Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin B6-Dependent Epilepsy

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms which are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP; by compounds accumulating as a result of inborn errors of other pathways or by ingested small molecules. Whole exome sequencing of 2 children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial) (PROSC), a PLPbinding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified 4 additional children with biallelic PROSC mutations. Pretreatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant, lacking the PROSC homologue (ΔYggS) is pyridoxine-sensitive; complementation with human PROSC restored growth whilst hPROSC bearing p.Leu175Pro, p.Arg241Gln and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells - how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Whilst the mechanism involved is not fully understood our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions

A multi-centre quality improvement project to reduce the incidence of obstetric anal sphincter injury (OASI): study protocol.

BACKGROUND: Third and fourth degree perineal tears, or obstetric anal sphincter injuries (OASI), sustained during childbirth can result in anal incontinence and psychosocial problems which require ongoing treatment. Within the English National Health System (NHS) reported rates of OASI have gradually increased. In response, a care bundle was developed incorporating four elements: 1) antenatal information to women, 2) manual perineal protection during all vaginal births, 3) episiotomy to be performed with a 60° mediolateral angle at crowning (when clinically indicated) and 4) perineal examination (including per rectum) after childbirth. Implementation of the OASI Care Bundle is aided by a skills development module and an awareness campaign. The project is a collaboration between two national professional bodies, an NHS hospital trust and an academic institution. METHODS: Implementation of the OASI Care Bundle will be evaluated using a stepped-wedge design. From January 2017 sixteen maternity units across England, Wales and Scotland will participate in the study over a 15-month period, with sequential roll-out of the intervention in four blocks (regions) of four units. The primary clinical outcome is OASI rate. Regression analysis will adjust for differences in organisational characteristics and obstetric risk factors in women who gave birth before and after implementation of the care bundle. Focus group discussions and in-depth interviews with clinicians will evaluate the feasibility of integrating the care bundle into routine practice. Interviews with women will explore the acceptability of the intervention. DISCUSSION: This protocol outlines the evaluation of our quality improvement project which aims to prevent OASI using a bundle of evidence-based interventions that are each widely used in practice. The OASI project aims to 1) standardise practice to prevent OASI in a way that is acceptable to clinicians and women and 2) identify the barriers and enablers associated with upscaling interventions within maternity units. If found to be effective, feasible and acceptable, the OASI Care Bundle will be shared with a range of audiences using the communication channels available to the professional bodies. TRIAL REGISTRATION: The OASI Project was retrospectively registered on the ISCTRN12143325 database date assigned 03/10/2017

"A renewed sense of purpose": mothers' and fathers' experience of having a child following a recent stillbirth.

Most research has focused on mothers' experiences of perinatal loss itself or on the subsequent pregnancy, whereas little attention has been paid to both parents' experiences of having a child following late perinatal loss and the experience of parenting this child. The current study therefore explored mothers' and fathers' experiences of becoming a parent to a child born after a recent stillbirth, covering the period of the second pregnancy and up to two years after the birth of the next baby. In depth interviews were conducted with 7 couples (14 participants). Couples were eligible if they previously had a stillbirth (after 24 weeks of gestation) and subsequently had another child (their first live baby) who was now under the age of 2 years. Couples who had more than one child after experiencing a stillbirth and those who were not fluent in English were excluded. Qualitative analysis of the interview data was conducted using Interpretive Phenomenological Analysis. Five superordinate themes emerged from the data: Living with uncertainty; Coping with uncertainty; Relationship with the next child; The continuing grief process; Identity as a parent. Overall, fathers' experiences were similar to those of mothers', including high levels of anxiety and guilt during the subsequent pregnancy and after the child was born. Coping strategies to address these were identified. Differences between mothers and fathers regarding the grief process during the subsequent pregnancy and after their second child was born were identified. Despite difficulties with bonding during pregnancy and at the time when the baby was born, parents' perceptions of their relationship with their subsequent child were positive. Findings highlight the importance of tailoring support systems not only according to mothers' but also to fathers' needs. Parents', and particularly fathers', reported lack of opportunities for grieving as well as the high level of anxiety of both parents about their baby's wellbeing during pregnancy and after birth implies a need for structured support. Difficulties experienced in bonding with the subsequent child during pregnancy and once the child is born need to be normalised

Att utvidga "mattebokens" ramar ­ Om lustfyllt och effektivt lärande i matematik.

___________________________________________________________________________ Sammanfattning I dagsläget går många elever ut grundskolan utan betyg i matematik. För att lösa detta dilemma fokuserar vårt arbete på hur man kan göra matematikämnet lustfyllt och effektivt för eleverna. Som grund har vi gjort olika undersökningar i en årskursoch i en årskurs 5 från två olika skolor. Eleverna besvarade en enkät och därefter intervjuade vi två flickor och två pojkar ur varje klass, alltså totalt åtta elever. Dessutom har vi observerat klassrumsmiljön och intervjuat klasslärarna i både årskursoch 5. Syftet med uppsatsen är att undersöka vad lustfylld och effektiv skolmatematik innebär. Främst fokuserar vi på elevernas perspektiv, men redovisar även lärarnas synpunkter. Den kanske viktigaste grundläggande frågan är hur eleverna förhåller sig till matematikämnet. Många verkar tro att matematik är det samma som att räkna i boken, sida upp och sida ner. Men bland annat styrdokumenten poängterar att matematik i vardagen är väldigt viktigt. Därför utforskar vi hur eleverna bland annat genom praktiska experiment kan få upp ögonen för att matematik faktiskt finns runt omkring dem. Resultaten av undersökningarna visar att eleverna var nöjda med matematiklektionerna. Det fanns inget speciellt de ville ändra på. Däremot förklarade vissa elever i årskurs 5 att de aldrig får experimentera med matte. De flesta elever tyckte om matematikämnet, trots att de oftast jobbade enskilt i läroboken. Majoriteten av eleverna önskade ändå att de skulle få arbeta mer i par och därigenom ta del av varandras tankar. Matematiken är ett av de absolut viktigaste skolämnena. Som lärare är det alltså vårt stora ansvar att planera, utföra och utvärdera matematikundervisningen så att alla elever gå ut grundskolan med åtminstone betyget godkänt i matematik. För att detta ska vara möjligt måste vi som är lärare för de yngre åldrarna erbjuda eleverna en bra och positiv start i det livslånga lärandet.

Natural value assessments – can they predict the species richness of red listed and bioindicator fungi in Fennoscandian coniferous forests?

The thesis aims to examine how well two standardised methods in nature conservation, namely natural value assessment and key biotope inventory, perform in terms of recognising an area with a high amount of red listed and bioindicator fungi. The two methods are compared to see if any method is superior to find areas with high presence of red listed and bioindicator fungi and if a larger area automatically means a larger number of species. A natural value assessment inventory is conducted on study sites with a performed key biotope inventory, with an addition of an inventory on fungi. Statistical tests are completed to give information about occurring correlations. The results display that the key biotope inventory and the natural value assessment do not differ in their evaluations of an area. Analysis also shows that there is no relationship between the forest sites area and the assessment performed by the natural value assessment. However, if the assessment is performed by the key biotope inventory there exist a relationship with the forest sites area. Further on, there is no correlation between the area and its number of species. The tests also indicate that neither of the methods predict presence or the number of red listed and bioindicator species in a forest. Based on the results, the presence of bioindicator and red listed species alone are not good indicators of forest nature value. In order to give more credible answers to these questions, more studies with increased number of replicates should be conducted. Avhandlingen syftar till att undersöka hur bra två standardmetoder inom naturvården (Skogsbiologernas naturvärdesbedömning och Nyckelbiotopsinventering) är på att upptäcka ett områdes förekomst av rödlistade svampar och signalarter. Metoderna jämförs för att upptäcka om någon metod är överlägsen den andra angående att finna områden med stor förekomst av rödlistade svampar och signalarter samt om ett större område automatiskt innebär fler arter. Detta undersöks genom att Skogsbiologernas naturvärdesbedömning utförs på områden som redan inventerats utifrån en Nyckelbiotopsinventering med tillägg av en svampinventering. Statistiska analyser genomförs därefter för att ge svar om förekommande samband. Analyser visar att Nyckelbiotopsinventeringen och Skogsbiologernas naturvärdesbedömning inte skiljer sig angående bedömningen av skogsområden. Utförda statistiska testerna tyder även på att det inte förekommer något samband mellan bedömda områdens areal och dess bedömning enligt Skogsbiologernas bedömning, däremot finns det ett samband mellan områdenas areal och Nyckelbiotopsinventeringens bedömning. Det förekommer dock inget art-area samband. Utförda tester indikerar även att ingen av metoderna kan förutsäga mängden rödlistade svampar samt signalarter i ett skogsområde. Baserat på detta resultat ger förekomsten av signalarter samt rödlistade svamparter ingen bra indikation på en skogs naturvärde. För att ge mer trovärdiga svar på dessa frågor krävs mer studier med en ökad mängd replikat

Ungdomar i kontakt med socialtjänsten : deras upplevelse och uppfattning av orsaker och bemötande

This master thesis has as purpose to answer the question how youths feel about and describe their contact with the social services. Can we, as socialworkers, claim that they have been listened to and do the youths, themselves, feel that they have been participating? The criteria for being a part of this studie has been youths between 15-18 years old, who have been part of investigation according to 50 § SoL during 2000-2001 in the community Tibro. The first part of this studie was to find out how socialworkers write and document their contacts with youths. The next step was to interview socialworkers about their view of making youths a part in their daily work and their view of social work. The last part was interviewing six youths about their feelings according to the contact with the social services. The analysis shows a big variation in the socialworkers methods and thoughts about making youths participating and about their daily work. This reflexes in the youths descriptions and feelings according to the contact with the social services. They who have got continuosly information about the social services work and plans also feel that they have been participating and listened to