Identification of new disease mechanisms and treatments for type 2 diabetes based on genetic variants and gene expression networks

Improved understanding of the disease mechanisms underlying type 2 diabetes (T2D) is needed, and so are new treatments.A new T2D risk variant was recently identified in ADRA2A, which encodes the α2A-adrenergic receptor. The risk allele leads to receptor overexpression in β-cells that causes increased adrenergic signaling and impaired insulin secretion. We showed that the α2A-adrenergic receptor antagonist yohimbine normalized insulin secretion in risk allele carriers with T2D, whereas it was without effect in non-risk allele carriers. These findings suggest that individualized, genotype-based treatment for T2D is possible. Next, in an attempt to identify new genes relevant for the pathogenesis of T2D and to identify new drugs for the treatment of T2D, we utilized microarray gene expression data to gain information about gene coexpression networks. Gene expression in human islets from T2D and non-diabetic donors, and gene expression in liver tissue from hyperglycemic and normoglycemic mice, was analyzed to find groups of coexpressed genes (modules) with disturbed expression in diabetes. “Disease signatures” derived from these modules were used to interrogate publically available microarray data sets. These data sets included gene expression profiles induced by a wide range of drugs and treatments. Data sets with an expression pattern similar to our islet disease signature gave clues to the underlying pathogenic process in β-cell failure, and data sets with a reverse expression pattern to our liver disease signature helped identify drug candidates for treatment of excessive hepatic glucose production. The islet disease signature was associated with β-cell dedifferentiation and loss of a mature β-cell state. We identified the transcription factor SOX5 as a regulator of the T2D-associated islet module. Overexpression of SOX5 increased the expression of β-cell specific genes in human islets and improved secretory function in islets from donors with T2D.The liver disease signature was used to rate compounds based on reverse expression compared with the disease signature. The rationale was that compounds with potential to reverse the disease signature mightaffect the pathophysiology. Sulforaphane, a sulfur-containing compound found naturally in e.g. broccoli, was identified as the top-rated compound. Sulforaphane reduced glucose production from hepatoma cells via amechanism that involves reduced expression of gluconeogenic enzymes. Sulforaphane improved glucose tolerance in animal models of diabetes. Moreover, in a small clinical study, sulforaphane-rich broccoli sproutextract reduced fasting blood glucose and HbA1c levels in obese T2D patients with poor glycemic control. Taken together, the data presented in this thesis demonstrate the opportunities of genotype-based treatment for T2D, and show the usefulness of gene network analysis to identify pathophysiological mechanisms and new potential therapies for T2D. By this approach, we have identified Sox5 as a new regulator of β-cell function, and sulforaphane as a liver-targeting therapy for T2D patients with poor glycemic control

Seedling and tree growth after Chequered-Gap-Shelterwood-Cutting and in conventional clear-cutting system

To achieve sustainability both ecological and production aspects need to be considered in forest management. Chequered gap shelter wood system (CGSS), consist of small clear-felled gaps with alternating areas of trees, giving the forest a chessboard appearance which potentially could combine the advantages from both the clear-cut system and continuous cover forestry. This approach will introduce more edges which might influence the effect of wind, temperature and solar radiation on seedlings and trees. In this study we evaluate 1) the influence of the forest edge and 2) the north- and south facing part in the gaps on the growth of seedlings and trees (Pinus sylvestris and Picea abies) in gaps and shelter forests, respectively, and compare the growth with that in a conventional clearcutting system. Overall, edges effected seedling growth negatively and tree growth positively. Seedlings also grew better at the northern sun exposed parts compared to the southern shaded parts of the gaps. As a consequence of these edge effects seedlings had a lower, and shelter trees a higher, growth in the CGS-system compared to the reference areas. Seedlings in the central part of the gaps grew better than seedlings in the reference area. Norwegian spruce seems to be the most suited tree species for this silvicultural approach. Given the contrasting effect of edges on seedlings and trees the production over the whole rotation need to be evaluated in future studies

The fibrillogenic L178H variant of apolipoprotein A-I forms helical fibrils.

A number of amyloidogenic variants of apolipoprotein A-I (apoA-I) have been discovered but most have not been analyzed. Previously, we showed that the G26R mutation of apoA-I leads to increased β-strand structure, increased N-terminal protease susceptibility and increased fibril formation after several days of incubation. In vivo, this and other variants mutated in the N-terminal domain (residues 26 to ~90) lead to renal and hepatic accumulation. In contrast, several mutations identified within residues 170 to 178 lead to cardiac, laryngeal, and cutaneous protein deposit. Here, we describe the structural changes in the fibrillogenic variant L178H. Like G26R, the initial structure of the protein exhibits altered tertiary conformation relative to WT protein along with decreased stability and an altered lipid binding profile. However, in contrast to G26R, L178H undergoes an increase in helical structure upon incubation at 37oC with a t1/2 of about 12 days. Upon prolonged incubation the L178H mutant forms fibrils of a diameter of 10 nm that ranges in length from 30 to 120 nm. JLR These results show that apoA-I, known for its dynamic properties, has the ability to form multiple fibrillar conformations, which may play a role in the tissue-specific deposition of the individual variants

"Om en strategi inte fungerar kan man ju använda en annan" : En studie om elevers olika uppfattningar om och erfarenheter av läsförståelse och läsförståelsestrategier

Syftet med denna studie är att få förståelse av elevers olika uppfattningar om och erfarenheter av läsförståelse och läsförståelsestrategier. Eftersom studiens fokus ligger på hur elever uppfattar och har erfarenheter av läsförståelse och läsförståelsestrategier ansåg vi den kvalitativa ansatsen lämplig att använda. Vår förförståelse och de teorier vi lutar oss mot har växelverkat med den empiri som vi ämnat fånga och därmed har den kvalitativa ansatsen varit abduktiv. I vår studie har vi också tagit inspiration av etnografin. I arbetet med studien observerade vi tre klasser och gjorde 31 intervjuer. Resultatet av studien visade att elever har uppfattningar om och erfarenheter av läsförståelse och läsförståelsestrategier. Angående läsförståelse uttrycker elever att det inte räcker med att läsa utan att man även måste förstå det man läser. Vad gäller läsförståelsestrategier uttrycker eleverna exempel på hur läsfixarna och andra läsförståelsestrategier hjälper dem eller inte i den egna läsningen. En del elever uttrycker också betydelsen av att läsa tillsammans. I resultatet ser vi att eleverna uppfattar avkodning och förståelse som faktorer i läsprocessen. Slutsatsen vi drar, utifrån studiens resultat, är att eleverna har förmåga att sätta ord på hur de själva uppfattar och har erfarenheter av läsförståelse och läsförståelsestrategier

Problematiska beteenden vid demens

Sveriges befolkning blir allt äldre och i takt med detta ökar andelen personer med demens och deras behov av vård. Svårigheter med att hantera beteendestörningar såsom aggression och agitation hos personer med demens har visat sig vara ett problem för vårdpersonal. Syftet med denna litteraturstudie har varit att samman-ställa aktuell vetenskaplig litteratur avseende vad som är viktigt i omvårdnaden av personer med demenssjukdom som uppvisar problematiska beteenden samt att undersöka vilket stöd vårdpersonalen behöver för att på ett professionellt sätt kun-na bemöta dessa personer. En systematisk litteraturstudie genomfördes utefter Goodmans sju forskningssteg (SBU, 1993), där vetenskapliga artiklar hittades efter sökningar i databaserna PubMed och Cinahl. Resultatet redovisar vikten av att som vårdpersonal försöka finna eventuella bakomliggande orsaker till de prob-lematiska beteendena samt att utforma omvårdnad som anpassas till individen. Även faktorer såsom god kommunikation, känslomässig närvaro samt kunskap hos personalen om patientens livshistoria tas upp som viktiga. När det gäller behoven hos personalen för att kunna genomföra detta på bästa sätt utkristalliserade sig områdena handledning och utbildning.The inhabitants of Sweden become older and older and following this an increase of the number of people suffering from dementia can be seen. Dementia is a progressive disease and the need for nursing care increases as the disease ad-vances. Difficulties in handling behaviours such as aggression and agitation displayed by people with dementia, has turned out to be a problem for nursing staff. The aim of this study has been to compile literature concerning different useful approaches towards people with dementia, in situations perceived as prob-lematic by nursing staff, and to examine what kind of support the staff need in order to deal with these people in a professional way. A systematic literature review was performed according to Goodman (SBU, 1993) where 13 scientific articles were used after searches in the PubMed and Cinahl databases. The result presents the importance of the nursing staff trying to find underlying reasons for the displayed problematic behaviours and also adjusting the nursing care accor-ding to the individual patient. Factors such as good communication, emotional presence and knowledge about the patients’ life history are emphasized. When it comes to the needs of the staff, the areas education and systematic guidance arose

Accelerating energy efficiency improvement in the public sector, using Energy Performance Contracting - a workshop on Nordic experiences and needs for improvements

This report provides documentation on a workshop on experiences of Energy Performance Contracting (EPC) in the Nordic countries, aiming to identify strengths, weaknesses and needs for improvements. The results of surveys undertaken to inform presentations and discussions at the workshop are reported. Furthermore, the outcomes of the discussions during the workshop and resulting recommend actions for different actors to further and accelerate the use of EPC in the public sector are reported. Target groups for this documentation are existing and potential EPC customers, providers and policy-makersThis report provides documentation on a workshop on experiences of Energy Performance Contracting (EPC) in the Nordic countries, aiming to identify strengths, weaknesses and needs for improvements. The results of surveys undertaken to inform presentations and discussions at the workshop are reported. Furthermore, the outcomes of the discussions during the workshop and resulting recommend actions for different actors to further and accelerate the use of EPC in the public sector are reported. Target groups for this documentation are existing and potential EPC customers, providers and policy-maker

Omhändertagande av våldsutsatta kvinnor ur ett sjuksköterskeperspektiv - en litteraturstudie

Intimate partner violence is the most common health issue for women between the ages of fifteen to sixty-four in Sweden as well as the majority of European countries according to the United Nations. Aim – The aim of the study was to illuminate nurses’ experiences when caring for women exposed to intimate partner violence. Method – This thesis was a literature review based on both qualitative and quantitative articles to give as comprehensive a view as possible. Findings – Findings were presented in five themes which emerged during our analysis. The findings showed that nurses’ expressed a desire to be more educated in intimate partner violence. Nurses’ were challenged by their own prejudices and feelings while meeting victims of intimate partner violence. Conclusion – Support and encouragement from authorities within the organization along with education and time for reflection could furnish nurses’ with the confidence required to provide adequate care for abused women

Faktorer som påverkar sjuksköterskans omvårdnad av mrsa bärande patienter

Mulitresistent staphylococcus aureus (MRSA) is a bacteria that is resistent against penicillin, this makes it difficulte to treat. MRSA causes woundinfections and other seriouse conditions. If MRSA establishes in an hospital environment it often spreads fast. Common ways of spreading MRSA is through direct or indirect contact. The nurse should work according to guidelines, apply hygienic routines and prevent the spread of infections. Aim: The aim of the literaturestudie was to illustrate factors that affects nurses care of patients carrying MRSA. Method: A literature study was carried out. Results: the study found four categories: knowledge, attitudes, guidelines and risk. They showed that nurses had to little knowledge about MRSA and the preventive routines that ought to be followed. If the nurse had knowledge she also had a positive attitude and was able to give same care to the patient carrying MRSA as to the ones that not carrying it. Conclusion: Knowledge, attitudes and guidelines about MRSA needs to be improved. This gives a better care of MRSA infected patients and decreases the infections risks for both medical personel and patients