Railway Tunnelling in Frozen Ground on Bothniabana

A new railway line was under construction in North-eastern Sweden, along the shoreline of the Gulf of Bothnia. The terrain consisted of Postglacial clay and silt valleys, and ridges of Precambrian bedrock, crossing the railway line. The railway level was about 20m below the ground surface. For the design of freezing, a freezing analysis was carried out to determine the pipeline depths and distances, to estimate the necessary time for freezing and to determine temperatures within the frozen zone. To estimate the deformations, displacements and safety level, a mechanical analysis of the tunnel cross-section was carried out. As input, the geometry of the soil layers, bedrock and temperature zones was given. Time- and temperature-dependent mechanical parameters were estimated for different soils and temperatures. The analysis was carried out for 12 phases simulating different phases during tunnelling. The estimated displacements for the tunnel arch were negligible, if the temperatures were at or below -15°C. The freezing was started in May 2002, and completed in September 2002. The tunnelling was started in September, and it was completed in November 2002, following with the casting of final liner. According to the experiences until now, the work has progressed successfully

Lääkkeiden ja ravintovalmisteiden käyttö harvinaisten sairauksien hoidossa : Kysely harvinaissairaita hoitaville lääkäreille

Euroopan unionin määritelmän mukaan harvinaissairauksiksi katsotaan sairaudet, joita sairastaa enintään viisi ihmistä 10 000 ihmistä kohti. Suomessa sosiaali- ja terveysministeriö asetti vuonna 2012 työryhmän, joka laati ehdotuksen harvinaisten sairauksien kansalliseksi ohjelmaksi vuosiksi 2014–2017. Yksi toimenpide-ehdotuksista on harvinaislääkkeiden saatavuuden parantaminen. Kela otti vastuulleen selvittää harvinaissairauksien hoidossa käytettäviä lääkehoitoja ja niiden korvattavuutta. Tämän tutkimuksen tarkoitus on kuvata, millaisia lääke- ja ravintovalmistehoitoja harvinaissairauksien hoidossa Suomessa käytetään ja kuinka usein lääkkeet kuuluvat avohoidossa käytettäessä lääkekorvausjärjestelmään. Tutkimusaineisto koottiin sähköisellä kyselyllä, joka lähetettiin harvinaissairauksia hoitaville lääkäreille henkilökohtaisessa sähköpostiviestissä maaliskuussa 2014. Kyselyyn vastasi 129 lääkäriä, eli 33 % niistä, joille kysely lähetettiin. Lääkärit mainitsivat kyselyssä 145 lääkeainetta ja 55 ravintovalmistetta, joita käytetään harvinaissairauksien hoidossa. Lääkärien mainitsemista lääkkeistä 86 % ja kolmannes ravintovalmisteista oli korvattavia. Varsinaisista harvinaislääkkeistä yhtä lukuun ottamatta kaikki olivat korvattavia. Vaikka valtaosa harvinaissairauksien hoidossa käytettävistä lääkkeistä on korvattavia, osalla potilaista kustannukset voivat kuitenkin kasvaa suuriksi, jos sairauden hoidossa tarvitaan useita valmisteita, jotka eivät ole korvattavia. Nykyinen lääkekorvausjärjestelmä ei riittävästi huomioi harvinaissairauksien lääkehoitoja, koska järjestelmä perustuu lääkeyritysten tekemiin hakemuksiin ja korvattavuuden edellytyksenä on, että valmisteen käyttöaihe sisältää harvinaissairauden

Deletion of the BDNF Truncated Receptor TrkB.T1 Delays Disease Onset in a Mouse Model of Amyotrophic Lateral Sclerosis

Brain Derived Neurotrophic Factor (BDNF) exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS). To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1G93A ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders

Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases

Small molecule activators of the Trk receptors for neuroprotection

The neurotophin signaling network is critical to the development and survival of many neuronal populations. Especially sensitive to imbalances in the neurotrophin system, cholinergic neurons in the basal forebrain are progressively lost in Alzheimer's disease. Therapeutic use of neurotrophins to prevent this loss is hampered, however, by a number of pharmacological challenges. These include a lack of transport across the blood-brain barrier, rapid degradation in the circulation, and difficulty in production. In this review we discuss the evidence supporting the neurotrophin system's role in preventing neurodegeneration and survey some of the pharmacological strategies being pursued to develop effective therapeutics targeting neurotrophin function

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates