No description available.

No description available.

Congenital insensitivity to pain is a rare hereditary neuropathy. We present patients from a large family in Norrbotten, Sweden with a mutation in the nerve growth factor β gene (NGFß). Using a model of recessive inheritance, we identified an 8.3-Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of candidate genes in the disease-critical region revealed a mutation in the coding region of the NGFß gene specific for the disease haplotype. All three severely affected individuals were homozygous for the mutation. The disease haplotype was also observed in both unaffected and mildly affected family members, but in heterozygote form. We have identified 43 patients, 3 homozygous and 40 heterozygous. The homozygous patients have a severe congenital form with onset of symptoms at an early age, most often affecting the lower extremities with insidious progressive joint swellings or painless fractures. Fracture healing was normal, but the arthropathy was progressive, resulting in disabling Charcot joints with gross deformity and instability. These patients lacked deep pain perception in bones and joints and had no protective reflexes, leading to gross bone and joint complications. They also had abnormal temperature perception but normal ability to sweat. There was no mental retardation. Clinically, they fit best into the group HSAN type V. Sural nerve biopsies showed a moderate loss of thin myelinated fibers (Ad-fibers) and a severe reduction of unmyelinated fibers (C-fibers). 14 of the 40 heterozygous adult patients had mild or moderate problems with joint deformities, usually with only slight discomfort. Treatment was conservative with (if needed) different kinds of orthosis and in some cases joint replacement. Three patients had only neuropathy, and 16 patients had no symptoms. In congenital disorders like these, it is important to evaluate the age and also the slowly progressive nature, when considering treatment. There is an increased risk of growth disturbances in the very young. The orthopedic operations should therefore be planned from a long-term point of view, but patient education and orthosis are cornerstones in the treatment—to delay the development of neuropathic arthropathy. Arthrodesis, limb lengthening and spinal decompression with fusions are the only elective procedures that seem reasonable. This Norrbottnian disease is also interesting as a model system for the study of pain.

A critical question for government officials, managers of NGOs, and politicians is how to respond to situations in which large numbers of lives are at risk. Theories in judgment and decision making as well as economics suggest diminishing marginal utility with increasing quantities of goods. In the domain of lifesaving, this form of non-linearity implies decreasing concern for individual lives as the number of affected people increases. In this paper, we show how intuitive valuations based on prosocial emotions can lead to scope insensitivity and suboptimal responses to lives at risk. We present both normative and descriptive models of valuations of lives and discuss the underlying psychological processes as they relate to judgments and decisions made in public policy and by NGOs.

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 4 uppsatser.

Monogenic diseases make excellent models for the study of gene functions and basal cellular mechanisms in humans. The aim of this thesis was to elucidate how genetic mutations affect the basal cellular mechanisms in the monogenic diseases Nerve growth factor (NGF) dependent pain insensitivity and Iron-Sulphur cluster assembly protein U (ISCU) myopathy. NGF dependent pain insensitivity is a rare genetic disorder with clinical manifestations that include insensitivity to deep pain, development of Charcot joints, and impaired temperature sensation but with no effect on mental abilities. The disease is caused by a missense mutation in the NGFβ gene causing a drastic amino acid substitution (R221W) in a well-conserved region of the protein. NGF is secreted in limited amounts by its target tissues and is important for the development and maintenance of the cholinergic forebrain neurons as well as the sensory and sympathetic neurons. To reveal the underlying mechanisms of disease we performed functional studies of the mutant NGF protein. We could show that mutant NGF was unable to induce differentiation of PC12 cells as a consequence of impaired secretion. Furthermore, mutant NGF had different intracellular localisation compared to normal NGF and resided mostly in its unprocessed form proNGF. Mature NGF and proNGF have different binding properties to the receptors TrkA and p75. Individuals with mutations in TRKA are, aside from pain insensitive mentally affected; therefore it has been proposed that the R221W mutation mainly affects the interaction with p75. In agreement with this, we could show that R221W NGF was able to bind and activate TrkA whereas the interaction with p75 was impaired as compared to normal NGF. ISCU myopathy is a monogenic disease where the affected patients suffer from severe exercise intolerance resulting in muscle cramps and sometimes severe lactic acidosis. The disease is caused by a point mutation in the last intron of the Iron sulphur cluster assembly gene, ISCU, resulting in the inclusion of a part of the intron in the mRNA. ISCU functions as a scaffold protein in the assembly of iron-sulphur (Fe-S) clusters important for electron transport in Kreb’s cycle and the respiratory chain. We have shown that ISCU is vital in mammals since complete knock-down of Iscu in mice results in early embryonic death. The deletion of ISCU homologous in lower organisms has also been shown fatal. In spite this central role in energy metabolism the disease is restricted to the patient’s skeletal muscles while other energy demanding organs seem unaffected. To address this contradiction we examined if tissue-specific differences in the splicing of mutant ISCU could explain the muscle-specific phenotype. We could show that the splicing pattern did, indeed, differ with more incorrectly spliced ISCU in muscle compared to other tissues. This was accompanied by a decrease in Fe-S containing proteins in muscle, while no decrease was observed in other tissues. Alternative splicing is more common then previously thought and may depend upon interacting factors and/or differences in the surrounding milieu. To reveal plausible mechanisms involved in the tissue-specific splicing we identified nuclear factors that interacted with the region where the mutation was located. Five interacting factors were identified, out of which three affected the splicing of ISCU. PTBP1 was shown to repress the incorrect splicing while IGF2BP1 and RBM39 repressed the formation of normal transcript and could also counteract the effect of PTBP1. IGF2BP1 was the only factor that showed higher affinity to the mutant sequence making it a possible key factor in the incorrect splicing of the mutant ISCU gene. Together, these results offer important insights into the cellular mechanisms causing these diseases. We found impaired secretion and inaccurate sorting of NGF to be cellular mechanisms contributing to NGF dependent pain insensitivity while tissue-specific splicing of ISCU was found to be the event contributing to the phenotype of ISCU myopathy.

This investigation assesses the role of poly(ADP-ribose) polymerase in ethanol-mediated hepatotoxicity using the untransfected HepG2 hepatocellular carcinoma line, an established, well-characterized toxicological model. HepG2 cells were treated with ethanol at concentrations between 100 mM and 800 mM, and assessed for markers of cytotoxicity. PARP-1 activity in total cell protein lysates was quantified as a proxy of apoptotic induction at six hours. Our results demonstrated a 1.43-fold AST activity increase in culture medium isolates of cells exposed to 800 mM without significant effect on cellular viability. PARP-1 activity varied greatly and results for enzyme activity remained inconclusive. The results suggest a high degree of insensitivity to ethanol toxicity and nuclear enzyme activity, demonstrating the metabolic irrelevance of untransfected HepG2 in ethanol toxicosis. There is a need to characterize phase 1 metabolic enzyme expression profiles relevant to ethanol for CYP2E1 and ADH pathways to facilitate comparisons across toxicological models using transfected, as well as the untransfected HepG2 model.

No description available.

In munitions technologies, hazard investigations for explosive (or more generally energetic material) including systems is a very important issue to achieve insensitivity. Determining the response of energetic materials to different types of mechanical or thermal threats has vital importance to achieve an effective and safe munitions design and since 1970&rsquo / s, lots of studies have been performed in this research field to simulate the dynamic response of energetic materials under some circumstances. The testing for hazard investigations is a very expensive and dangerous topic in munitions design studies. Therefore, especially in conceptual design phase, the numerical simulation tools for hazard investigations has been used by ballistic researchers since 1970s. The main modeling approach in such simulation tools is the numerical simulation of deflagration-todetonation transition (DDT) phenomenon. By this motivation, in this thesis study, the numerical simulation of DDT phenomenon in solid energetic materials which occurs under some mechanical effects is performed. One dimensional and two dimensional solvers are developed by using some well-known models defined in open literature for HMX (C4 H8 N8 O8) with 73 % particle load which is a typical granular, energetic, solid, explosive ingredient. These models include the two-phase conservation equations coupled with the combustion, interphase drag interaction, interphase heat transfer interaction and compaction source terms. In the developed solvers, the governing partial differential equation (PDE) system is solved by employing high-order central differences for time and spatial integration. The two-dimensional solver is developed by extending the complete two-phase model of the one-dimensional solver without any reductions in momentum and energy conservation equations. In one dimensional calculations, compaction, ignition, deflagration and transition to detonation characteristics are investigated and, a good agreement is achieved with the open literature. In two dimensional calculations, effect of blunt and sharp-nosed projectile impact situations on compaction and ignition characteristics of a typical explosive bed is investigated. A minimum impact velocity under which ignition in the domain fails is sought. Then the developed solver is tested with a special wave-shaper problem and the results are in a good agreement with those of a commercial software.

Psykopati är en personlighetsstörning där specifika beteendemönsteringår. Man kan hitta psykopatiska drag hos barn och ungdomar. Detfinns begränsat med forskning gällande ungdomar med psykopatiskadrag och okänslighet för bestraffning, samt hur föräldrabeteendenpåverkas. Syftet med denna studie är att undersöka om ungdomarsokänslighet för bestraffning medierar länken mellan psykopatiskadrag och föräldrabeteenden. Studien är gjord på tidigare insamladdata från en medelstor stad i Sverige. Sammanlagt deltog 968 flickoroch pojkar, samt svarade deras föräldrar på enkäter. Resultatetvisade att ungdomars okänslighet för bestraffning delvis medierarlänken mellan ungdomars psykopatiska drag och föräldrabeteenden.Dock visade fynden olika resultat för olika föräldrabeteenden. / Psychopathy is a personality disorder where specific patterns ofbehavior are included. It is possible to find psychopathic traits amongchildren and adolescents. There is limited research concerningadolescents with psychopathic traits and insensitivity to punishment,also how the parenting behaviors are affected. The purpose of thisstudy is to research if adolescents’ insensitivity to punishmentmediates the link between psychopathic traits and parenting behaviors.The study is conducted by using previously collected data from anaverage sized city in Sweden. There were 968 participants, where bothgirls and boys and their parents filled out questionnaires. The resultshowed that adolescents’ insensitivity to punishment partly mediatesthe link between youth’s psychopathic traits and parenting behaviors.However the findings showed different paths for different parentingbehaviors.