Kv1.1 null mice have enlarged hippocampus and ventral cortex

BACKGROUND: Mutations in the Shaker-like voltage-gated potassium channel Kv1.1 are known to cause episodic ataxia type 1 and temporal lobe epilepsy. Mice that express a malfunctional, truncated Kv1.1 (BALB/cByJ-Kv1.1(mceph/mceph)) show a markedly enlarged hippocampus and ventral cortex in adulthood. RESULTS: To determine if mice lacking Kv1.1 also develop a brain enlargement similar to mceph/mceph, we transferred Kv1.1 null alleles to the BALB/cByJ background. Hippocampus and ventral cortex was then studied using in vivo 3D-magnetic resonance imaging and volume segmentation in adult Kv1.1 null mice, BALB/cByJ-Kv1.1(mceph/mceph), BALB/cByJ-Kv1.1(mceph/+), BALB.C3HeB -Kv1.1(-/+ )and wild type littermates. The Kv1.1 null brains had dramatically enlarged hippocampus and ventral cortex. Mice heterozygous for either the null allele or the mceph allele had normal-sized hippocampus and ventral cortex. CONCLUSION: Total absence of Kv1.1 can induce excessive overgrowth of hippocampus and ventral cortex in mice with a BALB/cByJ background, while mice with one wild type Kv1.1 allele develop normal-sized brains

A truncated Kv1.1 protein in the brain of the megencephaly mouse: expression and interaction

BACKGROUND: The megencephaly mouse, mceph/mceph, is epileptic and displays a dramatically increased brain volume and neuronal count. The responsible mutation was recently revealed to be an eleven base pair deletion, leading to a frame shift, in the gene encoding the potassium channel Kv1.1. The predicted MCEPH protein is truncated at amino acid 230 out of 495. Truncated proteins are usually not expressed since nonsense mRNAs are most often degraded. However, high Kv1.1 mRNA levels in mceph/mceph brain indicated that it escaped this control mechanism. Therefore, we hypothesized that the truncated Kv1.1 would be expressed and dysregulate other Kv1 subunits in the mceph/mceph mice. RESULTS: We found that the MCEPH protein is expressed in the brain of mceph/mceph mice. MCEPH was found to lack mature (Golgi) glycosylation, but to be core glycosylated and trapped in the endoplasmic reticulum (ER). Interactions between MCEPH and other Kv1 subunits were studied in cell culture, Xenopus oocytes and the brain. MCEPH can form tetramers with Kv1.1 in cell culture and has a dominant negative effect on Kv1.2 and Kv1.3 currents in oocytes. However, it does not retain Kv1.2 in the ER of neurons. CONCLUSION: The megencephaly mice express a truncated Kv1.1 in the brain, and constitute a unique tool to study Kv1.1 trafficking relevant for understanding epilepsy, ataxia and pathologic brain overgrowth

The megencephaly mouse : From gene to neuronal proliferation

Megalencephaly, enlarged brain, can be associated with a wide range of symptoms from benign to severe. Severe cases are often associated with mental retardation and seizures. The megencephaly mouse shows a dramatic, progressive increase in size of the hippocampus and ventral cortex. The enlargement is colocalized with expression disturbances of molecules in the insulin-like growth factor system and several neuropeptides. The mceph mutation has previously been mapped to a 3 centi-Morgan interval on distal chromosome 6. The aims of this thesis was to identify the mceph mutation, perform functional studies of the MCEPH protein and to characterize the brain enlargement. Using a positional cloning approach the mceph mutation was identified as an 11 bp deletion in the Shaker-like voltage gated potassium channel Kv1.1. The deletion leads to a frame shift and a premature stop codon. The predicted truncated protein would retain only 230 out of 495 amino acids. Kv1.1 mRNA was upregulated in the brain of mceph/mceph mice. Expression patterns of Kv1.2 and Kv1.3 was disturbed in the hippocampus suggesting an interaction between these proteins and the putative MCEPH protein. The presence of abnormal electrical activity suggests that the mceph/mceph mice are epileptic. Low levels of the truncated MCEPH protein is expressed in the brain of mceph/mceph mice, mainly in the hippocampus and ventral cortex. Glycosylation analysis suggests that MCEPH is retained in the endoplasmic reticulum. Studies in cell culture shows that MCEPH has the ability to assemble with full length Kv 1.1. In addition, it has a dominant negative effect on Kv1.2 and Kv1.3 currents in Xenopus oocytes. However, no interaction could be detected with Kv1.2 in the brain. Compositional analysis had suggested that the underlying cause of the brain enlargement in the mceph/mceph mice was hypertrophy rather than hyperplasia. By applying the optical fractionator method and the Cavalieri principle, the volume and total number of neurons, and astrocytes in the hippocampus of 12 weeks old mceph/mceph and wild type mice was estimated. The number of both neurons (expressing NeuN) and astrocytes (expressing GFAP), as well as structure volume, were increased approximately 2-fold within dentate gyrus, CA3 and hilus of mceph/mceph versus wild type mice. As a first step towards understanding the mechanisms underlying the hyperplasia, cell proliferation was studied within the subgranular zone of the dentate gyrus using BrdU. At three weeks of age, before onset of epileptic symptoms, there was a 3-fold increase in proliferation in mceph/mceph mice compared to control mice. In the severely epileptic 9 weeks old mceph/mceph mice there was a less dramatic increase in proliferation, reaching 1.5-fold more BrdU labeled cells in relation to wild type mice. The Kv1.1 null mouse is epileptic but has not been reported to have an enlarged brain. Since the mceph trait showed a reduced penetrance in intercrosses, genetic background was suspected to be important. To minimize the differences between mceph/mceph and the Kv 1.1 null mice, the Kv 1.1 null alleles were transferred to BAL13/c13y.J. At this genetic background, lack of Kv1.1 was found to induce excessive growth of the hippocampus and the ventral cortex. In summary, the enlarged mceph/mceph hippocampus has an increased rate of proliferation and more neurons as well as astrocytes. The causative mutation is an 11 bp deletion in the gene encoding Kv1. 1. It results in a truncated protein that is functional in vitro. However, lack of functional Kv1.1 in combination with a BAL13/c13y.J genetic background is sufficient for the excessive growth of hippocampus and ventral cortex

When your days and night´s are filled with the infant´s inconsolable crying : Mothers experiences of having lived with their colicy baby A qualitative interview study

Att bli förälder är oftast ett av de största ögonblicken i en människas liv. Många förväntar sig att få en ljuvlig tid, men om barnet får kolik kan denna tid istället bli fylld av barnskrik som vänder upp och ned på hela familjesituationen. Flertal föräldrar till barn med kolik upplever att de tappar kontrollen över sina liv. Syftet med studien var att beskriva mödrars erfarenheter av att ha levt med spädbarn som haft kolik. Metoden var en kvalitativ intervjustudie. Åtta mödrar från tre olika barnavårdcentraler intervjuades. Intervjumaterialet analyserades med hjälp av en kvalitativ innehållsanalys. Intervjumaterialet resulterade i ett tema och fem kategorier. Resultatet visade att det var viktigt att mödrarna fick avlastning och stöttning ifrån släkt, vänner och via bvc, för att klara den egentligen korta kolikperioden, som en del föräldrar benämner som en hel evighet när de är mitt i den. Till följ av tidsbrist och sömnbrist var det svårt att känna glädje över vardagen. Studien kan bidra till att sjuksköterskan på barnavårdscentralen (bvc) ökar sin lyhördhet och tar del av föräldrarnas upplevelser, genom att bemöta föräldrarna på ett stödjande och professionellt sätt.Becoming a parent is usually one of the greatest expectations a person can have. Many expect this time to be one of life´s happiest. Instead this newborn period may be filled with incessant crying, turning the family expectations completely upside down. Many parents of colicy children feel that they lose control over their lives. The purpose of this study was to share mother´s knowledge of this situation through a qualitative interview study. Eight mothers from three different child welfare clinics were interviewed. The interview material was analysed using qualitative content analysis ending up with one theme and five categories. The result showed that it was important that mother’s were relieved from this situation by family, friends and through child welfare clinic, to be able to cope with this comparatively short colicy period. Some parents felt this was never ending when they were in the midst of it. Without relief and lack of sleep parents felt that they could not get their expected pleasure out of daily doings. This study may contribute to the child welfare clinic nurses sensitivity and comprehension of the parents experiences by meeting these parents with a supportive and competent manner

Two sides of the same coin - an interview study of Swedish obstetricians' experiences using ultrasound in pregnancy management

Background: The extended use of ultrasound that is seen in maternity care in most Western countries has not only affected obstetric care but also impacted on the conception of the fetus in relation to the pregnant woman. This situation has also raised concerns regarding the pregnant woman’s reproductive freedom. The purpose of this study was to explore Swedish obstetricians’ experiences and views on the role of obstetric ultrasound particularly in relation to clinical management of complicated pregnancy, and in relation to situations where the interests of maternal and fetal health conflict. Methods: A qualitative study design was applied, and data were collected in 2013 through interviews with 11 obstetricians recruited from five different obstetric clinics in Sweden. Data were analysed using qualitative content analysis. Results: The theme that emerged in the analysis ‘Two sides of the same coin’ depicts the view of obstetric ultrasound as a very important tool in obstetric care while it also was experienced as having given rise to new and challenging issues in the management of pregnancy. This theme was built on three categories: I. Ultrasound is essential and also demanding; II. A woman’s health interest is prioritised in theory, but not always in practice; and III. Ultrasound is rewarding but may also cause unwarranted anxiety. Conclusions: The widespread use of ultrasound in obstetric care has entailed new challenges for clinicians due to enhanced possibilities to diagnose and treat fetal conditions, which in turn might conflict with the health interests of the pregnant woman. There is a need for further ethical discussions regarding the obstetrician’s position in management of situations where maternal and fetal health interests conflict. The continuing advances in the potential of ultrasound to impact on pregnancy management will also increase the need for adequate and appropriate information and counselling. Together with other health care professionals, obstetricians therefore need to develop improved ways of enabling pregnant women and their partners to make informed decisions regarding pregnancy management

Two sides of the same coin - an interview study of Swedish obstetricians' experiences using ultrasound in pregnancy management

Background: The extended use of ultrasound that is seen in maternity care in most Western countries has not only affected obstetric care but also impacted on the conception of the fetus in relation to the pregnant woman. This situation has also raised concerns regarding the pregnant woman’s reproductive freedom. The purpose of this study was to explore Swedish obstetricians’ experiences and views on the role of obstetric ultrasound particularly in relation to clinical management of complicated pregnancy, and in relation to situations where the interests of maternal and fetal health conflict. Methods: A qualitative study design was applied, and data were collected in 2013 through interviews with 11 obstetricians recruited from five different obstetric clinics in Sweden. Data were analysed using qualitative content analysis. Results: The theme that emerged in the analysis ‘Two sides of the same coin’ depicts the view of obstetric ultrasound as a very important tool in obstetric care while it also was experienced as having given rise to new and challenging issues in the management of pregnancy. This theme was built on three categories: I. Ultrasound is essential and also demanding; II. A woman’s health interest is prioritised in theory, but not always in practice; and III. Ultrasound is rewarding but may also cause unwarranted anxiety. Conclusions: The widespread use of ultrasound in obstetric care has entailed new challenges for clinicians due to enhanced possibilities to diagnose and treat fetal conditions, which in turn might conflict with the health interests of the pregnant woman. There is a need for further ethical discussions regarding the obstetrician’s position in management of situations where maternal and fetal health interests conflict. The continuing advances in the potential of ultrasound to impact on pregnancy management will also increase the need for adequate and appropriate information and counselling. Together with other health care professionals, obstetricians therefore need to develop improved ways of enabling pregnant women and their partners to make informed decisions regarding pregnancy management

Multigenic Control of Disease Severity after Virulent Mycobacterium tuberculosis Infection in Mice

Following challenge with virulent Mycobacterium tuberculosis, mice of the I/St inbred strain exhibit shorter survival time, more rapid body weight loss, higher mycobacterial loads in organs, and more severe lung histopathology than mice of the A/Sn strain. We previously performed a genome-wide scan for quantitative trait loci (QTLs) that control the severity of M. tuberculosis-triggered disease in [(A/Sn × I/St) F1 × I/St] backcross-1 (BC1) mice and described several QTLs that are significantly or suggestively linked to body weight loss. In the present study we expanded our analysis by including the survival time phenotype and by genotyping 406 (A/Sn × I/St) F2 mice for the previously identified chromosomal regions of interest. The previously identified 12-cM-wide QTL on distal mouse chromosome 3 was designated tbs1 (tuberculosis severity 1); the location of the QTL on proximal chromosome 9 was narrowed to a 9-cM interval, and this QTL was designated tbs2. Allelic variants of the tbs2 locus appeared to be involved in control of both body weight loss and survival time. Also, the data strongly suggested that a QTL located in the vicinity of the H-2 complex on chromosome 17 is involved in control of tuberculosis in mice of both genders, whereas the tbs1 locus seemed to have an effect on postinfection body weight loss in female mice. Interestingly, these loci appeared to interact with each other, which suggests that there might be a basic genetic network for the control of intracellular parasites. Overall, linkage data reported here for F2 mice are in agreement with, and add to, our previous findings concerning the control of M. tuberculosis-triggered disease in the BC1 segregation