Muscle Protein Alterations in LGMD21 Patients With Different Mutations in the Fukutin-related Protein Gene

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 21 form (LGMD21). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, alpha-DG, and alpha 2-laminin, in muscle biopsies from 13 unrelated LGMD21 patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of alpha 2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented a-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD21 patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of alpha 2-laminin and alpha-DG on sections are prevalent, independently of mutation type or clinical severity.

Animal models for genetic neuromuscular diseases

The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for delta-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy(2J)/dy(2J) mouse, both presenting significant reduction of alpha 2-laminin in the muscle and a severe phenotype. The myodystrophy mouse (Large(myd)) harbors a mutation in the glycosyltransferase Large, which leads to altered glycosylation of alpha-DG, and also a severe phenotype. Other informative models for muscle proteins include the knockout mouse for myostatin, which demonstrated that this protein is a negative regulator of muscle growth. Additionally, the stress syndrome in pigs, caused by mutations in the porcine RYR1 gene, helped to localize the gene causing malignant hypertermia and Central Core myopathy in humans. The study of animal models for genetic diseases, in spite of the existence of differences in some phenotypes, can provide important clues to the understanding of the pathogenesis of these disorders and are also very valuable for testing strategies for therapeutic approaches.

Atrophy and Neuron Loss: Effects of a Protein-Deficient Diet on Sympathetic Neurons

Protein deficiency is one of the biggest public health problems in the world, accounting for about 30-40% of hospital admissions in developing countries. Nutritional deficiencies lead to alterations in the peripheral nervous system and in the digestive system. Most studies have focused on the effects of protein-deficient diets on the enteric neurons, but not on sympathetic ganglia, which supply extrinsic sympathetic input to the digestive system. Hence, in this study, we investigated whether a protein-restricted diet would affect the quantitative structure of rat coeliac ganglion neurons. Five male Wistar rats (undernourished group) were given a pre- and postnatal hypoproteinic diet receiving 5% casein, whereas the nourished group (n = 5) was fed with 20% casein (normoproteinic diet). Blood tests were carried out on the animals, e.g., glucose, leptin, and triglyceride plasma concentrations. The main structural findings in this study were that a protein-deficient diet (5% casein) caused coeliac ganglion (78%) and coeliac ganglion neurons (24%) to atrophy and led to neuron loss (63%). Therefore, the fall in the total number of coeliac ganglion neurons in protein-restricted rats contrasts strongly with no neuron losses previously described for the enteric neurons of animals subjected to similar protein-restriction diets. Discrepancies between our figures and the data for enteric neurons (using very similar protein-restriction protocols) may be attributable to the counting method used. In light of this, further systematic investigations comparing 2-D and 3-D quantitative methods are warranted to provide even more advanced data on the effects that a protein-deficient diet may exert on sympathetic neurons. (C) 2009 Wiley-Liss, Inc.

Autoimmunity in common variable immunodeficiency

immunodeficiency (CVID), the most common symptomatic primary immunodeficiency in adulthood. Different authors report high prevalences of autoimmune diseases in CVID, and several mechanisms have been proposed to explain this apparent paradox. Genetic predisposition, under current surveillance, innate and adaptive immunity deficiencies leading to persistent/recurrent infections, variable degrees of immune dysregulation, and possible failure in central and peripheral mechanisms of tolerance induction or maintenance may all contribute to increased autoimmunity. Conclusions Data on the clinical/immunological profile of affected patients and treatment are available mostly concerning autoimmune cytopenias, the most common autoimmune diseases in CVID. Treatment is based on conventional alternatives, in association with short experience with new agents, including rituximab and infliximab. Benefits of early immunoglobulin substitutive treatment and hypothetical premature predictors of autoimmunity are discussed as potential improvements to CVID patients` follow-up.

A reduction of CETP activity, not an increase, is associated with modestly impaired postprandial lipemia and increased HDL-Cholesterol in adult asymptomatic women

Background: The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women. Methods: Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd <= 4.5%, n = 8), high activity (CETPi >= 23.8, n = 6) and controls (CTL, CETP >= 4.6% and <= 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m(2) of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-epsilon 3/epsilon 2/epsilon 4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed. Results: In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R(2) = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R(2) = 85% negatively) and phospholipids (R(2) = 13%), at the 6(th)h point. Conclusion: The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins` competition to active lipolysis sites, reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences.

Structure, Dynamics, and RNA Interaction Analysis of the Human SBDS Protein

Shwachman-Bodian-Diamond syndrome is an autosomal recessive genetic syndrome with pleiotropic phenotypes, including pancreatic deficiencies, bone marrow dysfunctions with increased risk of myelodysplasia or leukemia, and skeletal abnormalities. This syndrome has been associated with mutations in the SBDS gene, which encodes a conserved protein showing orthologs in Archaea and eukaryotes. The Shwachman-Bodian-Diamond syndrome pleiotropic phenotypes may be an indication of different cell type requirements for a fully functional SBDS protein. RNA-binding activity has been predicted for archaeal and yeast SBDS orthologs, with the latter also being implicated in ribosome biogenesis. However, full-length SBDS orthologs function in a species-specific manner, indicating that the knowledge obtained from model systems may be of limited use in understanding major unresolved issues regarding SBDS function, namely, the effect of mutations in human SBDS on its biochemical function and the specificity of RNA interaction. We determined the solution structure and backbone dynamics of the human SBDS protein and describe its RNA binding site using NMR spectroscopy. Similarly to the crystal structures of Archaea, the overall structure of human SBDS comprises three well-folded domains. However, significant conformational exchange was observed in NMR dynamics experiments for the flexible linker between the N-terminal domain and the central domain, and these experiments also reflect the relative motions of the domains. RNA titrations monitored by heteronuclear correlation experiments and chemical shift mapping analysis identified a classic RNA binding site at the N-terminal FYSH (fungal, Yhr087wp, Shwachman) domain that concentrates most of the mutations described for the human SBDS. (C) 2010 Elsevier Ltd. All rights reserved.

Kvalitetssäkring av Clas Ohlson AB´s grafiska produktionsflöde

The question formulation in the essay brought up whether Clas Ohlson works today with their graphical productionflow and if that way of working leads to a desirable result in press. After a dialogue with Clas Ohlson it emerged thatthey had certain problems with the material that came out of the printing presses. Certain colours were not reproducedaccording to the stated values that had been developed. In March -08 an analysis of the graphical production flowspresent situation were done at Clas Ohlsons in order to find out how they worked with their production of print materials.In the analysis, their way to work with color spaces, displays, ICC-profiles, PDF-exports, pictures and printerswere examined. Occasional interviews were also implemented with responsible personnel about how they worked withdifferent aspects.Deficiencies were found on almost all examined parts in their graphical production flow. Wrong colorspaces andCMYK-profiles was used in big extent, the displays where uncalibrated or incorrectly calibrated, wrong PDF-presetswas used frequently and it also showed that six different suppliers for their printing materials were used. The solutionsthat were relevant for the problems and defects were later on presented as proposals on measures.

Who Should do What to Whom? : Occupational Groups´Views on Special Needs

The overall aim of this thesis is to increase our knowledge of different occupational groups´ views on work with children in need of special support. This is explored in four separate studies. The first study investigates the views of occupational groups in preschools and schools in one municipality. A questionnaire was handed out to all personnel (N=1297) in the municipality in 2008 (72.5 % response rate). The second study explores the views of educational leaders (N=45) in the same municipality. Questionnaire # 2 was distributed in 2009. All the educational leaders responded to the questionnaire. The third study describes the views of different occupational groups concerning special educational needs coordinators´ (SENCOs) role and work. This was highlighted by comparing responses from questionnaire #1 and # 2. Responses concerning SENCOs´ work were also added using a third questionnaire. This questionnaire was handed out in 2006 to chief education officers (N=290) in all municipalities in Sweden. The response rate was 90.3%. Finally, the fourth study presents five head teachers´ descriptions of their work with special needs issues. Study four was a follow-up study of questionnaire # 2. These head teachers were selected because of their inclusive values and because they seemed to be effective according to certain criteria. They were interviewed in January 2012. The results reveal a number of interesting findings. For example, there are both similar and different views among the occupational groups concerning work with children in need of special support. A majority of the respondents in all groups state that children´s individual deficiencies is one common reason why children need special support in preschools/schools. Differences between the occupational groups become especially visible regarding their views of SENCOs‟ work. Critical pragmatism (Cherryholmes, 1988) is applied as a theoretical point of departure. Skrtic´s (1991) critical reading and analysis of special education relative to general education is specifically used to interpret and discuss the outcome of the studies. Additionally, Abbott´s (1988) reasoning concerning the “division of expert labor” is used to discuss the occupational groups´ replies concerning “who should do what to whom”. The findings in the studies are contextualized and theoretically interpreted in the separate articles. However in the first part of this thesis (in Swedish: Kappa), the theoretical interpretations of the empirical outcome are discussed in more detail and the results are further contextualized and synthesised. Inclusion and premises for inclusive education are also discussed in more depth in the first part of the present thesis.

Vårdpersonalens kunskapsläge i hjärtlungräddning samt följsamhet till det svenska hjärtlungräddningsregistret på ett länssjukhus i Mellansverige : En kvantitativ tvärsnittsstudie

Syfte: Att kartlägga vårdpersonalens kunskapsläge samt utbildningsfrekvens i hjärtlungräddning på ett länssjukhus i Mellansverige, samt beskriva följsamheten till att registrera behandlade hjärtstopp till det svenska hjärt-lungräddningsregistret. Metod: Enkätstudie med kvantitativ ansats bestående av 177 respondenter samt även som en retrospektiv observationsstudie. Huvudresultat: Enskilda personer svarade rätt på alla kunskapsfrågorna men som grupp fanns det brister i kunskapen i hjärtlungräddning. Då man jämförde vårdpersonalens kunskap påvisades att i fyra av sju kunskapsfrågor fanns en signifikant skillnad i kunskap mellan den vårdpersonal som har mer regelbunden utbildning, än den som har mindre. De som hade mer regelbunden utbildning hade flera rätt. En signifikant skillnad påvisades även beroende på när man hade haft sin senaste HLR-utbildning, där de som haft sin utbildning nyligen hade flera rätt. Följsamheten hos vårdpersonalen till att registrera patienter som behandlats för hjärtstopp på sjukhus till det svenska hjärt-lungräddningsregistret, kan sammanfattas med att det brister i rapporteringen. Konklusion: Det är viktigt att skapa förutsättningar för frekventa utbildningar till vårdpersonal för att öka kunskap och beredskap i hjärt- och lungräddning, vilket även kan ses som ett kvalitetssäkringsarbete. Ett förbättringsarbete är nödvändigt för att förbättra följsamheten till registreringen.

Kostnader och risker med internationell verksamhet i Mexiko

Detta examensarbetes syfte är att identifiera vilka faktorer som påverkar kostnader och risker som kan finnas vid internationellt företagande i Mexiko utifrån ett perspektiv där företagande samt företagsomgivningar vanligtvis är stöttande och välfungerande. En litteraturstudie utfördes på Internationella verksamheter (International Business), och skapade intervjuunderlaget som användes för att intervjua företagare i Mexiko med erfarenheter av både internationell verksamhet samt USA/EU, och enbart erfarenheter från företagande inom landet. Resultat visar att det finns sex stycken samlingsområden som påverkar kostnader och risker; Politiska faktorer som innebär att drastiska förändringar orsakas i ett lands affärsomgivning, och som negativt påverkar ett företags vinster eller andra mål; Ekonomiska faktorer som innebär att det kostar mer att ha verksamhet på grund av brister inom infrastruktur och stödjande verksamheter; Den ekonomiska utvecklingen; Det finns utbredd korruption hos Mexikanska myndigheter på både lokal- och statsnivå; Ledningsprocesser och metoder kan behöva anpassas enligt kulturellt bestämda arbetsrelaterade värderingar; och Internationella verksamheter bör anställa lokala individer till hjälp att utföra affärer inom en specifik kultur.

Non-challenging education and teacher control as factors for marginalization of students in diverse settings

This article discusses teachers’ attitudes towards immigrant students in poor settings and the effect these attitudes have on organization of education on classroom level. It draws on results from two ethnographic studies where some primary school classes in Sweden were followed with participant observation and interviews as main research methods. The article focuses on classroom activities and teachers’ attitudes towards immigrant students and students with low socio-economic status. In the article is argued for the importance of presenting students in poor settings with demanding tasks and challenging education. In these cases, intellectually undemanding tasks in combination with little room for students’ own initiatives resulted in low enthusiasm among students regarding schoolwork and accordingly low learning, while classroom work that demanded active involvement by students in combination with high level of students’ influence on what took place in classrooms resulted in high level of students’ engagement and high outcome.

ARBETSRELATERADE STRESSFAKTORER FÖR SJUKSKÖTERSKOR INOM AKUTSJUKVÅRDEN Litteraturöversikt

Bakgrund: Arbetsrelaterad stress hos sjuksköterskor bidrar till hög andel sjukskrivningar. Inom akutsjukvården så är arbetstempot ofta högre än inom andra delar av sjukvården och omsättningen av patienter är stor. Sjuksköterskor som arbetar inom akutsjukvården är mer utsatta för stress. För att hantera stress så kan copingstrategier användas. Syfte: Syftet är att ta reda på vilka stressfaktorer som påverkar sjuksköterskans hälsa inom akutsjukvården, samt vilka copingstrategier som kan användas för att hantera dessa. Metod: Litteraturöversikt med tolv kvalitativa samt kvantitativa vetenskapliga artiklar som berör sjuksköterskan inom akutsjukvården, arbetsrelaterade stressfaktorer samt copingstrategier. Resultat: Det finns ett antal arbetsrelaterade stressfaktorer som bidrar till ohälsa och lidande för sjuksköterskan inom akutsjukvården. Copingstrategier som stöttning av kollegor, avlastande samtal, genomgång av verksamheten och mindfulness, bidrar till att den arbetsrelaterade stressen blir hanterbar och att hälsa uppnås Slutsats: Stressfaktorer som brist på sjuksköterskor, dödsfall eller sexuella övergrepp på barn, våld och hot från patienter och anhöriga, samt brister i arbetsmiljön bidrar till arbetsrelaterad stress. Copingstrategier kan hjälpa att motverka den stress som uppstår. Men för att copingstrategier ska fungera så är det viktigt att använda sig av de strategier som finns och att tid samt möjlighet finns på arbetsplatsen att utföra dessa.

Maskrosbarn : En litteraturstudie om barn i riskzon

Syftet med denna studie är att nå en djupare förståelse om hur samhället ska kunna stödja barn som växer upp under ogynnsamma förhållanden på ett bättre sätt. Studien baseras på en litteraturstudie på sex stycken självbiografier som valts ut efter vissa kriterier. Dessa självbiografier har sammanställts utifrån en kvalitativ innehållsanalys och ett antal teman som svarar på våra forskningsfrågor identifierades. Utifrån studiens syfte och frågeställningar har teorier om risk- och skyddsfaktorer, KASAM, skam, resiliens samt anknytning valts ut. Tidigare forskning visar på att utsatta barn och social barnavård är ett eftersatt forskningsområde. Vårt resultat av denna studie visar på brister inom såväl socialtjänsten som samhället i övrigt. Det finns ett omfattande behov av att ständigt uppmärksamma och tydliggöra vilket stöd dessa barn kan få.

School leaders as agents of change : a case study on how two head teachers are trying to implement the learning study method in their school

This paper seeks to describe and discuss the impact of inspections of schools in Sweden. It outlines the political context, based on New Public Management (NPM) theory, according to what role the Schools Inspectorate is supposed to play in order to govern and control. Attention is also devoted, referring an on-going case study, to how inspections influence head teachers and their leadership in their everyday work.   Reports from the Schools inspectorate are public. This forces both politicians and head teachers to take measures. In this case, the head teachers perceived that the inspection reports confirmed what they already knew, but it also gave them an alibi and a tool to push their teachers to take part in everyday school development work. During the first year after the inspection the head teachers mainly strived to adjust formal deficiencies in local steering documents. However, some of the deviations reported from the Schools inspectorate are regarding pedagogical problems that are complicated and difficult to handle. As interventions in many cases will show up much later the results are, for example as increased goal fulfilment, in this case, still an open question. Nevertheless, it seems obvious that the Schools Inspectorate must be seen as a result of the governing philosophy that denotes New Public Management NPM).

Do inspections of schools influence head teachers’ leadership?

This paper seeks to describe and discuss the impact of inspections of schools in Sweden. It outlines the political context, based on New Public Management (NPM) theory, according to what role the Schools Inspectorate is supposed to play in order to govern and control. Attention is also devoted, referring an on-going case study, to how inspections influence head teachers and their leadership in their everyday work.   Reports from the Schools inspectorate are public. This forces both politicians and head teachers to take measures. In this case, the head teachers perceived that the inspection reports confirmed what they already knew, but it also gave them an alibi and a tool to push their teachers to take part in everyday school development work. During the first year after the inspection the head teachers mainly strived to adjust formal deficiencies in local steering documents. However, some of the deviations reported from the Schools inspectorate are regarding pedagogical problems that are complicated and difficult to handle. As interventions in many cases will show up much later the results are, for example as increased goal fulfilment, in this case, still an open question. Nevertheless, it seems obvious that the Schools Inspectorate must be seen as a result of the governing philosophy that denotes New Public Management NPM).