outpatient clinic where the visiting child was likely to be fearful. Observations were performed. Data were analysed by qualitative content analysis. The behaviours most frequently observed as expressing fear were being quiet, withdrawn or providing detailed descriptions of experiences. Within the theme `Recognition of the fear', an attentive attitude to the fear was traced; fear was confirmed and cooperation was seen. Although many efforts were made to meet the fear, this was not always successful. Within the theme `Lack of attention to the fear', the fear was not in focus due to parental worries and concerns about the child's health, and organizational disturbances. The results can serve as a basis for collegial reflections of how to handle fear in children with cancer.
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| 9. |
- Annerbäck, Eva-Maria, 1948-, et al.
(författare)
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Severe child abuse: a study of cases reported to the police
- 2007
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 96:12, s. 1760-1764
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate the characteristics of severe abuse of children and possible differences in comparison with less severe abuse. Method: Cases of abuse reported to the police within a single police district (n = 142) in Sweden were studied. The severe cases were compared to all the remaining cases. Results: Severe abuse constituted 14% of the total cases and was reported by agencies to a greater degree than minor cases. The suspected perpetrators were socially disadvantaged people in both groups. Half of the most serious cases led to conviction in the courts, compared to 8% in the reference group. The children who had been subjected to abuse were often already known to social services and reports of child abuse had frequently been made. Conclusion: In comparison between cases of severe and minor child abuse reported to the police, the results did not show any crucial differences except the pattern of reporting and a higher occurrence of prosecution/conviction in the severe cases. This finding places a responsibility on agencies outside of the justice system to consider all cases of reported abuse as serious warning signals and to make independent evaluations to identify risks and the possible need for child protection.
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| 10. |
- Axaeus, Jennie, 1974-, et al.
(författare)
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Portar till språk och litteratur : CSL 2007
- 2007
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Språk och litteratur öppnar portar till nya världar. Detta var temat för 2007 års CSL-dag. I denna bok har vi samlat fjorton av bidragen som presenterades på konferensen, skrivna av forskare och studenter vid Karlstads universitet.Håller engelskan på att förstöra svenskan? Är dagens elever sämre på att skriva än ungdomarna var för tjugo år sedan? Skall vi ha en litteraturkanon i skolan - och läser eleverna över huvud taget böcker nu för tiden? Detta är några av de frågor som ställs i artiklarna där svaren kanske kan överraska.Andra artiklar handlar om hur man stimulerar elever till att läsa och skriva, problematiken när det gäller att undervisa i svenska som andraspråk och varför elever väljer - eller inte väljer - att studera något annat främmande språk än engelska. Porten kanske finns där - men den är inte alltid helt lätt att öppna!
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| 11. |
- Axelsson, Viktoria, et al.
(författare)
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Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.
- 2006
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Ingår i: Biochem Biophys Res Commun. - 0006-291X. ; 345:3, s. 1068-74
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.
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| 12. |
- Benrick, Anna, 1979, et al.
(författare)
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A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
- 2008
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 189-96
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
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| 13. |
- Bondesson, Maria, et al.
(författare)
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A CASCADE of effects of bisphenol A.
- 2009
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 28:4, s. 563-7
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Tidskriftsartikel (refereegranskat)
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| 14. |
- Broberg Palmgren, Karin, et al.
(författare)
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Genetic variant of the human homologous recombination-associated gene RMI1 (S455N) impacts the risk of AML/MDS and malignant melanoma.
- 2007
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 258:1, s. 38-44
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Tidskriftsartikel (refereegranskat)abstract
- The newly identified protein BLAP75/RMI1 associates with the helicase BLM and is critical for the function of the homologous recombination complex. Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom's syndrome). We have analyzed the common polymorphism Ser455Asn in RMI1 and its association with cancer risk in acute myeloid leukemia (AML, N=93), myelodysplatic syndromes (MDS, N=74), and malignant melanoma (MM, N=166). Two control groups were used: one population-based (N=119) and one recruited from spouses of cancer patients (N=189). The results showed a consistent pattern, where carriers of the Asn variant had a significantly increased risk of AML/MDS. The risk of AML/MDS for SerAsn+AsnAsn subjects was odds ratio (OR)=1.7, 95% confidence interval (CI) 1.1-2.5 or MM was OR=1.5, 95% CI 1.0-2.2. Age might modify the effect of RMI1 on cancer risk. This was most evident for MM: AsnAsn homozygotes > or =64 years showed OR=2.7, 95% CI 1.1-6.0, whereas individuals <64 years showed OR=0.87, 95% CI 0.31-2.5. These results indicate a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk.
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| 15. |
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| 16. |
- Forsman, Åsa, et al.
(författare)
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Rattfylleriets omfattning : en metodstudie i Södermanlands, Örebro och Östergötlands län
- 2007
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report presents the results from a study with the aim of estimating the prevalence of drink driving in three Swedish counties, as well as testing the used method in practice. Data was collected by the police that conducted breath tests of drivers of passenger cars and light trucks on randomly selected road sections. The planned sample size was 25,000 drivers, but due to missing data, 22,937 drivers were finally used in the calculations. The study was conducted between 7 am and 11 pm all days of the week during the period June 2006 to May 2007. The estimated prevalence of drink driving is 0.24 % (0.15 %; 0.32 %) where the numbers in parenthesis is a 95 per cent confidence interval. The results show significant difference in the prevalence of drink driving between men and women (0.32 and 0.04 per cent). Differences between different age groups are also present; the prevalence is lower for youngest group (16-34 years) than for the two other groups (25-64 years and over 65 years). Drink driving also turned out to be more prevalent in the morning than in the afternoon/evening, 0.62 against 0.11 per cent. In general, the method worked well, but a few things need to be changed in a future study. For example, we must ensure that the control sites are safe for the policemen also in the dark and in bad weather. It is also necessary to discuss how the police can get sufficient resources to conduct the survey.
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| 17. |
- Fryknäs, Mårten, et al.
(författare)
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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
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| 18. |
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| 19. |
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| 20. |
- Gustafsson, Anna-Maria, et al.
(författare)
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Influence of natural convection in water-filled boreholes for GCHP
- 2008
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Ingår i: ASHRAE Transactions. - 0001-2505. ; 114:1, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- In groundwater filled borehole heat exchangers (BHE), convective flow inside the borehole water will affect the heat transfer. Since the convective flow is dependent of the temperature gradient, different injection rates and ground temperatures will result in different borehole thermal resistance. This paper describes the influence of natural convection in water-filled boreholes in impermeable bedrock for ground-coupled heat pump (GCHP) systems. An overview of groundwater-filled boreholes and the influence of groundwater movements are presented followed by numerical simulations and field measurements to further investigate the influence. The results from the simulations of the three-dimensional, steady-state model of a 9.8 ft (3 m) deep BHE are compared to evaluated results from performed thermal response test (TRT). The results show that convective flow in groundwater-filled BHE results in 5-9 times more efficient heat transfer compared to stagnant water when heat carrier temperatures are in the range of 50-86°F (10-30°C). The size of the convective flow depends on the temperature gradients in the borehole. This shows the importance of on-site investigation of thermal properties using appropriate power injection rates similar to those in the system to be built. This research is part of an on-going project to find ways to estimate the heat transfer including convective flow and to incorporate the findings into the design of GCHP systems. TRT are today a common way to determine heat transfer properties for a BHE and its surroundings. Performing TRT measurements with several injection rates is a way to evaluate the dynamic thermal response including the change in convective flow due to changes in temperature levels. If this dynamic response would be included in design tools a more thorough design of the BHE system is performed. Here, the early result of this research is presented
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| 21. |
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| 22. |
- Gustafsson, Anna-Maria
(författare)
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Thermal response test : numerical simulations and analyses
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When constructing large borehole heat exchanger (BHE) systems, bedrock and borehole thermal properties are vital for a good design. Today's design programs presume conductive heat transfer in both borehole and bedrock. In groundwater-filled boreholes, however, convective flow will be induced in the groundwater due to the occurring temperature gradients. The resulting more efficient heat transfer lowers the borehole thermal resistance. A 3 m long borehole was numerically studied to investigate the effect of heat injection on natural convection in a groundwater-filled borehole heat exchanger in impermeable bedrock. A convective flow with rising water close to the U-pipe and descending water at the borehole wall was induced. The flow rates in the groundwater are determined by the temperature gradient in the borehole. A higher injection rate results in a larger convective heat transfer, lowering the borehole thermal resistance. An equivalent radius model was also constructed in order to examine possible model simplifications. Using an annulus instead of a more complex U-pipe geometry may radically decrease the required computer capacity and calculation time. The result shows that for a solid bedrock model, borehole mean heat transfer patterns are similar for both models. Therefore, it may be possible to use the simpler equivalent radius model to simulate the convective heat transfer in borehole heat exchangers. Thermal response tests in boreholes were also conducted to investigate the effect of different power and temperature levels on convective heat transfer. A decrease in borehole thermal resistance is seen for higher fluid temperatures. A cold injection test was also performed. The resulting lower temperatures in the borehole increase the borehole thermal resistance, and leading to the formation of ice in the borehole. These tests indicate the importance of using different borehole thermal resistances in BHE design calculations, if the system should operate under several power levels. Thermal response test while drilling was investigated as an alternative method to the standard thermal response test. With this new method, bedrock conductivity would be continuously determined along the borehole. Therefore, bedrock anomalies such as fractures may be detected. The method is investigated for water driven down-the-hole hammers. A numerical model was developed to investigate the thermal response to heat release during drilling. The results show that by providing measurements of high accuracy and precision, occurring small changes in conductivity may be detectable. This licentiate thesis is the first part of a PhD thesis. It summarises the results of the study on the effect of natural convection on BHEs, as well as theoretical investigation of a new thermal response test method. To fulfil the PhD, the influence of groundwater movement on thermal response tests will be further studied with numerical models and field tests. The goal is to implement the result in BHE design calculation programs and TRT analysis. This licentiate thesis includes two submitted journal articles and one conference paper.
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| 23. |
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| 24. |
- Gustafsson, Anna-Maria, et al.
(författare)
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Thermal response test while drilling
- 2006
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Ingår i: Thermal energy storage. - Pomona, NJ : Richard Stockton College of NJ.
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Konferensbidrag (refereegranskat)
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| 25. |
- 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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| 26. |
- Gustafsson Liljefors, Maria
(författare)
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Immunotherapy with the anti-EpCAM monoclonal antibody and cytokines in patients with colorectal cancer : a clinical and experimental study
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tumor-associated antigen EpCAM (epithelial cell-adhesion molecule) (C017-1A) is over expressed by various human carcinomas, including colorectal carcinoma (CRC). This antigen can be used as a target structure for specific immunotherapy with vaccines and monoclonal antibodies (MAb). Addition of cytokines to MAb therapy may augment immune effector functions and chemotherapeutic agents may also add to therapeutic efficacy. In this thesis, we have analysed clinical and immunological responses of patients with advanced CRC treated with either the murine anti-EpCAM MAb (anti-EpCAM mMAb) or its chimeric counterpart (antiEpCAM cMAb) in combination with cytokines and chemotherapeutics. Additionally, sequential analysis of cytokeratin positive (CK+) cells in the bone marrow (BM) were made in CRC patients receiving MAb based therapy for advanced disease or as adjuvant therapy. Pretreatment natural killer (NK) cell cytotoxicity in vitro of peripheral blood mononuclear cells was an independent prognostic factor for overall survival and progression free survival (PFS) in patients receiving anti-EpCAM MAb based therapy as first-line therapy. The results from this study might be used for future patient selection and indicate that agents that activate NK cells should be considered to MAbbased treatment regimens. The addition of GM-CSF, alpha-interferon and 5-fluorouracil to anti-EpCAM mMAb seemed to improved the antitumor response rate compared to historical control patients treated with anti-EpCAM mMAb alone (54% vs 15%) as well as PFS (15 vs 7 weeks). Clinical effects were mainly stable disease > 3months (11 of 14 responders) and responding patients survived longer than non-responders. The clinical efficacy of antiEpCAM cMAb and GMCSF was not better than in a historical control group who had received the antiEpCAM mMAb and GM-CSF (overall response rates=21% vs 27%, respectively). Anti-idiotypic antibody (Ab2) concentrations as well as the frequency of patients mounting an Ab2response in antiEpCAM eMAb treated patients were lower as compared to anti-EpCAM mMAb-treated patients (69% vs 100%). Following repeated daily subcutaneous (s.c.) injections of exogenous non-glycosylated E.coli-derived GM-CSF (molgramostim), the peak serum GM-CSF concentrations declined days 5 and 10 as compared to day 1. A dose-dependent increment in total white blood cell count was observed, the total numbers of GM-CSF receptor expressing cells increased during treatment while a transient decline in expression intensity was observed at day 5. The majority of patients developed binding but not neutralizing antiGM-CSF antibodies. These results might support a receptor-mediated clearance of GM-CSF from the circulation. Importantly, high dose of GM-CSF resulted in lower antibody-dependent cellular cytotoxicity that may reflect immune suppression. Further studies are required to establish the optimal biological dose of different cytokines. CK+ cells in BM were examined by immunohistochemistry on routinely processed BM clots, and CK+ cells were divided into different subtypes; Group A (CK+ probably malignant epithelial cells), Group B (CK+ morphologically non-epithelial cells) and Group C (CK+ contaminating cells). The presence of Group A cells did not adversely affect the prognosis while the presence of Group B cells probably indicates a poor prognosis in patients receiving adjuvant therapy. Sequential BM aspirations do not seem to add to the existing methods to follow the effect of treatment in CRC. These results might provide further clinical studies with MAbs, combined with other agents with different modes of action to increase the clinical efficacy of MAb. Ideally, patients with a well preserved immune system and low or minimal tumor burden should be selected to MAb-based therapy.
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| 27. |
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| 28. |
- Gustafsson, Maria, 1976, et al.
(författare)
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Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse. Evidence for a Role of Lipoprotein Lipase
- 2007
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Ingår i: Circ Res. - 1524-4571. ; 101:8, s. 777-783
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Tidskriftsartikel (refereegranskat)abstract
- Direct binding of apolipoprotein (apo)B-containing lipoproteins to proteoglycans is the initiating event in atherosclerosis, but the processes involved at later stages of development are unclear. Here, we investigated the importance of the apoB-proteoglycan interaction in the development of atherosclerosis over time and investigated the role of lipoprotein lipase (LPL) to facilitate low-density lipoprotein (LDL) retention at later stages of development. Atherosclerosis was analyzed in apoB transgenic mice expressing LDL with normal (control LDL) or reduced proteoglycan-binding (RK3359-3369SA LDL) activity after an atherogenic diet for 0 to 40 weeks. The initiation of atherosclerosis was delayed in mice expressing RK3359-3369SA LDL, but they eventually developed the same level of atherosclerosis as mice expressing control LDL. Retention studies in vivo showed that although higher levels of (131)I-tyramine cellobiose-labeled control LDL ((131)I-TC-LDL) were retained in nonatherosclerotic aortae compared with RK3359-3369SA (131)I-TC-LDL, the retention was significantly higher and there was no difference between the groups in atherosclerotic aortae. Lower levels of control (125)I-TC-LDL and RK3359-3369SA (125)I-TC-LDL were retained in atherosclerotic aortae from ldlr(-/-) mice transplanted with lpl(-/-) compared with lpl(+/+) bone marrow. Uptake of control LDL or RK3359-3369SA LDL into macrophages with specific expression of human catalytically active or inactive LPL was increased compared with control macrophages. Furthermore, transgenic mice expressing catalytically active or inactive LPL developed the same extent of atherosclerosis. Thus, retention of LDL in the artery wall is initiated by direct LDL-proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL.
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| 29. |
- Gustafsson, Maria
(författare)
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Signal integration between notch and hypoxia : insights into development and disease
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oxygen is essentially required for aerobic metabolism in most eukaryotic organisms. Therefore, it is striking that a number of tissues develop, and are maintained at low oxygen (hypoxic) conditions in the body. For instance, the human embryo is located in a hypoxic environment. At the cellular level, hypoxia activates a signaling pathway, governed by hypoxia inducible factor (HIF-1α). Hypoxic adaptation leads to induced erythropoiesis and angiogenesis, as well as a switch to glycolytic metabolism. In addition, hypoxia also promotes the undifferentiated cell state in various stem and precursor cell populations. One of the principal signaling mechanisms that controls development, is Notch signaling, an evolutionarily conserved pathway involved in cell fate decisions. In this thesis, I have investigated the interplay of hypoxia with the Notch signaling pathway. Here we showed that Notch signaling is required for hypoxia-mediated reduction of progenitor cell differentiation (Paper I). Hypoxia blocked neuronal and myogenic differentiation in a Notch-dependent manner. Furthermore, the Notch intracellular domain (ICD) interacted with HIF-1α, and HIF-1α was recruited to Notch-responsive promoters upon Notch activation during hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process. Hypoxia signaling pathway is frequently involved in several adult pathologies, including cardiovascular disease and cancer. Therefore, it is interesting from at therapeutic prospective to investigate whether the link between hypoxia and Notch signaling also synergize during tumor development. Specifically, hypoxia induces epithelial-mesenchymal transition (EMT), which leads to increased migration of tumor cells, and clinically associates with an aggressive tumor phenotype. However, the molecular mechanisms linking hypoxia to EMT in tumors are poorly understood. In Paper II, we report that Notch signaling is critically required to convert a hypoxic stimulus into EMT in tumor cells. Inhibition of Notch signaling abrogated the hypoxia-induced EMT and reduced cell migration. Furthermore, Notch positively regulated the level of the EMT inducer Snail-1 in two distinct ways: through direct transcriptional control of Snail-1 and indirectly, through increased lysyl oxidase expression. In sum, these data provide support for a hypoxia-Notch-EMT link in tumor cells. The hypoxia inducible transcription factors (HIFs) are regulated at the level of protein stability and transcriptional activity in an oxygen-dependent manner by prolyl and asparaginyl hydroxylation, respectively. Both these families of hydroxylating enzymes use oxygen as co-substrates, and thus are oxygen sensors in the cell. In the presence of oxygen, the hydroxylase Factor inhibiting HIF-1α (FIH-1) targets a conserved asparaginyl residue within the C-terminal transactivation activation domain (C-TAD) of HIF-α, leading to repression of HIF-mediated transcription by abrogating recruitment of cofactors. In Paper III, we identify Notch as a novel substrate for hydroxylation by FIH-1, providing yet another interaction point between hypoxia and Notch signaling. Notch ICD was hydroxylated at an asparaginyl residue within its ankyrin repeat region. In addition, FIH-1 interacted with Notch, and enforced expression of FIH-1 resulted in abrogated Notch activity. Furthermore, FIH-1 increased differentiation of myocytes, in keeping with the inhibitory effect of FIH on Notch signaling. These data show that FIH-1 interacts with Notch ICD, and is capable of reducing Notch activity. To more closely investigate the temporal and spatial aspects of Notch signaling, we designed a fluorescent reporter assay that allows Notch activation to be followed in real time in individual cell (Paper IV). We generated a reporter construct composed of 12 CSL-binding motifs linked to two fluorescent proteins. After transfection into cells, the reporters rapidly responded to various forms of Notch activation, including ligand activation of full-length Notch receptors. Finally, we used this assay to gain insights into the level of Notch signaling in CNS progenitor cells in culture and in vivo. To conclude, we have identified a crosstalk between hypoxia and Notch signaling. Our results show that there is a functional relationship between Notch, hypoxia and FIH in the control of progenitor cell differentiation. In addition, we have shown that the hypoxia-Notch link also occurs in tumors, and is specifically important for hypoxia-induced EMT.
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| 30. |
- Gustafsson, Sofia B, et al.
(författare)
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Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells : synergism with 5-fluorouracil
- 2009
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Berlin/Heidelberg. - 0344-5704 .- 1432-0843. ; 63:4, s. 691-701
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Tidskriftsartikel (refereegranskat)abstract
- Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [3H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, α-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.
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| 31. |
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| 32. |
- Gustafsson, Ulla-Maria, 1957-
(författare)
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Anal Fistula : Aspects of Aetiology, Diagnosis and Prognosis After Surgical Treatment
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with idiopathic anal fistula (n=85) were compared with 215 control subjects, matched for age and sex, through a 180-item questionnaire. Obesity, smoking, constipation and bowel symptoms associated with IBS were more common in the patients.Endoanal ultrasound (EUS) and magnetic resonance imaging (MRI) were compared in the preoperative evaluation of anal fistula in 23 patients. For classifying the primary tract, EUS and surgical findings agreed in 14 cases, and MRI and surgery for 11: for identifying an internal opening, the corresponding figures were 17 and 10.Healing and sphincter function were studied in 42 patients operated with fistula excision and closure of the internal opening. Twenty-three patients healed primarily and another 10 after one re-operation, whereas nine required further surgery until healed. Anal resting pressure was reduced after three and 12 months, and squeeze pressure after 12 months.Eighty-three patients were randomised to surgery with or without application of gentamicin-collagen underneath the flap: 26/42 of patients randomised to gentamicin-collagen healed primarily compared with 21/41 of patients randomised to surgery only (n.s).Micro perfusion in the flap was studied by laser Doppler flowmetry during surgery in 16 patients. No correlation was seen between change in blood flow during surgery and non-healing/recurrence of the fistula.In conclusion, obesity, functional bowel symptoms and possibly smoking are more common in patients with idiopathic anal fistula than in the general population. Endoanal ultrasound is a useful tool in the preoperative evaluation of anal fistula. Advancement flap repair has a reasonably high primary recurrence rate and healing is not significantly improved by local application of gentamicin-collagen: impaired intraoperative blood perfusion of the flap is an unlikely reason for non-healing. A decrease in continence occurs also after this kind of surgery, probably due to an impaired internal anal sphincter function.
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| 33. |
- Gustafsson, Ulla Maria, et al.
(författare)
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Randomized clinical trial of local gentamicin-collagen treatment in advancement flap repair for anal fistula
- 2006
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 93:10, s. 1202-1207
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Tidskriftsartikel (refereegranskat)abstract
- Background: Endoanal advancement flap repair is widely used in sphincter-preserving surgery for anal fistula, but the high recurrence rate is a major problem. A possible cause of non-healing is local infection of the flap. The aim of this study was to evaluate whether local antibiotic treatment with gentamicin-collagen improves healing after endoanal advancement flap repair for anal fistula. Methods: Eighty-three patients (52 men and 31 women; mean age 47 (range 17-71) years) who had endoanal advancement flap repair for anal fistula between September 1998 and January 2004 were randomized to surgery with (42 patients) or without (41 patients) application of gentamicin-collagen beneath the flap. Patients were evaluated at 1-3 and 12 months after surgery for healing and/or recurrence. Results: The overall healing rate with no recurrence at 1 year after surgery was 57 per cent (47 of 83). Twenty-six of 42 patients randomized to gentamicin-collagen healed primarily compared with 21 of 41 patients randomized to surgery only. There were no overall differences in healing rate according to sex, previous fistula surgery, complexity of fistula, smoking habit or body mass index. Conclusion: Endoanal advancement flap repair for anal fistula has a fairly high primary recurrence rate. Healing was not significantly improved by local application of gentamicin-collagen.
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| 34. |
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| 35. |
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| 36. |
- Halldin Stenlid, Maria U., et al.
(författare)
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Increased lipolysis in LCHAD deficiency
- 2007
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 30:1, s. 39-46
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of fatty acid oxidation defects are being detected owing to diagnostic improvements and a greater awareness among clinicians. The metabolic block leads to energy disruption, fatty infiltration, and toxic effects on organ functions exerted by β-oxidation metabolites. This investigation was undertaken to assess the influence of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency on lipolysis and energy turnover. We addressed the question whether the lipolysis and glucose production rates would be altered in the fasting state in a child with this disease. Lipolysis, glucose production and resting energy expenditure (REE) were studied in a 17-month-old girl with LCHAD deficiency and her healthy twin sister. Lipolysis and glucose production were determined after a 4–6 h fast by constant-rate infusion of [1,1,2,3,3-2H5]glycerol and [6,6-2H2]glucose and analysis by gas chromatography–mass spectrometry. REE was estimated by indirect calorimetry. The affected girl showed 50% higher lipolysis than did her sister, whereas the glucose production rates were similar. Plasma levels of dicarboxylic acids of 6–12 carbon atoms chain length, 3-hydroxy fatty acids of 6–18 carbon atoms chain length, total free fatty acids, and acylcarnitines were increased in the patient, as was REE. Since glucose production rates and plasma glucose levels were similar in the two girls, the increased lipolysis observed in the patient probably represents a compensatory mechanism for energy generation. This is achieved at the price of an augmented risk for fatty acid infiltration and toxic effects of β-oxidation intermediates. This highlights the importance of avoiding fasting in these patients.
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| 37. |
- Henricsson, Cecilia, 1975, et al.
(författare)
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Engineering of a novel Saccharomyces cerevisiae wine strain with a respiratory phenotype at high external glucose concentrations
- 2005
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Ingår i: Applied and Environmental Microbiology. - 0099-2240 .- 1098-5336. ; 71:10, s. 6185-6192
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Tidskriftsartikel (refereegranskat)abstract
- The recently described respiratory strain Saccharomyces cerevisiae KOY.TM6*P is, to our knowledge, the only reported strain of S. cerevisiae which completely redirects the flux of glucose from ethanol fermentation to respiration, even at high external glucose concentrations (27). In the KOY.TM6*P strain, portions of the genes encoding the predominant hexose transporter proteins, Hxt1 and Hxt7, were fused within the regions encoding transmembrane (TM) domain 6. The resulting chimeric gene, TM6*, encoded a chimera composed of the amino-terminal half of Hxt1 and the carboxy-terminal half of Hxt7. It was subsequently integrated into the genome of an hxt null strain. In this study, we have demonstrated the transferability of this respiratory phenotype to the V5 hxt1-7 strain, a derivative of a strain used in enology. We also show by using this mutant that it is not necessary to transform a complete hxt null strain with the TM6* construct to obtain a nonethanol- producing phenotype. The resulting V5.TM6*P strain, obtained by transformation of the V5 hxt1-7 strain with the TM6* chimeric gene, produced only minor amounts of ethanol when cultured on external glucose concentrations as high as 5%. Despite the fact that glucose flux was reduced to 30% in the V5.TM6*P strain compared with that of its parental strain, the V5.TM6*P strain produced biomass at a specific rate as high as 85% that of the V5 wild-type strain. Even more relevant for the potential use of such a strain for the production of heterologous proteins and also of low-alcohol beverages is the observation that the biomass yield increased 50% with the mutant compared to its parental strain.
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| 38. |
- Häger, Mattias, et al.
(författare)
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Cib2 binds integrin a7Bb1D and is reduced in laminin a2 chain deficient muscular dystrophy
- 2008
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 283:36, s. 24760-24769
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the gene encoding laminin alpha 2 chain cause congenital muscular dystrophy type 1A. In skeletal muscle, laminin alpha 2 chain binds at least two receptor complexes: the dystrophin-glycoprotein complex and integrin alpha 7 beta 1. To gain insight into the molecular mechanisms underlying this disorder, we performed gene expression profiling of laminin alpha 2 chain-deficient mouse limb muscle. One of the down-regulated genes encodes a protein called Cib2 (calcium-and integrin-binding protein 2) whose expression and function is unknown. However, the closely related Cib1 has been reported to bind integrin alpha IIb and may be involved in outside-in-signaling in platelets. Since Cib2 might be a novel integrin alpha 7 beta 1-binding protein in muscle, we have studied Cib2 expression in the developing and adult mouse. Cib2 mRNA is mainly expressed in the developing central nervous system and in developing and adult skeletal muscle. In skeletal muscle, Cib2 colocalizes with the integrin alpha 7B subunit at the sarcolemma and at the neuromuscular and myotendinous junctions. Finally, we demonstrate that Cib2 is a calcium-binding protein that interacts with integrin alpha 7B beta 1D. Thus, our data suggest a role for Cib2 as a cytoplasmic effector of integrin alpha 7B beta 1D signaling in skeletal muscle.
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| 39. |
- Ihre, E, et al.
(författare)
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Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge
- 2006
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 27:6, s. 1152-9
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Tidskriftsartikel (refereegranskat)abstract
- Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (F(e,NO)) and urinary biomarkers of airway inflammation. Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and F(e,NO) and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine. Despite no change in pulmonary function (forced expiratory volume in one second mean+/-sem fall 0.3+/-0.7 versus 0.6+/-1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in F(e,NO) (up to a doubling from baseline) and a small increase in the mast cell marker 9alpha11beta-prostaglandin F(2) after adenosine challenge. In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.
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| 40. |
- Klemedtsson, Leif, 1953, et al.
(författare)
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Bayesian calibration method used to elucidate carbon turnover in forest on drained organic soil
- 2008
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Ingår i: Biogeochemistry. - : Springer Science and Business Media LLC. - 0168-2563 .- 1573-515X. ; 89:1, s. 61-79
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Tidskriftsartikel (refereegranskat)abstract
- Depending on the balance between sink and source processes for C, drained organic forest soil ecosystems can be in balance or act as net sinks or sources of CO2 to the atmosphere. In order to study the effect of groundwater level and soil temperature on C-flux, the CoupModel was calibrated (climate data, groundwater levels, soil CO2 flux, net ecosystem fluxes of CO2-exchange, sensible heat flux and latent heat flux, forest production etc.) for a drained forest in Sweden. Bayesian calibration techniques were used to elucidate how different parameters and variables were interlinked in C-circulation. The calibrated model reproduced abiotic and biotic variables reasonably well except for root respiration, which was largely underestimated. Bayesian calibration reduced the uncertainties in the model and highlighted the fact that calibrations should be performed with a high number of parameters instead of specific parameter values.
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| 41. |
- Kneider, Maria, et al.
(författare)
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Sequence analysis of human rhinovirus aspirated from the nasopharynx of patients with relapsing-remitting MS.
- 2009
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 15:4, s. 437-42
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundUpper respiratory infections were reported to trigger multiple sclerosis relapses. A relationship between picornavirus infections and MS relapses was recently reported.ObjectiveTo evaluate whether human rhinovirus is associated with multiple sclerosis relapses and whether any particular strain is predominant.MethodNasopharyngeal fluid was aspirated from 36 multiple sclerosis patients at pre-defined critical time points. Reverse-transcriptase-PCR was performed to detect human rhinovirus-RNA. Positive amplicons were sequenced.ResultsWe found that rhinovirus RNA was present in 17/40 (43%) of specimens obtained at the onset of a URTI in 19 patients, in 1/21 specimens during convalescence after URTI in 14 patients, in 0/6 specimens obtained in 5 patients on average a week after the onset of an "at risk" relapse, occurring within a window in time from one week before to three weeks after an infection, and in 0/17 specimens obtained after the onset of a "not at risk" relapse not associated with any infection in 12 patients. Fifteen specimens from healthy control persons not associated with URTI were negative. The frequency of HRV presence in URTI was similar to that reported for community infections. Eight amplicons from patients represented 5 different HRV strains.ConclusionWe were unable to reproduce previous findings of association between HRV infections and multiple sclerosis relapses. HRV was not present in nasopharyngeal aspirates obtained during "at risk" or "not at risk" relapses. Sequencing of HRV obtained from patients during URTI did not reveal any strain with predominance in multiple sclerosis.
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| 42. |
- Kriström, Berit, et al.
(författare)
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Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature
- 2009
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:2, s. 483-490
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.
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| 43. |
- Lalander, Rickard, et al.
(författare)
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Movimiento indígena y liderazgo político local en la Sierra ecuatoriana: : ¿Actores políticos o proceso social?
- 2008
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Ingår i: Provincia: Revista venezolana de estudios territoriales. ; :19
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Tidskriftsartikel (refereegranskat)abstract
- The indigenous movement in Ecuador has combined social mobilization with political institutionalization. The organic relation between the social movement CONAIE and the political party (or movement) Pachakutik has been successful, but also complicated, giving rise to internal conflicts and fragmentation. In this study the relations between Pachakutik and CONAIE are analyzed at the local level in Otavalo and Cotacachi. The authors argue for the importance to analyze the organizational structures locally, since the indigenous movements has been strongest at this level. In Otavalo the ethnic tensions have been clearly manifested through rupture of the mayor, Mario Conejo who left Pachakutik and created a new political movement – Minga Intercultural-. The case of Cotacachi is likewise particular since an alliance is established between the mayor Auki Tituaña and the peasant movement, UNORCAC (with links to the Socialist Party). Drawing on an analytical framework of collective action and decentralization the authors argue that it is impossible to draw an exact line between what is the social and the political movement.
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| 44. |
- Lalander, Rickard, et al.
(författare)
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¿Proceso social o actores políticos? : Reflexiones sobre Pachakutik y CONAIE desde Imbabura
- 2008
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Ingår i: Aportes Andinos. ; :21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- El movimiento indígena ecuatoriano ha combinado movilización social con institucionalización política. La relación orgánica entre el movimiento social –CONAIE- y el partido (o movimiento) político -Pachakutik- ha sido tanto exitosa como complicada, con implicaciones en formas de conflictos internos y fragmentación. En el presente estudio se analizan las relaciones entre Pachakutik y la CONAIE a nivel local: los casos de los cantones Otavalo y Cotacachi. Se argumenta sobre la importancia de analizar las estructuras organizativas a nivel local, ya que es allí donde el movimiento indígena ecuatoriano ha tenido su fortaleza principal. En Otavalo las tensiones de carácter étnico se han manifestado claramente, incluso con la reciente desafiliación del Alcalde Mario Conejo de las filas de Pachakutik y la emergencia de otro movimiento político local –la Minga Intercultural- alrededor del alcalde. El caso de Cotacachi igualmente se presenta contradictorio, ya que allí la alianza principal del Alcalde Auki Tituaña es con una organización campesina indígena fuera de la CONAIE, la UNORCAC (asociada al Partido Socialista Ecuatoriano). Dentro del marco analítico de acción colectiva y la descentralización, los autores arguyen que en la práctica es imposible crear una frontera definitiva entre lo que se debería clasificar como movimiento social y/o político respectivamente.
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| 45. |
- Landtblom, Anne-Marie, et al.
(författare)
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Absolute metabolite concentrations in cerebral white matter of multiple sclerosis patients with beta interferon treatment
- 2008
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 14:Suppl. 1, s. S162-S162
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Tidskriftsartikel (refereegranskat)abstract
- Background: A few investigations concern interferon (IFN)-treated multiple sclerosis (MS) patients using proton spectroscopy, however not with an absolute quantitation or during extended treatment.Objective: To quantify metabolite changes during IFN therapy using magnetic resonance spectroscopy.Methods: We included 14 MS patients, (9 men, 5 women, mean age 41.8 years, mean disease duration 10.9 years, 9 with relapsing-remitting MS, 6 with secondary progressive and bouts) scheduled for immunomodulatory treatment (5 IFN1A, 9 IFN1B) as well as 14 healthy controls, (8 men, 6 women, mean age 40.2 years). All patients had clinically definite MS (Poser criteria). Measurements were performed in white matter (four voxels).Results: Longitudinal results: N-acetylaspartate + Nacetylapartylglutamate (NAA+NAAG) showed a trend to higher values before treatment. Myo-inositol concentrations were significantly and increasingly elevated (p=0.03). Glutamine and glutamate concentrations dropped significantly (p=0.009) after treatment started but raised later. MS patients/ healthy controls: Creatine and myo-inositol concentrations were significantly higher in MS patients before and after treatment. NAA + NAAG concentrations were significantly lower before and after treatment. Glutamine and glutamate concentrations were higher before therapy, later equal to healthy controls.Conclusions: IFN-treated patients demonstrate increasing myoinositol, a marker of progressive glial proliferation. Also, decreasing concentrations of total NAA derivatives despite IFN therapy suggest ongoing progressive pathology and constant neuronal loss in the course of MS. MS patients compared with matched healthy controls show highly significant differences regarding metabolites (Cr, myo- Ins, NAA) that increase during the therapy period, also indicating that the medication can only moderately influence the metabolites. The most interesting finding is related the excitatory molecules, glutamine and glutamate. Before IFN therapy statistical analysis showed significant elevation in the concentrations; however after IFN therapy this difference is no longer observed. This finding underlines a possible role of IFN in the expression of down-regulating excitotoxic molecules.
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| 46. |
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| 47. |
- Linder, Tomas, et al.
(författare)
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A family of putative transcription termination factors shared amongst metazoans and plants.
- 2005
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Ingår i: Current genetics. - : Springer Science and Business Media LLC. - 0172-8083 .- 1432-0983. ; 48:4, s. 265-9
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Tidskriftsartikel (refereegranskat)abstract
- The human mitochondrial transcription termination factor (mTERF) is involved in the regulation of transcription of the mitochondrial genome. Similarity searches and phylogenetic analysis demonstrate that mTERF is a member of large and complex protein family (the MTERF family) shared amongst metazoans and plants. Interestingly, we identify three novel MTERF genes in vertebrates, which all encode proteins with predicted mitochondrial localization. Members of the MTERF family have so far not been detected in fungi, supporting the notion that mitochondrial transcription regulation may have evolved separately in yeast and animal cells.
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| 48. |
- Lindhagen, Elin, et al.
(författare)
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In vitro activity of 20 agents in different prognostic subgroups of chronic lymphocytic leukaemia : rolipram and prednisolone active in cells from patients with poor prognosis
- 2009
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 83:1, s. 22-34
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a need for development of new drugs for treatment of B-cell chronic lymphocytic leukemia (CLL), especially for poor-prognostic subgroups resistant to conventional therapy. Objective: The in vitro antileukaemic activity of 20 different anticancer agents was characterized in tumour cells from CLL, aiming at identifying agents active in poor-prognostic subgroups.Design and methods: In tumour cells from 40 CLL patients and in peripheral blood mononuclear cells (PBMC) from 3 healthy controls, the activity of 20 substances was assessed using a non-clonogenic assay. The CLL samples were characterized regarding genomic aberrations by interphase FISH and immunoglobulin heavy-chain variable (IGHV) gene mutational status.Results:In line with clinical experience, cells from patients with unfavourable genomic aberrations (del(11q)/del(17p)) showed lower drug sensitivity to fludarabine and chlorambucil than cells from patients with favourable cytogenetics (del(13q)/no aberration). Most investigated drugs demonstrated similar activity in CLL cells from patients with unmutated and mutated IGHV genes as well as in CLL cells versus PBMC. Interestingly, prednisolone and rolipram displayed high CLL specificity, high activity in CLL cells with unmutated IGHV genes and retained the effect in several cases with 11q/17p deletion. Further studies on prednisolone and rolipram revealed a synergy when these agents were combined in CLL cells, and suggested correlation between drug sensitivity and difference in downstream signalling.Conclusion:Prednisolone and rolipram are interesting for further studies in CLL with inferior prognosis. The study can also be considered a basis for future efforts to find drugs active in subsets of CLL patients that are resistant to conventional therapy.
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- Monsén, Maria, et al.
(författare)
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Noise and sleep disturbance factors before and after implementation of a behavioural modification programme
- 2005
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Ingår i: Intensive & Critical Care Nursing. - : Elsevier BV. - 0964-3397 .- 1532-4036. ; 21:4, s. 208-219
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to examine sleep disturbance factors documented by the personnel and recorded noise level during two weeks before (measurement one M1) and after (measurement two M2) the implementation of a behavioural modification programme. The behavioural modification programme included non-disturbance periods on a neurointensive care unit (NICU) in a University hospital. Sleep disturbance factors were identified as general and specific nursing care, and medical treatment documented over fourteen 24-h periods. Minimum, maximum and peak mean noise levels in dBA were recorded continuously during fourteen 24-h periods by a decibel meter. The behavioural modified programme included changing nursing and medical routines and the introduction of afternoon and night non-disturbance periods. The most disturbing documented factors at both M1 and M2 were general nursing care activities. Noise levels showed great variation at both M1 and M2. At M2 minimum and maximum noise levels varied when compared to M1. Implementation of a behavioural modification programme and non-disturbance periods co-ordinated routines resulted in reduced sleep disturbance factors and partly reduced noise levels on the NICU. Changes of the physical care/working environment, preparations before non-disturbance periods, regular evaluations of routines and education are needed to improve sleep on NICUs. © 2004 Elsevier Ltd. All rights reserved.
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